71 results on '"Antti Haapalinna"'
Search Results
2. Pharmacodynamics of intrathecal and epidural fadolmidine, an α2-adrenoceptor agonist, after bolus and infusion in dogs—comparison with clonidine
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Tony L. Yaksh, Tiina Leino, Kjersti A. Horais, and Antti Haapalinna
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Pharmacology ,Bradycardia ,Agonist ,business.industry ,medicine.drug_class ,Sedation ,Analgesic ,General Medicine ,Clonidine ,Bolus (medicine) ,Blood pressure ,Pharmacodynamics ,Anesthesia ,medicine ,medicine.symptom ,business ,medicine.drug - Abstract
An α2-adrenoceptor agonist, clonidine, is extensively used in both anesthesia and intensive care medicine. However, clonidine may produce pronounced hemodynamic side effects such as hypotension and bradycardia which may limit its usefulness in certain conditions. Fadolmidine is a potent α2-adrenoceptor agonist with different physicochemical properties than clonidine. Here, the effects of fadolmidine and clonidine on analgesia (an increase in thermal skin twitch response latency), sedation, blood pressure, heart rate, respiratory rate, and body temperature were evaluated either up to 8 h after either intrathecal or epidural bolus injections or during a 24-h continuous intrathecal infusion at equipotent analgesic doses in non-anesthetized Beagle dogs. Fadolmidine and clonidine produced a dose-dependent and equipotent maximal antinociception after intrathecal bolus injection (ED50: 67 μg and 78 μg, respectively), but the duration of action of fadolmidine was more long-lasting. During the intrathecal infusion, fadolmidine achieved a good analgesic effect without evoking cardiovascular side effects, e.g., hypotension; these were evident during clonidine infusion. Epidurally, the antinociceptive potency of fadolmidine was weaker (ED50: 128 μg) than when intrathecally administered and weaker than that of epidural clonidine (ED50: 51 μg). At analgesic doses, fadolmidine injection induced moderate initial hypertension concomitantly with a decrease in heart rate whereas clonidine evoked hypotension and bradycardia. These results suggest that especially when non-opioid long-term pain relief is needed, an intrathecal infusion of fadolmidine can provide long-term antinociception with less of the known use-limiting adverse effects associated with clonidine.
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- 2020
3. Tasipimidine—the pharmacological profile of a novel orally active selective α2A-adrenoceptor agonist
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Jyrki Lehtimäki, Niina Jalava, Kaisa Unkila, John Aspegren, Antti Haapalinna, and Ullamari Pesonen
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Pharmacology - Published
- 2022
4. Fadolmidine - Favourable adverse effects profile for spinal analgesia suggested by in vitro and in vivo models
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Ari Koivisto, Ullamari Pesonen, Jyrki Lehtimäki, Tiina Leino, and Antti Haapalinna
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0301 basic medicine ,Agonist ,Male ,Mean arterial pressure ,medicine.drug_class ,Sedation ,Analgesic ,Guinea Pigs ,Pharmacology ,Kidney ,Open field ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Heart Rate ,Ileum ,Heart rate ,medicine ,Adrenergic alpha-2 Receptor Agonists ,Animals ,Humans ,Arterial Pressure ,Adverse effect ,Injections, Spinal ,Analgesics ,business.industry ,Imidazoles ,030104 developmental biology ,HEK293 Cells ,Indans ,medicine.symptom ,Analgesia ,Receptors, Serotonin, 5-HT3 ,business ,030217 neurology & neurosurgery - Abstract
Fadolmidine is an α2-adrenoceptor full agonist developed for spinal analgesia with a local mode of action. The purpose of this study was to demonstrate the safety of fadolmidine on known α2-adrenoceptor-related effects: kidney function, urodynamics and cardiovascular variables. Furthermore, the binding affinity of fadolmidine for the 5-HT3 receptor prompted functional studies on 5-HT3. According to the binding affinity data, fadolmidine demonstrated partial agonism on the 5-HT3 receptor in transfected cells and in guinea pig ileum preparation. However, intravenous (IV) fadolmidine did not produce any 5-HT3-related hemodynamic effects in anaesthetised rats. In urodynamic studies, intrathecal (IT) fadolmidine interrupted volume-evoked voiding cycles and induced overflow incontinence at high concentrations in anaesthetised rats; however, at the analgesic dose range, the effects were mild. The effects of fadolmidine on kidney function were studied in conscious rats after IV and IT dosing. While IT fadolmidine increased dose-dependent urine output, sodium ion concentration, IV doses increased only sodium ion concentration The effects of IT fadolmidine on heart rate (HR), mean arterial pressure (MAP) and sedation were evaluated in the home cage and in the open field using a telemetry system. In resting conditions, fadolmidine decreased HR dose-dependently and increased initial MAP, whereas in actively moving rats, there were no effects at analgesic doses. The results suggest that at anticipated analgesic clinical doses, IT fadolmidine provides analgesia without significant adverse effects on sedation, MAP or HR and with only modest effects on kidney function and urodynamics.
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- 2020
5. Pharmacodynamics of intrathecal and epidural fadolmidine, an α
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Tiina, Leino, Tony, Yaksh, Kjersti, Horais, and Antti, Haapalinna
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Male ,Pain Threshold ,Analgesics ,Imidazoles ,Injections, Epidural ,Blood Pressure ,Clonidine ,Dogs ,Respiratory Rate ,Heart Rate ,Indans ,Adrenergic alpha-2 Receptor Agonists ,Animals ,Infusions, Spinal ,Injections, Spinal ,Body Temperature Regulation - Abstract
An α
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- 2019
6. Pharmacological Characterisation of a Structurally Novel α2C-Adrenoceptor Antagonist ORM-10921 and its Effects in Neuropsychiatric Models
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Jelena Mijatovic, Petteri Piepponen, Katja Kuokkanen, Heikki Tanila, Johanna Holappa, Jukka Sallinen, Raimo Virtanen, Jouni Sirviö, Hugh Chapman, Antti Haapalinna, Ari Koivisto, and Jyrki Lehtimäki
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Central Nervous System ,Male ,Microdialysis ,Quinolizidines ,Dopamine ,Phencyclidine ,Hypothermia ,Pharmacology ,Biology ,Toxicology ,Piperazines ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Central Nervous System Diseases ,Receptors, Adrenergic, alpha-2 ,In vivo ,medicine ,Animals ,Rats, Wistar ,Receptor ,Benzofurans ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,Antagonist ,General Medicine ,Adrenergic alpha-2 Receptor Antagonists ,Antidepressive Agents ,Rats ,Neuroprotective Agents ,Acridines ,Antidepressant ,Dizocilpine Maleate ,030217 neurology & neurosurgery ,Behavioural despair test ,medicine.drug - Abstract
The α2-adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α2-AR subtypes (α2A , α2B and α2C ) have been available, the pharmacological profile of a new α2C-selective AR antagonist ORM-10921 is reported. Standard in vitro receptor assays and antagonism of α2, and α1-AR agonist-evoked responses in vivo were used to demonstrate the α2C-AR selectivity for ORM-10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK-801. The Kb values of in vitro α2C-AR antagonism for ORM-10921 varied between 0.078-1.2 nM depending on the applied method. The selectivity ratios compared to α2A-AR subtype and other relevant receptors were 10-100 times in vitro. The in vivo experiments supported its potent α2C-antagonism combined with only a weak α2A-antagonism. In the pharmacodynamic microdialysis study, ORM-10921 was found to increase extracellular dopamine levels in prefrontal cortex in the baseline conditions. In the behavioural tests, ORM-10921 displayed potent antidepressant and antipsychotic-like effects in the forced swimming test and prepulse-inhibition models analogously with the previously reported results with structurally different α2C-selective AR antagonist JP-1302. Our new results also indicate that ORM-10921 alleviated the NMDA-antagonist-induced impairments in social behaviour and watermaze navigation. This study extends and further validates the concept that α2C -AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α2C-antagonism to treat such disorders.
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- 2013
7. Pharmacological profile of intrathecal fadolmidine, a α2-adrenoceptor agonist, in rodent models
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Timo Viitamaa, Tiina Leino, Jyrki Lehtimäki, Antti Haapalinna, and Raimo Virtanen
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Male ,Serotonin ,Analgesic ,Pharmacology ,Clonidine ,Body Temperature ,Rats, Sprague-Dawley ,Norepinephrine ,Bolus (medicine) ,Adrenergic alpha-2 Receptor Agonists ,medicine ,Mydriasis ,Animals ,Dexmedetomidine ,Injections, Spinal ,Behavior, Animal ,Dose-Response Relationship, Drug ,business.industry ,Imidazoles ,Brain ,General Medicine ,Hypothermia ,Rats ,Monoamine neurotransmitter ,Anesthesia ,Indans ,medicine.symptom ,Gastrointestinal Motility ,business ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The present experiments compared the peripheral and central pharmacological effects of three alpha(2)-adrenoceptor agonists: fadolmidine, clonidine, and dexmedetomidine after single intrathecal bolus injections at analgesic dose level in rats. Effects on mydriasis and cardiovascular functions were studied in anaesthetised rats, the effects on sedation/motor performance, body temperature, and gastrointestinal motility were evaluated in conscious rats, and also the effects on brain biogenic amines were studied. All compounds caused dose-dependent mydriasis, a decrease in blood pressure and heart rate, sedation, hypothermia, and inhibition of gastrointestinal transit, but in contrast to the analgesic effects, dexmedetomidine and clonidine were much more potent than fadolmidine. In accordance with the other systemic effects, dexmedetomidine and clonidine, but not fadolmidine, reduced the turnover of the monoamine neurotransmitters, noradrenaline and serotonin, in brain at the analgesic dose. The difference in the systemic effect profile between fadolmidine and clonidine or dexmedetomidine is most probably explained by differences in their ability to spread from the site of administration at the lumbar level into the periphery and/or the brain and further the concentrations of the compounds in the side of action. These results supports that intrathecally administered fadolmidine could have potential to be used as an analgesic agent with less subraspinal or spinal adverse effects at analgesic doses than dexmedetomidine and clonidine.
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- 2009
8. In vitro and in vivo profiling of fadolmidine, a novel potent α2-adrenoceptor agonist with local mode of action
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Ari Koivisto, Raimo Virtanen, Tiina Leino, Tarja Lehtimäki, Katja Kuokkanen, Antti Haapalinna, Jyrki Lehtimäki, and Timo Viitamaa
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Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Endogeny ,CHO Cells ,Pharmacology ,Transfection ,Cell Line ,Rats, Sprague-Dawley ,Mice ,Cricetulus ,Vas Deferens ,In vivo ,Cell Line, Tumor ,Cricetinae ,Receptors, Adrenergic, alpha-1 ,Internal medicine ,Adrenergic alpha-2 Receptor Agonists ,medicine ,Animals ,Humans ,Dexmedetomidine ,Receptor ,Dose-Response Relationship, Drug ,Chemistry ,Imidazoles ,Vas deferens ,Electric Stimulation ,Rats ,medicine.anatomical_structure ,Endocrinology ,Mechanism of action ,Blood-Brain Barrier ,Indans ,Systemic administration ,Adrenergic alpha-1 Receptor Agonists ,medicine.symptom ,Adrenergic alpha-Agonists ,Muscle Contraction ,medicine.drug - Abstract
Alpha2-adrenergic receptors (alpha2-adrenoceptors) mediate various physiological actions of endogenous catecholamines in the central and peripheral nervous systems being involved in alertness, heart rate regulation, vasomotor control and nociceptive processing. In the present study, the pharmacological profile of a novel alpha2-adrenoceptor agonist, fadolmidine, was studied in various in vitro and in vivo assays and compared to the well characterised alpha2-adrenoceptor agonist, dexmedetomidine. Fadolmidine displayed high affinity and full agonist efficacy at all three human alpha2-adrenoceptor subtypes (A, B and C) in transfected CHO cells with EC50 values (nM) of 0.4, 4.9 and 0.5, respectively. Fadolmidine inhibited also electrically evoked contractions in rat vas deferens demonstrating the activation of rodent presynaptic alpha2D-adrenoceptors with an EC50 value of 6.4 nM. Moreover, fadolmidine was a full agonist at human alpha1A-adrenoreceptor (EC50 value 22 nM) and alpha1B-adrenoreceptor (EC50 value 3.4 nM) in human LNCaP cells and transfected HEK cells, respectively. Agonism at the alpha1-adrenoceptor was also observed in rat vas deferens preparations although at lower potency (EC50 value 5.6 microM). Fadolmidine demonstrated potent alpha2-adrenoceptor agonist activity also in vivo by inhibiting electrically induced tachycardia in pithed rats and increasing mean arterial pressure in anaesthetised rats. However, after systemic administration, fadolmidine had considerably weaker CNS-mediated effects (mydriasis and sedation) compared to dexmedetomidine possibly due to limited penetration through the blood brain barrier by fadolmidine. In a conclusion, fadolmidine is a potent full agonist at all three alpha2-adrenoceptor subtypes with a pharmacological profile compatible with a therapeutic value e.g. after spinal administration.
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- 2008
9. MAO-B Inhibition by a Single Dose of l-Deprenyl or Lazabemide Does Not Prevent Neuronal Damage Following Focal Cerebral Ischaemia in Rats
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Antti Haapalinna, Leena Nyman, Juhani Sivenius, Risto A. Kauppinen, and Jukka Jolkkonen
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Pharmacology ,business.industry ,Health, Toxicology and Mutagenesis ,Toxicology ,Neuroprotection ,chemistry.chemical_compound ,L-Deprenyl ,chemistry ,Neuronal damage ,Medicine ,Cerebral ischaemia ,Lazabemide ,Monoamine oxidase B ,business - Published
- 2008
10. Pharmacological characterization and CNS effects of a novel highly selective α 2C -adrenoceptor antagonist JP-1302
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Höglund I, Juha-Matti Savola, Siegfried Wurster, Jyrki Lehtimäki, M. Engstrom, Jukka Sallinen, Jouni Sirviö, Antti Haapalinna, and Raimo Virtanen
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Pharmacology ,medicine.medical_specialty ,Chemistry ,Antagonist ,Atipamezole ,Startle reaction ,Endocrinology ,Internal medicine ,Moro reflex ,medicine ,Antidepressant ,Antagonism ,Prepulse inhibition ,Behavioural despair test ,medicine.drug - Abstract
Background and purpose: Pharmacological validation of novel functions for the α2A-, α2B-, and α2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective α2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine). Experimental approach: Standard in vitro binding and antagonism assays were employed to demonstrate the α2C-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered α2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. Key results: JP-1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human α2A-, α2B-, and α2C-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the α2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize α2-agonist–induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, α2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the α2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit. Conclusions and implications: The results provide further support for the hypothesis that specific antagonism of the α2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders. British Journal of Pharmacology (2007) 150, 391–402. doi:10.1038/sj.bjp.0707005
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- 2007
11. The adrenergic α2 receptor and sexual incentive motivation in male rats
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Timo Viitamaa, Anders Ågmo, and Antti Haapalinna
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Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Clinical Biochemistry ,Adrenergic ,Stimulation ,Pharmacology ,Toxicology ,Biochemistry ,Arousal ,Sexual Behavior, Animal ,Behavioral Neuroscience ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Copulation ,medicine ,Animals ,Rats, Wistar ,Dexmedetomidine ,Adrenergic alpha-Antagonists ,Biological Psychiatry ,Motivation ,Imidazoles ,Antagonist ,Yohimbine ,Atipamezole ,Rats ,Endocrinology ,Female ,Psychology ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The purpose of the present series of experiments was to determine whether drugs acting at the alpha2-adrenoceptor modify unconditioned sexual incentive motivation in the male rat. To that end a highly specific agonist, dexmedetomidine, a corresponding antagonist, atipamezole, and a less specific antagonist, yohimbine, were administered to groups of sexually inexperienced male rats. The subjects were tested in a large rectangular arena, where a sexually receptive female and an intact male were employed as incentives. The incentive animals were confined behind a wire mesh in opposite corners of the arena. The animals could see, hear and smell each other, but no sexual interaction was possible. Approach to the incentives constituted the measure of incentive motivation. In addition, the test provided data on ambulatory activity and general arousal. Dexmedetomidine, at a dose of 8 microg/kg, produced a slight reduction of sexual incentive motivation. Ambulatory activity and general arousal were also inhibited. Atipamezole, in doses of 0.1 and 0.3mg/kg enhanced the positive incentive properties of the receptive female. A high dose of 1mg/kg did not have any significant effect. Ambulatory activity was slightly reduced by the two larger doses of atipamezole. Yohimbine had a slight stimulatory effect on sexual incentive motivation at a dose (4 mg/kg) that also reduced ambulatory activity and general arousal. It is concluded that blockade of the adrenergic alpha2 receptor stimulates sexual incentive motivation in the male rat whereas stimulation of it has the opposite effect. At present it is not clear if these drug effects are caused by pre- or postsynaptic actions of the drugs, and the importance of secondary changes in other neurotransmitter systems remains unknown.
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- 2006
12. Uptake of 6-[18F]fluoro-L-dopa and [18F]CFT reflect nigral neuronal loss in a rat model of Parkinson's disease
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Sarita Forsback, Riitta Niemi, Jörgen Bergman, Antti Haapalinna, Merja Haaparanta, Juha O. Rinne, Olli Eskola, Olof Solin, Tove J. Grönroos, and Päivi Marjamäki
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medicine.medical_specialty ,Levodopa ,Parkinson's disease ,biology ,Dopaminergic ,Substantia nigra ,Striatum ,medicine.disease ,Apomorphine ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,nervous system ,chemistry ,Internal medicine ,medicine ,biology.protein ,Neuroscience ,Oxidopamine ,medicine.drug ,Dopamine transporter - Abstract
In order to characterize the sensitivity of an analog of levodopa and a dopamine transporter ligand to detect defects in nigrostriatal function, the uptake of [(18)F]FDOPA and [(18)F]CFT was studied ex vivo in a rat model of Parkinson's disease. The brains of these rats were unilaterally lesioned with an intranigral injection of 6-hydroxydopamine. The lesioned animals were divided into three groups subject to their behavior after pharmacological challenges. Circling behavior was recorded after amphetamine, apomorphine, and L-DOPA challenge in order to predict lesion size. The spatial distribution of radioactivity after [(18)F]FDOPA or [(18)F]CFT injection in brain sections was determined with digital autoradiography. Regions of interest were left/right striatum, left/right substantia nigra, and cerebellum. The degree of unilateral lesion for each animal was confirmed by counting of nigral tyrosine hydroxylase-positive cell bodies. With both tracers the uptake in the lesioned side was lower than in the intact side in the striatum and in the substantia nigra. In conclusion, both tracers clearly demonstrated nigrostriatal dopaminergic hypofunction and correlated with the number of nigral dopaminergic neurons. However, [(18)F]FDOPA showed a much higher unspecific uptake of radioactivity, due to extensive metabolism; therefore, this tracer was less sensitive than the transporter tracer [(18)F]CFT to detect these defects.
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- 2003
13. Selegiline reduces N-methyl-D-aspartic acid induced perturbation of neurotransmission but it leaves NMDA receptor dependent long-term potentiation intact in the hippocampus
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Antti Haapalinna, Minna Niittykoski, and Jouni Sirviö
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Male ,Monoamine Oxidase Inhibitors ,N-Methylaspartate ,Long-Term Potentiation ,Glutamic Acid ,N-Methyl-D-aspartic acid ,In Vitro Techniques ,Pharmacology ,Neurotransmission ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,chemistry.chemical_compound ,Selegiline ,medicine ,Animals ,Drug Interactions ,Rats, Wistar ,Biological Psychiatry ,Neurons ,Dose-Response Relationship, Drug ,Excitatory Postsynaptic Potentials ,Long-term potentiation ,Pargyline ,Rats ,Psychiatry and Mental health ,nervous system ,Neurology ,chemistry ,Synaptic plasticity ,Excitatory postsynaptic potential ,NMDA receptor ,Neurology (clinical) ,Neuroscience ,medicine.drug - Abstract
This study examined the effects of monoamine oxidase (MAO) inhibitors on N-methyl-D-aspartic acid (NMDA)-induced perturbation of neurotransmission and normal NMDA-receptor dependent function (long-term potentiation, LTP) in the CA1 field of hippocampus. During baseline recording, neurotransmission was unaffected by long-term bath perfusion with MAO inhibitors (selegiline, pargyline). After NMDA (100 microM) infusion, the presence of selegiline (1 microM) promoted the recovery rate and increased the size of recovered extracellular field excitatory postsynaptic potentials (fEPSPs). Selegiline (1 microM) also prevented the NMDA-induced increase in paired pulse facilitation (PPF). The induction and maintenance of LTP were normal with this same concentration of selegiline. The presence of lower concentration (10 nM) of selegiline or pargyline (1 microM) did not improve the recovery process. These results suggest that selegiline partially protects the function of CA3-CA1 hippocampal connections against overactivation of NMDA receptors. Further, the same concentration of selegiline does not interfere with the physiological function of NMDA receptors in the CA1 field of the hippocampus. The exact mechanism of action remains to be determined, but it is apparently downstream to the overactivation of NMDA receptors.
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- 2003
14. α-Adrenoceptor-Mediated Modulation of 5-HT2 Receptor Agonist Induced Impulsive Responding in a 5-Choice Serial Reaction Time Task
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Tiina Koskinen, Jouni Sirvi, and Antti Haapalinna
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Pharmacology ,Agonist ,medicine.medical_specialty ,Chemistry ,medicine.drug_class ,Health, Toxicology and Mutagenesis ,5-HT2 receptor ,Antagonist ,Atipamezole ,Toxicology ,Serotonergic ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,Neuromodulation ,medicine ,Prazosin ,Receptor ,medicine.drug - Abstract
The activation of 5-HT2A receptors has been shown to enhance the probability of premature responding, regarded as a form of motor impulsive behaviour. At the behavioural level, the interaction of alpha-adrenoceptors and 5-HT2 receptors has been linked to head twitch behaviour, regarded as an experimental model of compulsive behaviour. The aim was to determine whether the probability of premature responding induced by an excess activation of 5-HT2A receptors can be modulated by the blockade of alpha1- or alpha2- adrenoceptors. In the experiments, the 5-choice serial reaction time task was used to measure attention and response control of the rats. The experiments assessed the effects of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) 0.1-0.2 mg/kg subcutaneously, a 5-HT2A/2C agonist, and prazosin, an alpha1-adrenoceptor antagonist, alone or in combination, on the performance of rats. In an additional experiment to examine the possible role of the alpha2-adrenoceptors, a potent, selective and specific alpha2-adrenoceptor antagonist, atipamezole, was given alone or in combination with DOI. Results showed that DOI increased the probability of premature responses, but it did not affect the choice accuracy. Prazosin (0.1 or 0.3 mg/kg, subcutaneously), given on its own had no effects on probability of responding prematurely, but prazosin (0.3 mg/kg.) was able to attenuate the DOI-induced responding. Atipamezole (0.1 mg/kg, s.c.) did not attenuate the effect of DOI on probability of premature responding. When given at lower doses, DOI (0.03 mg/kg) and atipamezole (0.03 mg/kg) synergistically increased the probability of premature responding, whereas a higher dose of atipamezole (0.3 mg/kg) on its own increased the probability of responding prematurely, but this effect was not additive to that of 0.1 mg/kg DOI. These data indicate that 5-HT2 receptor activation enhances impulsive responding and this effect can be diminished by the blockade of alpha1-adrenoceptors. Atipamezole, an alpha2-antagonist, enhances the probability of premature responding and shares the mechanism of action with the 5-HT2 agonist in this respect. These results provide evidence for an interaction between the serotonergic 5-HT2 receptors and alpha-adrenoceptors in the modulation of response control to the motor impulsivity type of behaviour (premature responding) in addition to that of compulsory behaviour (head shakes) found previously.
- Published
- 2003
15. Atipamezole, an α2-adrenoceptor antagonist, augments the effects of l-DOPA on evoked dopamine release in rat striatum
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Aarne Ylinen, Jouni Sirviö, Antti Haapalinna, Pekka T. Männistö, and Leonid Yavich
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Male ,medicine.medical_specialty ,Time Factors ,Dopamine ,Caudate nucleus ,Nucleus accumbens ,Nucleus Accumbens ,Levodopa ,Dopamine receptor D1 ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Medial forebrain bundle ,Adrenergic alpha-Antagonists ,Pharmacology ,Chemistry ,Dopaminergic ,Imidazoles ,Antagonist ,Atipamezole ,Drug Synergism ,Adrenergic alpha-2 Receptor Antagonists ,Corpus Striatum ,Electric Stimulation ,Rats ,Endocrinology ,Caudate Nucleus ,medicine.drug - Abstract
The effects of atipamezole, an α2-adrenoceptor antagonist, l -3,4-dihydroxyphenylalanine ( l -DOPA) and the combination of these drugs on dopamine overflow were studied in dopaminergic presynaptic terminals of rat caudate and nucleus accumbens. Dopamine overflow evoked by 100 pulses of electrical stimulation of the medial forebrain bundle at a low (20 Hz) and high (50 Hz) frequency was measured by in vivo voltammetry. l -DOPA (15 mg/kg) increased dopamine overflow in the caudate nucleus, but this dose had no effects in the nucleus accumbens. Atipamezole (300 μg/kg) had no effects on its own on dopamine overflow, but it did increase the size of the readily releasable storage pool and the effects of l -DOPA treatment in both structures. The combination of the drugs increased dopamine overflow to a larger extent at high compared to low stimulation frequencies. We conclude that the rat caudate nucleus is more sensitive than the nucleus accumbens to the effects of l -DOPA, and the effects of l -DOPA treatment might be effectively enhanced by antagonism of α2-adrenoceptors.
- Published
- 2003
16. Inhibition of MAO-A Activity Enhances Behavioural Activity of Rats Assessed Using Water Maze and Open Arena Tasks
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Jouni Sirviö, Leena Nyman, Antti Haapalinna, and Alexandra Barbelivien
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Pharmacology ,biology ,business.industry ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,Selegiline ,Biological activity ,Water maze ,Toxicology ,Pargyline ,Clorgyline ,biology.protein ,Medicine ,Clorgiline ,Monoamine oxidase A ,business ,Saline ,medicine.drug - Abstract
To determine if the inhibition of MAO-A and/or MAO-B activities can influence cognitive processes in adult rats, we analysed whether chronic treatment with clorgyline, l-deprenyl and pargyline could modify the performance of adult rats in a modified version of the water maze task. The effects of these treatments on locomotor activity and enzyme activities were also assessed. Rats were treated for 24 days with clorgyline (0.2 mg/kg), l-deprenyl (0.25 mg/kg) and pargyline (1 or 10 mg/kg). The treatments were started two weeks before the water maze experiment and continued until the end of testing. The rats were trained to find a submerged platform (6 days:1 trial/day; 7 th day: probe trial). Over the next three days, locomotor activity was assessed in an open arena. Treatments with clorgyline (MAO-A inhibitor), l-deprenyl (MAO-B inhibitor) and pargyline (non-selective MAO inhibitor) did not improve the finding of the hidden platform, when compared to treatment with saline, but significantly increased the swimming speed of the rats. The different treatments, when compared to saline, failed to modify the distance covered and the number of groomings performed in the open arena. However, clorgyline and pargyline, 10 mg/kg, increased the number of faecal boli and clorgyline enhanced the number of rearings made when compared to saline, l-deprenyl and pargyline, 10 mg/kg. These results indicate that near total inhibition of MAO-A by clorgyline and pargyline as assessed by MAO activity measurement induces an increase in locomotor activity but that inhibition of MAO-A or MAO-B, either alone or combined, does not facilitate spatial learning in adult rats.
- Published
- 2001
17. Inhibition of MAO-A Activity Enhances Behavioural Activity of Rats Assessed Using Water Maze and Open Arena Tasks
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Alexandra Barbelivien, Leena Nyman, Antti Haapalinna, and Jouni Sirvio
- Subjects
Male ,Pharmacology ,Clorgyline ,Monoamine Oxidase Inhibitors ,Behavior, Animal ,Health, Toxicology and Mutagenesis ,Motor Activity ,Weight Gain ,Toxicology ,Rats ,Pargyline ,Memory ,Selegiline ,Animals ,Rats, Wistar ,Maze Learning ,Swimming - Abstract
To determine if the inhibition of MAO-A and/or MAO-B activities can influence cognitive processes in adult rats, we analysed whether chronic treatment with clorgyline, 1-deprenyl and pargyline could modify the performance of adult rats in a modified version of the water maze task. The effects of these treatments on locomotor activity and enzyme activities were also assessed. Rats were treated for 24 days with clorgyline (0.2 mg/kg), 1-deprenyl (0.25 mg/kg) and pargyline (I or 10 mg/kg). The treatments were started two weeks before the water maze experiment and continued until the end of testing. The rats were trained to find a submerged platform (6 days: I trial/day; 7 th day: probe trial). Over the next three days, locomotor activity was assessed in an open arena. Treatments with clorgyline (MAO-A inhibitor), 1-deprenyl (MAO-B inhibitor) and pargyline (non-selective MAO inhibitor) did not improve the finding of the hidden platform, when compared to treatment with saline, but significantly increased the swimming speed of the rats. The different treatments, when compared to saline, failed to modify the distance covered and the number of groomings performed in the open arena. However, clorgyline and pargyline, 10 mg/kg, increased the number of faecal boli and clorgyline enhanced the number of rearings made when compared to saline, 1-deprenyl and pargyline, 10 mg/kg. These results indicate that near total inhibition of MAO-A by clorgyline and pargyline as assessed by MAO activity measurement induces an increase in locomotor activity but that inhibition of MAO-A or MAO-B, either alone or combined, does not facilitate spatial learning in adult rats.
- Published
- 2001
18. Evaluation of the α2C-adrenoceptor as a neuropsychiatric drug target
- Author
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Jukka Sallinen, Mika Scheinin, and Antti Haapalinna
- Subjects
Genetically modified mouse ,business.industry ,Transgene ,Poison control ,General Medicine ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,Genetically Engineered Mouse ,Moro reflex ,Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,business ,Prepulse inhibition ,Behavioural despair test - Abstract
The functional characterization of the three distinct alpha2-adrenoceptor (Q2-AR) subtypes was for long hampered by the inavailability of subtype-selective pharmacological probes. Recent studies with gene-targeted mice have revealed that the alpha2A-AR has a major role in the mediation of many prominent effects of subtype non-selective alpha2-AR agonists, i.e. sedation, analgesia, hypothermia, sympatho-inhibition, and reduction of blood pressure. We have now employed several neuropsychopharmacological test models to investigate the effects mediated by the alpha2C-AR subtype and this receptor's potential as a CNS drug target. The studies employed two genetically engineered mouse strains, having either a targeted inactivation of the alpha2C-AR gene (alpha2C-KO) or over-expressing the alpha2C-AR (alpha2C-OE). Lack of alpha2C-AR expression was associated with increased amphetamine-induced locomotor activity, startle reactivity, aggression, and activity in the forced swimming test; prepulse inhibition of the startle reflex was attenuated. Opposite changes were observed in the alpha2C-OE mice. The results suggest that the alpha2C-AR subtype has a distinct inhibitory role in the processing of sensory information and in the control of motor and emotion-related activities in the CNS. It is therefore possible that alpha2C-AR-selective drugs may have therapeutic value in the treatment of various neuropsychiatric disorders.
- Published
- 2001
19. Effects of dexmedetomidine after transient and permanent occlusion of the middle cerebral artery in the rat
- Author
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Antti Haapalinna, Johanna Kuhmonen, and Juhani Sivenius
- Subjects
Blood Glucose ,Male ,Agonist ,medicine.drug_class ,Ischemia ,Blood Pressure ,Striatum ,Neuroprotection ,Body Temperature ,Central nervous system disease ,medicine.artery ,Occlusion ,medicine ,Animals ,cardiovascular diseases ,Rats, Wistar ,Dexmedetomidine ,Biological Psychiatry ,business.industry ,Brain ,Infarction, Middle Cerebral Artery ,medicine.disease ,Rats ,Psychiatry and Mental health ,Neuroprotective Agents ,Neurology ,Reperfusion Injury ,Anesthesia ,Hypoxia-Ischemia, Brain ,Middle cerebral artery ,Neurology (clinical) ,business ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
Increased sympathetic tone is a consequence of cerebral ischemia. Although the role of catecholamines in ischemic damage is still unclear, in some experimental ischemia models alpha2-adrenergic agonism has proved to be neuroprotective. In the present work we have compared the effects of transient and permanent middle cerebral artery occlusion (MCAO) on the infarct volume, and, also, examined whether a selective alpha2-adrenergic receptor agonist, dexmedetomidine (9 microg/kg or 15 microg/kg i.v.), is able to reduce ischemic damage after transient or permanent MCAO in rats. Permanent MCAO led to a significantly larger infarct volume than transient occlusion (p0.05). The rats receiving the higher dose of dexmedetomidine were detectected to have smaller (statistically non-significant) infarct volume in the cortex (30.9%) and in the striatum (20.3%) after transient occlusion. Additionally, dexmedetomidine caused significant variations in the physiological parameters.
- Published
- 2001
20. Enhanced locomotor stimulation by NMDA receptor antagonists in alcohol-sensitive ANT rats
- Author
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Jari Heikkilä, Aapo Honkanen, Olga Y. Vekovischeva, Riitta Näkki, Maija Sarviharju, Antti Haapalinna, and Esa R. Korpi
- Subjects
Male ,medicine.medical_specialty ,Alcohol Drinking ,Clinical Biochemistry ,Stimulation ,Motor Activity ,Biology ,Toxicology ,Receptors, N-Methyl-D-Aspartate ,Biochemistry ,Behavioral Neuroscience ,Species Specificity ,Internal medicine ,medicine ,Animals ,Ketamine ,Phencyclidine ,Biological Psychiatry ,Pharmacology ,Glutamate receptor ,Antagonist ,Isoquinolines ,ANT ,Rats ,Endocrinology ,Competitive antagonist ,NMDA receptor ,Dizocilpine Maleate ,Excitatory Amino Acid Antagonists ,Proto-Oncogene Proteins c-fos ,medicine.drug - Abstract
The ability of the antagonists for the N-methyl-D-aspartate (NMDA) type of glutamate receptor to modulate locomotor activity were compared in alcohol-sensitive (or alcohol-nontolerant, ANT) and alcohol-insensitive (or alcohol-tolerant, AT) rat lines. Both rat lines showed altered locomotor activity after acute injections of a competitive antagonist (LY235959), a glycine-site antagonist (L-701,324), or noncompetitive antagonists [MK-801, phencyclidine (PCP), and ketamine] of the NMDA receptor. MK-801 at 0.5 mg/kg caused a strong increase in horizontal activity in both rat lines, the effect being significantly greater in the ANT rats. There was a subpopulation among AT rats that was almost completely unresponsive to MK-801. This insensitivity to MK-801 correlated with the lack of c-fos induction in the retrosplenial and cingulate cortices. Fos immunoreactive cells in these brain regions after MK-801 treatment were more numerous in ANT than AT rats, although c-fos induction in the inferior olivary nucleus was similar in all animals after MK-801. The ANT rats showed greater locomotor stimulation also after ketamine and LY235959, while stimulation induced by PCP and depression induced by L-701,324 did not differ between the rat lines. The data suggest that altered NMDA receptor-mediated processes may correlate with differences in innate alcohol sensitivity in the ANT/AT rat model.
- Published
- 2000
21. The neuroprotective effects of (−)deprenyl in the gerbil hippocampus following transient global ischemia
- Author
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Johanna Kuhmonen, Juhani Sivenius, Jukka Jolkkonen, and Antti Haapalinna
- Subjects
Monoamine Oxidase Inhibitors ,Ischemia ,Hippocampus ,Pharmacology ,Hippocampal formation ,Gerbil ,medicine.disease_cause ,Neuroprotection ,Brain Ischemia ,Selegiline ,medicine ,Animals ,Biological Psychiatry ,Cell Death ,business.industry ,Pyramidal Cells ,medicine.disease ,Psychiatry and Mental health ,nervous system ,Neurology ,Female ,Neurology (clinical) ,Monoamine oxidase B ,Gerbillinae ,business ,Neuroscience ,Oxidative stress ,medicine.drug - Abstract
(-)Deprenyl (selegeline) is a monoamine oxidase B (MAO-B) inhibitor, but it also exerts several effects independent of MAO-B inhibition. For example, it has been shown to improve neuronal survival in different neurodegenerative models. In the present study, we have tested whether (-)deprenyl attenuates the neuronal damage in the hippocampus that is induced in a model of transient global ischemia in gerbils. (-)Deprenyl was administered 1) at a low daily dose starting two weeks before occlusion, 2) at a single high dose administered 3h after occlusion, or 3) at a low daily dose for one or two weeks after occlusion. A nonsignificant trend of reduced neuronal damage in the hippocampal CA1 area was seen in all experimental groups treated with (-)deprenyl, regardless of the timing of treatment. The results together with previous evidence suggest that (-)deprenyl may protect CA1 neurons from ischemia-induced delayed death by several possible mechanisms, including the suppression of oxidative stress and apoptotic processes.
- Published
- 2000
22. Behavioral effects of the α2-adrenoceptor antagonist, atipamezole, after focal cerebral ischemia in rats
- Author
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Antti Haapalinna, Sanna Rantakömi, Jukka Jolkkonen, Juhani Sivenius, Kirsi Puurunen, and Anu Härkönen
- Subjects
Male ,medicine.medical_treatment ,Ischemia ,Central nervous system disease ,α2 adrenoceptor ,Receptors, Adrenergic, alpha-2 ,Desipramine ,medicine ,Animals ,Rats, Wistar ,Adrenergic alpha-Antagonists ,Pharmacology ,Chemotherapy ,Adrenergic Uptake Inhibitors ,Behavior, Animal ,business.industry ,Vascular disease ,Imidazoles ,Antagonist ,Atipamezole ,Infarction, Middle Cerebral Artery ,Adrenergic alpha-2 Receptor Antagonists ,medicine.disease ,Rats ,Ischemic Attack, Transient ,Anesthesia ,business ,Psychomotor Performance ,medicine.drug - Abstract
The present study characterized the behavioral effects of the selective alpha(2)-adrenoceptor antagonist, atipamezole, in a rat model of focal cerebral ischemia. Atipamezole (1 mg/kg, s.c.) or desipramine (5 mg/kg, i.p.), a noradrenaline reuptake blocker, was administered either as a single injection 2 days after ischemia induction or for 10 days thereafter (subacute administration). A subacute atipamezole treatment given 30 min before behavioral assessment improved performance in the limb-placing test (days 5, 7, 9, and 11) and in the foot-slip test (days 3 and 7), but not in the beam-walking test. There was no difference between experimental groups in behavioral performance following a single administration of atipamezole or following single or subacute administration of desipramine. The drug treatments did not attenuate the impairment of spatial cognitive performance of ischemic rats in the Morris water-maze test. These results suggest that repeated use-dependent release of noradrenaline by atipamezole facilitates the sensorimotor recovery following focal cerebral ischemia in rats.
- Published
- 2000
23. Diminution of N-methyl-d-aspartate-induced perturbation of neurotransmission by dexmedetomidine in the CA1 field of rat hippocampus in vitro
- Author
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Minna Niittykoski, Jouni Sirviö, and Antti Haapalinna
- Subjects
Male ,Agonist ,medicine.medical_specialty ,N-Methylaspartate ,medicine.drug_class ,Long-Term Potentiation ,In Vitro Techniques ,Hippocampal formation ,Neurotransmission ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Rats, Wistar ,Dexmedetomidine ,Chemistry ,General Neuroscience ,Glutamate receptor ,Excitatory Postsynaptic Potentials ,Long-term potentiation ,Rats ,Endocrinology ,nervous system ,Excitatory postsynaptic potential ,NMDA receptor ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The effects of α 2 -adrenoceptor activation on N -methyl- d -aspartic acid (NMDA)-induced perturbation of neurotransmission and normal NMDA-receptor dependent function (long-term potentiation, (LTP)) were investigated in the hippocampal CA1 field in vitro. Bath perfusion of dexmedetomidine hydrochloride (50 nM), which was initiated before NMDA (100 μM) exposure, enhanced the extent of recovery of extracellular field excitatory postsynaptic potentials after NMDA infusion. On the other hand, the induction and early maintenance of LTP was normal in the presence of dexmedetomidine. Thus, dexmedetomidine can diminish acute NMDA-induced perturbation of neurotransmission while the same dose of this drug does not influence the normal activation of NMDA receptors.
- Published
- 2000
24. The effects of a specific α2-adrenoceptor antagonist, atipamezole, on cognitive performance and brain neurochemistry in aged Fisher 344 rats
- Author
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Esa Heinonen, Antti Haapalinna, Jouni Sirviö, Raimo Virtanen, and Ewen MacDonald
- Subjects
Male ,Aging ,Central nervous system ,Choline O-Acetyltransferase ,Cognition ,Dopamine ,medicine ,Animals ,Biogenic Monoamines ,Neurochemistry ,Effects of sleep deprivation on cognitive performance ,Maze Learning ,Adrenergic alpha-Antagonists ,Pharmacology ,Imidazoles ,Antagonist ,Brain ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Choline acetyltransferase ,Rats, Inbred F344 ,Rats ,medicine.anatomical_structure ,Anesthesia ,Serotonin ,Psychology ,medicine.drug - Abstract
The present experiments investigated the effects of a specific and potent alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and neurochemistry in aged rats. Aged control Fisher 344 rats, which had lower activities of choline acetyltransferase in the frontal cortex, were impaired in the acquisition of the linear arm maze task both in terms of repetition errors and their behavioural activity (the speed of arm visits), and they needed longer time to complete this task as compared to adult control rats. Atipamezole treatment (0.3 mg/kg) facilitated the acquisition of this task in the aged rats as they committed fewer errors and completed the task more quickly than saline-treated aged control rats. A separate experiment indicated that atipamezole enhanced the turnover of noradrenaline both in the adult and aged rats, but this effect was more pronounced in the aged rats. Furthermore, atipamezole enhanced significantly the turnover of serotonin and dopamine only in the aged rats when analysed in the whole brain samples. As alpha(2)-adrenoceptor antagonists are known to alleviate akinesia in the experimental models of Parkinson's disease, the present results could be especially relevant for the development of palliative treatment for demented Parkinsonian patients.
- Published
- 2000
25. Genetic alteration of the α2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels
- Author
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Janne Lähdesmäki, M Pelto-Huikko, Mika Scheinin, Antti Haapalinna, E Rybnikova, Brian K. Kobilka, Jukka Sallinen, Timo Viitamaa, and Ewen MacDonald
- Subjects
Genetic Markers ,Restraint, Physical ,Serotonin ,medicine.medical_specialty ,Proto-Oncogene Proteins c-jun ,JUNB ,Dopamine ,Central nervous system ,Mice, Transgenic ,Learned helplessness ,Hippocampus ,Methoxyhydroxyphenylglycol ,Mice ,Norepinephrine ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Receptors, Adrenergic, alpha-2 ,Stress, Physiological ,Corticosterone ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Genes, Immediate-Early ,Molecular Biology ,In Situ Hybridization ,Swimming ,Cerebral Cortex ,Behavior, Animal ,Depression ,Antagonist ,Homovanillic Acid ,Hydroxyindoleacetic Acid ,Corpus Striatum ,Psychiatry and Mental health ,Endocrinology ,medicine.anatomical_structure ,chemistry ,3,4-Dihydroxyphenylacetic Acid ,Psychology ,Proto-Oncogene Proteins c-fos ,Behavioural despair test ,medicine.drug - Abstract
alpha2-Adrenoceptors (alpha2-AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three alpha2-AR subtypes (alpha2A, alpha2B, and alpha2C) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, alpha2-AR subtype-selective pharmacological probes are not available, mice with genetically altered alpha2C-AR expression were studied in order to investigate the possible involvement of the alpha2C-AR in physiological and behavioral responses to acute and repeated stress. A modified version of Porsolt's forced swimming test was used to assess the possible effects of altered alpha2C-AR expression on the development of behavioral despair. alpha2C-Overexpression increased and the lack of alpha2C-AR (alpha2C-KO) decreased the immobility of mice in the forced swimming test, ie alpha2C-AR expression appeared to promote the development of behavioral despair. In addition, alpha2C-KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of alpha2C-ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on alpha2C-AR expression, and the expression of c-fos and junB mRNA was increased in alpha2C-KO mice. Since alpha2C-KO produced stress-protective effects, and alpha2C-AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective alpha2C-AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.
- Published
- 1999
26. Cerebellar GABAA receptors and anxiolytic action of diazepam
- Author
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Maija Sarviharju, Antti Haapalinna, Esa R. Korpi, Aapo Honkanen, and Olga Y. Vekovischeva
- Subjects
Male ,Elevated plus maze ,Cerebellum ,medicine.drug_class ,Anxiety ,Pharmacology ,Anxiolytic ,Rats, Mutant Strains ,Reaction Time ,medicine ,Animals ,Point Mutation ,Maze Learning ,Receptor ,Molecular Biology ,Analysis of Variance ,Benzodiazepine ,Diazepam ,Ethanol ,Chemistry ,GABAA receptor ,General Neuroscience ,fungi ,food and beverages ,biochemical phenomena, metabolism, and nutrition ,Receptors, GABA-A ,ANT ,Rats ,medicine.anatomical_structure ,Neurology (clinical) ,Developmental Biology ,medicine.drug - Abstract
Alcohol-sensitive ANT rats have a point mutation in the cerebellum-enriched GABA(A) receptor alpha6 subunit, which makes this subunit and the ANT rats in vivo highly sensitive to benzodiazepine agonists. In the elevated plus maze test of anxiety, diazepam produced a greater anxiolytic response in the ANT rats than in the control, alcohol-insensitive AT rats. The ANT rats were less sensitive to the sedative effect of diazepam in the staircase test of exploration. The results thus suggest that the mutant cerebellar granule cell layer receptors can participate in GABA(A) receptor-activation-induced anxiolysis.
- Published
- 1999
27. Neuroprotection by the α2-adrenoceptor agonist, dexmedetomidine, in rat focal cerebral ischemia
- Author
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Juhani Sivenius, Kirsi Puurunen, Jukka Jolkkonen, Lauri Nieminen, Risto A. Kauppinen, Antti Haapalinna, and Jari Koistinaho
- Subjects
Male ,Agonist ,medicine.drug_class ,Ischemia ,Arterial Occlusive Diseases ,Pharmacology ,Neuroprotection ,chemistry.chemical_compound ,Quinoxalines ,medicine ,Animals ,Glutamate receptor antagonist ,Rats, Wistar ,Dexmedetomidine ,Cerebral Cortex ,business.industry ,Body Weight ,Imidazoles ,Glutamate receptor ,Cerebral Infarction ,Cerebral Arteries ,Medetomidine ,medicine.disease ,Corpus Striatum ,Rats ,Neuroprotective Agents ,chemistry ,Ischemic Attack, Transient ,Pipecolic Acids ,Anesthesia ,NBQX ,business ,Adrenergic alpha-Agonists ,Excitatory Amino Acid Antagonists ,medicine.drug - Abstract
The present study was undertaken to explore the possible neuroprotective effect of the selective alpha2-adrenoceptor agonist, dexmedetomidine in a rat model of focal cerebral ischemia. The effect of dexmedetomidine (9 microg kg(-1)) on infarct volume was assessed and compared to that of glutamate receptor antagonists cis-4(phosphonomethyl)-2-piperidine carboxylic acid (CGS-19755) (20 mg kg(-1)) or 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (50 mg kg(-1)). Dexmedetomidine decreased total ischemic volume by 40% in the cortex (P
- Published
- 1999
28. Effects of Dexmedetomidine on Rat Locus Coeruleus and Ethanol Withdrawal Symptoms During Intermittent Ethanol Exposure
- Author
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Pia Jaatinen, Kalervo Kiianmaa, Antti Haapalinna, Päivi Riihioja, and Antti Hervonen
- Subjects
Male ,medicine.medical_specialty ,Central nervous system ,Medicine (miscellaneous) ,Toxicology ,Neuroprotection ,Central nervous system disease ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Dexmedetomidine ,Ethanol ,Behavior, Animal ,business.industry ,Imidazoles ,Medetomidine ,medicine.disease ,Rats ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,Neuroprotective Agents ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Anesthesia ,Toxicity ,Locus coeruleus ,Locus Coeruleus ,business ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
In the present study, the neuroprotective effects of dexmedetomidine on rat locus coeruleus were studied during a 5-week intermittent ethanol exposure. Male Wistar rats (3 to 4 months old) were given ethanol or isocaloric sucrose by intragastric intubations three times a day for 4 days, which was followed by a 3-day withdrawal period. This 7-day cycle of ethanol exposure and withdrawal was repeated five times. Dexmedetomidine (at a dose decreasing from 30 microg/kg to 10 microg/kg, s.c.) was given to the treatment group during the withdrawal phase. The results showed that, during the 5-week experiment, dexmedetomidine significantly relieved the ethanol withdrawal syndrome, measured as the sum of the three most specific symptoms (rigidity, tremor, and irritability). The total neuron number of locus coeruleus (LC) decreased in the ethanol-treated group by 24%, compared with the nontreated control group and by 11%, compared with the sucrose-treated control group. Interestingly, the LC neuron numbers were found to decrease in the sucrose-intubated rats as well, compared with the nontreated control group. Dexmedetomidine was found to relieve ethanol-induced neuronal loss in the LC. Dexmedetomidine might be a new interesting alternative in the treatment of ethanol withdrawal syndrome, particularly due to its possible neuroprotective effects in the central nervous system.
- Published
- 1999
29. Systemic Administration of Atipamezole, a Selective Antagonist of Alpha-2 Adrenoceptors, Facilitates Behavioural Activity but does not Influence Short-term or Long-term Memory in Trimethyltin-intoxicated and Control Rats
- Author
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Paavo Riekkinen, Raimo Lappalainen, Minna Niittykoski, Jukka Jolkkonen, Jouni Sirviö, and Antti Haapalinna
- Subjects
Male ,medicine.medical_specialty ,Injections, Subcutaneous ,Cognitive Neuroscience ,Hippocampus ,Water maze ,Motor Activity ,Eating ,Behavioral Neuroscience ,Limbic system ,Neurochemical ,Memory ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Maze Learning ,Adrenergic alpha-Antagonists ,Radial arm maze ,Behavior, Animal ,Trimethyltin Compounds ,Long-term memory ,Imidazoles ,Antagonist ,Brain ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Rats ,Memory, Short-Term ,Neuropsychology and Physiological Psychology ,Endocrinology ,medicine.anatomical_structure ,Psychology ,human activities ,Neuroscience ,Injections, Intraperitoneal ,medicine.drug - Abstract
NIITTYKOSKI M., R. LAPPALAINEN, J. JOLKKONEN, A. HAAPALINNA, P. RIEKKINEN Sr and J. SIRVIO. Systemic administration of atipamezole, a selective antagonist of alpha-2 adrenoceptors, facilitates behavioural activity but does not influence short-term or long-term memory in trimethyltin-intoxicated and control rats . NEUROSCI BIOBEHAV REV 22 (6) 735–750, 1998.—The present study used trimethyltin (TMT)-intoxicated rats as a model for the behavioural syndrome seen after neuronal damage to the limbic system. Behavioural assessments indicated increased locomotor activity and reduced number of groomings in an open-arena task in TMT-intoxicated (6.6 mg/kg as a free base) rats, as has been found previously. A novel finding was the severe deficit in swimming to a visible platform in the water maze task, with reduced swimming speed at the beginning of the training period. During the reacquisition phase of a radial arm maze task, TMT-intoxicated rats made more short-term and long-term memory errors, and their behavioural activity was increased in comparison with controls. The administration of atipamezole (300 μg/kg), a selective antagonist of α 2 -adrenoceptors, enhanced locomotor activity compared to saline-treated rats, but these effects did not differ between the TMT group and their controls. Atipamezole did not enhance short-term or long-term memory in either TMT or control groups. Taken together, the present data indicate that TMT intoxication is a model for global dementia rather than for a specific loss of relational memory. Previous studies on the neurochemical effects of TMT and the alleviation or prevention of neurotoxicity of TMT are reviewed.
- Published
- 1998
30. Adrenergic α2C-Receptors Modulate the Acoustic Startle Reflex, Prepulse Inhibition, and Aggression in Mice
- Author
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Jukka Sallinen, Mika Scheinin, Brian K. Kobilka, Antti Haapalinna, and Timo Viitamaa
- Subjects
Male ,Reflex, Startle ,Startle response ,Phencyclidine ,Mice, Transgenic ,Article ,Mice ,Receptors, Adrenergic, alpha-2 ,Dopamine ,Moro reflex ,medicine ,Animals ,Social Behavior ,Adrenergic alpha-Antagonists ,Prepulse inhibition ,Mice, Inbred BALB C ,Adrenergic Uptake Inhibitors ,Dose-Response Relationship, Drug ,medicine.diagnostic_test ,General Neuroscience ,Imidazoles ,Neural Inhibition ,Medetomidine ,medicine.disease ,Aggression ,Mice, Inbred C57BL ,Amphetamine ,Monoamine neurotransmitter ,Mutagenesis ,Schizophrenia ,Acoustic Startle Reflex ,Reflex ,Psychology ,Adrenergic alpha-Agonists ,Excitatory Amino Acid Antagonists ,Neuroscience ,medicine.drug - Abstract
Studies on animal models of stress, anxiety, aggression, and sensorimotor gating have linked specific monoamine neurotransmitter abnormalities to the cognitive and behavioral disturbances associated with many affective neuropsychiatric disorders. Although α2-adrenoceptors (α2-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each α2-AR subtype (α2A, α2B, and α2C) are largely unknown. The restricted availability of relevant animal models and the lack of subtype-selective α2-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the α2C-AR subtype in two well established behavioral paradigms: prepulse inhibition (PPI) of the startle reflex and isolation-induced aggression. The α2C-AR-altered mice appear grossly normal, but subtle changes have been observed in their brain dopamine (DA) and serotonin (5-HT) metabolism. In this study, the mice with targeted inactivation of the gene encoding α2C-ARs (α2C-KO) had enhanced startle responses, diminished PPI, and shortened attack latency in the isolation–aggression test, whereas tissue-specific overexpression of α2C-ARs (α2C-OE) was associated with opposite effects. Correlation analyses suggested that both the magnitude of the startle response and its relative PPI (PPI%) were modulated by the mutations. In addition, the differences in PPI, observed between drug-naive α2C-OE mice and their wild-type controls, were abolished by treatment with a subtype nonselective α2-agonist and antagonist. Thus, drugs acting via α2C-ARs might have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as schizophrenia, attention deficit disorder, post-traumatic stress disorder, and drug withdrawal.
- Published
- 1998
31. Facilitation of cognitive functions by a specific α2-adrenoceptor antagonist, atipamezole
- Author
-
Risto Lammintausta, Antti Haapalinna, and Jouni Sirviö
- Subjects
Male ,Spatial Behavior ,Stimulation ,Substrate Specificity ,Rats, Sprague-Dawley ,Cognition ,α2 adrenoceptor ,Memory ,Avoidance Learning ,medicine ,Animals ,Effects of sleep deprivation on cognitive performance ,Maze Learning ,Adrenergic alpha-Antagonists ,Pharmacology ,Memoria ,Imidazoles ,Antagonist ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Rats ,Anesthesia ,Facilitation ,Psychology ,Neuroscience ,medicine.drug - Abstract
The present experiments investigated the effects of a specific and potent α2-adrenoceptor antagonist, atipamezole (as a stimulator of the noradrenergic system) on cognitive performance in rats. Atipamezole enhanced the acquisition of a linear-arm maze test and also improved the choice accuracy of poorly performing rats in a delayed (20 min) three-choice maze test. Furthermore, atipamezole improved the achievement of a one-trial appetite-maze when injected immediately after teaching, thus having an effect on consolidation. Atipamezole clearly impaired the acquisition of the active avoidance test. The present results indicate that stimulation of noradrenergic system by atipamezole improves the performance of animals in tasks assessing relational learning and memory, possibly affecting attention, short-term memory and the speed of information processing. It has also an effect on a consolidation process unrelated to attentional or motivational mechanisms. In a stressful test, stimulation of noradrenaline release leads to impairment of performance.
- Published
- 1998
32. 5 -HT1A Receptor agonist (8-OH-DPAT) and 5-HT2 receptor agonist (DOI) disrupt the non-cognitive performance of rats in a working memory task
- Author
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Esa Koivisto, Ewen MacDonald, Sirja Ruotsalainen, Antti Haapalinna, Paavo Riekkinen, Jouni Sirviö, and Roman Stefanski
- Subjects
Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Hippocampus ,Norepinephrine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Receptor, Serotonin, 5-HT2C ,medicine ,Animals ,Receptor, Serotonin, 5-HT2A ,Pharmacology (medical) ,Rats, Wistar ,Receptor ,5-HT receptor ,Pharmacology ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Dose-Response Relationship, Drug ,8-OH-DPAT ,5-HT2 receptor ,Amphetamines ,Brain ,Hydroxyindoleacetic Acid ,Rats ,Serotonin Receptor Agonists ,030227 psychiatry ,Psychiatry and Mental health ,Endocrinology ,chemistry ,Receptors, Serotonin ,Mental Recall ,Conditioning, Operant ,5-HT1A receptor ,Serotonin ,Psychology ,Receptors, Serotonin, 5-HT1 ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The present study investigated the role of 5-HT1A and 5-HT2 receptors in the execution of a working memory task (delayed non-matching to position, DNMTP) by assessing the influence of 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT 2 receptor agonist) on the performance of rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT) and their controls. Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid levels were reduced in examined brain areas (especially in the hippocampus where there was a 90 percent reduction). Noradrenaline concentrations were also decreased (mostly on the same side of the injection) by about 20 percent. 5,7-DHT lesioned rats did not significantly differ from their controls in performance in the DNMTP task. At the 30 μg/kg dose, 8-OH-DPAT did not affect the DNMTP-performance of rats, but at the higher dose (100 μg/kg) it reduced the probability of responding to the sample lever. DOI (100 and 300 μg/kg) also interfered with the non-cognitive performance of rats. Since neither of these agonists affected significantly the choice accuracy, they do not appear to influence the working memory per se. The 5,7-DHT lesioned rats did not differ from their controls in response to these agonists. These results suggest that the combination of 5-HT1A receptor stimulation by 8-OH-DPAT and 5-HT2 receptor stimulation by DOI can interfere with the non-cognitive performance of rats in the DNMTP task. The results further indicate that the effect of 8-OH-DPAT may be mediated through post-synaptic rather than pre-synaptic 5-HT1A receptors.
- Published
- 1998
33. Stimulation of alpha-1 adrenergic receptors facilitates spatial learning in rats
- Author
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Tarja Puumala, Jouni Sirviö, Kaisa Narinen, Paavo Riekkinen, Antti Haapalinna, and Susanna Greijus
- Subjects
Male ,Agonist ,Receptor complex ,medicine.medical_specialty ,Antimetabolites ,medicine.drug_class ,Scopolamine ,Morris water navigation task ,Stimulation ,Muscarinic Antagonists ,Water maze ,Receptors, N-Methyl-D-Aspartate ,Partial agonist ,Clonidine ,Receptors, Glycine ,Glycine binding ,Internal medicine ,Prazosin ,medicine ,Animals ,Pharmacology (medical) ,Rats, Wistar ,Maze Learning ,Adrenergic alpha-Antagonists ,Swimming ,Biological Psychiatry ,Pharmacology ,Rats ,Psychiatry and Mental health ,Endocrinology ,Neurology ,Cycloserine ,Adrenergic alpha-1 Receptor Agonists ,Neurology (clinical) ,Psychology ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of D-cycloserine, a partial agonist at the glycine binding site on the N-methyl-D-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 micrograms kg-1 or 1500 micrograms kg-1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300-2000 micrograms kg-1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 micrograms kg-1, but not 300 micrograms kg-1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 micrograms kg-1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 micrograms kg-1, but not 500 micrograms kg-1, slightly ameliorated the scopolamine-induced (200 micrograms kg-1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 micrograms kg-1 or St-587 at doses 500 micrograms kg-1 or 1500 micrograms kg-1 did not have any significant influence on the scopolamine-induced (200 micrograms kg-1) increase of swimming speed. Furthermore, D-cycloserine at the dose of 300 micrograms kg-1 but not 1000 or 3000 micrograms kg-1 reversed the scopolamine (200 micrograms kg-1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that D-cycloserine may be effective in alleviating states of central cholinergic hypofunction.
- Published
- 1998
34. Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat
- Author
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Esa Heinonen, Antti Hervonen, Hanna Oksanen, Pia Jaatinen, Päivi Riihioja, and Antti Haapalinna
- Subjects
Male ,Agonist ,Health (social science) ,medicine.drug_class ,Injections, Subcutaneous ,medicine.medical_treatment ,Toxicology ,Irritability ,Biochemistry ,Behavioral Neuroscience ,chemistry.chemical_compound ,medicine ,Animals ,Rats, Wistar ,Dexmedetomidine ,Saline ,Ethanol ,business.industry ,Imidazoles ,General Medicine ,Medetomidine ,Effective dose (pharmacology) ,Rats ,Substance Withdrawal Syndrome ,Kinetics ,Neurology ,chemistry ,Anesthesia ,Alpha-2 adrenergic receptor ,medicine.symptom ,Hypoactivity ,business ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The effect of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms was studied in chronically ethanol-fed rats. After a 4-day ethanol intoxication period the rats were given s.c. injections of dexmedetomidine (3, 10, or 30 micrograms/kg) or saline (control group) at 10, 16, 22, and 39 h after the last dose of ethanol. The severity of ethanol withdrawal symptoms (rigidity, tremor, irritability, hypoactivity) was rated up to 58 h, blind to the treatments. The results showed that dexmedetomidine at doses 10 and 30 micrograms/kg significantly diminished the severity of the ethanol withdrawal reaction as measured by the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability). Dexmedetomidine at 10 micrograms/kg was the most effective dose, especially in the latter half of the withdrawal period (23-58 h after last dose of ethanol). The results suggest that dexmedetomidine in the treatment of ethanol withdrawal symptoms should be further studied.
- Published
- 1997
35. Evaluation of the effects of a specific α2-adrenoceptor antagonist, atipamezole, on α1- and α2-adrenoceptor subtype binding, brain neurochemistry and behaviour in comparison with yohimbine
- Author
-
Juha-Matti Savola, Ewen MacDonald, Timo Viitamaa, Leena Tuomisto, Raimo Virtanen, Esa Heinonen, and Antti Haapalinna
- Subjects
Male ,Biogenic Amines ,Serotonin ,medicine.medical_specialty ,Alpha (ethology) ,Motor Activity ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Dopamine ,Internal medicine ,medicine ,Animals ,Adrenergic alpha-Antagonists ,Behavior, Animal ,Chemistry ,Dopaminergic ,Imidazoles ,Antagonist ,Brain ,Yohimbine ,Atipamezole ,Prazosin ,General Medicine ,Medetomidine ,Receptors, Adrenergic, alpha ,Rats ,Endocrinology ,Female ,Alpha-2 adrenergic receptor ,Rabbits ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
In the present study we evaluated the alpha 1- and alpha 2-adrenoceptor subtype binding, central alpha 2-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two alpha 2-adrenoceptor antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for alpha 2- vs. alpha 1-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the alpha 2A-, alpha 2C- and alpha 2B-adrenoceptors, but yohimbine had significantly lower affinity for the alpha 2D-subtype. This may account for the fact that significantly higher doses of yohimbine than atipamezole were needed for reversal of alpha 2-agonist (medetomidine)-induced effects in rats (mydriasis) and mice (sedation and hypothermia). The effect on central monoaminergic activity was estimated by measuring the concentrations of transmitters and their main metabolites in whole brain homogenate. At equally effective alpha 2-antagonising doses in the rat mydriasis model, both drugs stimulated central noradrenaline turnover (as reflected by increase in metabolite levels) to the same extent. Atipamezole increased dopaminergic activity only slightly, whereas yohimbine elevated central dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural tests, atipamezole (0.1-10 mg/kg) did not affect motor activity but stimulated food rewarded operant (FR-10) responding (0.03-3 mg/kg) whereas yohimbine both stimulated (1 mg/kg) and decreased (or = 3 mg/kg) behaviour in a narrow dose range in these tests. In the staircase test, both antagonists increased neophobia, but in the two compartment test only yohimbine (or = 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non alpha 2-adrenoceptor properties of yohimbine. In conclusion, the alpha 2-antagonist atipamezole blocked all alpha 2-adrenoceptor subtypes at low doses, stimulated central noradrenergic activity and had only slight effects on behaviour under familiar conditions, but increased neophobia. The low affinity for the alpha 2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study alpha 2-adrenoceptor physiology and pharmacology.
- Published
- 1997
36. Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models
- Author
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Eero Vasar, Päivi Tuomainen, Marton Fekete, Aavo Lang, Erkka Syvälahti, Eva Schmidt, Pekka T. Männistö, Istvan Gyertyan, Jarmo Hietala, Istvan Gacsalyi, and Antti Haapalinna
- Subjects
Agonist ,Elevated plus maze ,medicine.medical_specialty ,medicine.drug_class ,Chemistry ,5-HT2 receptor ,Pharmacology ,Anxiolytic ,Marble burying ,Deramciclane ,Endocrinology ,Anxiogenic ,Internal medicine ,Drug Discovery ,medicine ,ED50 - Abstract
The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic, antidepressant, and antidopaminergic tests in rodents. A striking property of deramciclane was its high affinity to both 5-HT2A and 5-HT2C receptors (Ki = 8.7–27 nM/l). Deramciclane had also a moderate affinity to dopamine D2 and sigma receptors but did not interact with any of the adrenergic receptors. Deramciclane was active in several animal models predicting anxiolytic efficacy in humans. The active dose range of deramciclane was narrow in some tests, but generally the active dose range extended from 0.5 mg/kg (1.2 μmol/kg) to 10 mg/kg (23.9 μmol/kg). Statistically significant results were obtained in Vogel's test (1 mg/kg; 2.4 μmol/kg), social interaction (0.7 mg/kg; 1.7 μmol/kg), two-compartment box (3 mg/kg; 7.2 μmol/kg), and marble-burying tests (10 mg/kg; 23.9 μmol/kg). Although deramciclane as such was not active in the elevated plus maze, it antagonized the anxiogenic effect of the CCK agonist caerulein in this test, although significantly only at one dose (0.5 mg/kg; 1.2 μmol/kg). Deramciclane (1.4 and 14 mg/kg; 3.3 and 32.5 μmol/kg) was active in the learned helplessness paradigm. However, it had no antidepressant activity in tetrabenazine-induced ptosis or forced swimming test at ≤150 mg/kg (359 μmol/kg). Deramciclane elevated serum prolactin levels and brain dopamine metabolites (DOPAC, HVA) only at 20–40 mg/kg (48–96 μmol/kg). Deramciclane up to 40–100 mg/kg (96–239 μmol/kg) did not modify apomorphine-induced climbing, amphetamine-induced hyperlocomotion, or the conditioned avoidance reaction. Swimming-induced grooming was inhibited only by 50 mg/kg (112 μmol/kg) of deramciclane. Deramciclane reduced the motor activity at doses well above the established anxiolytic doses: ED50 18 mg/kg; 43 μmol/kg (rats) and 31.5. mg/kg; 75 μmol/kg (mice). Based on these results the anxiolytic-type selectivity of deramciclane appears satisfactory and to have a psychopharmacological profile of its own. Drug Dev. Res. 40:333–348, 1997. © 1997 Wiley-Liss, Inc.
- Published
- 1997
37. Lack of Relationship Between Thalamic Oscillations and Attention in Rats: Differential Modulation by an Alpha-2 Antagonist
- Author
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Tarja Puumala, Paavo Riekkinen, Pekka Jäkälä, Jouni Sirviö, Minna Riekkinen, Erkki Björk, Antti Haapalinna, Markus Björklund, and Sirja Ruotsalainen
- Subjects
Male ,Serial reaction time ,Methylphenidate ,General Neuroscience ,Imidazoles ,Antagonist ,Atipamezole ,Stimulus (physiology) ,Impulsivity ,Rats ,Electrophysiology ,Thalamus ,Task Performance and Analysis ,medicine ,Animals ,Attention ,Alpha-2 adrenergic receptor ,Rats, Wistar ,medicine.symptom ,Psychology ,Neuroscience ,Adrenergic alpha-Antagonists ,medicine.drug - Abstract
A five-choice serial reaction time (5-CSRT) task was used to assess attention in rats. In this behavioral paradigm, the rats are required to spatially discriminate a short visual stimulus that will occur randomly in one of five locations while maintaining a sufficient activity level. The ability of a rat to maintain attention on the task can be measured by counting the choice accuracy (percent correct responses), whereas the probability of premature responses indicates the level of impulsivity. According to previous results [24], rats performing poorly in the task have a lower choice accuracy and make more premature responses than normally behaving individuals, i.e., a clear, inverse correlation was observed between choice accuracy and impulsiveness of rats. Methylphenidate, a psychostimulant that has been shown to alleviate the symptoms in attention deficit-hyperactivity disorder (ADHD), improved the choice accuracy of poor performing rats in this task [24]. The present results show that the correlation between choice accuracy and impulsivity exists also when the rats are tested using a reduced stimulus intensity or curtailed stimulus duration. The results of a pharmacological experiment suggested that atipamezole (30, 300, or 1000 micrograms/kg), a potent and specific alpha-2 antagonist that is known to increase the activity of monoaminergic systems in the brain, did not affect the percent correct responses in poor performers or in controls tested either at the baseline conditions or at a curtailed stimulus duration (which impaired their choice accuracy). At the doses of 300 and 1000 micrograms/kg, however, atipamezole slightly increased the probability of premature responses in all group of rats. The results of an electrophysiological study indicated that the poor choice accuracy or impulsiveness of rats is not related to the amount of cortically recorded spike-wave discharges/high voltage spindle (HVS) activity, which reflect thalamo-cortical oscillation. Atipamezole dose-dependently reduced the incidence and duration of HVSs. The present data, therefore, indicate that (a) alpha-2 antagonist treatment is not superior to methylphenidate treatment when investigated using acute administrations of the agents in poor performers of the 5-CSRT task, and (b) thalamic oscillations are not the reason for the attention deficit of rats in this model of ADHD. The relationship between choice accuracy and impulsivity is discussed.
- Published
- 1997
38. Genetic Alteration of α2C-Adrenoceptor Expression in Mice: Influence on Locomotor, Hypothermic, and Neurochemical Effects of Dexmedetomidine, a Subtype-Nonselective α2-Adrenoceptor Agonist
- Author
-
Gregory S. Barsh, Richard E. Link, Timo Viitamaa, Antti Haapalinna, Tiina Leino, Birgitta Sjöholm, Ewen MacDonald, Brian K. Kobilka, Maya Kulatunga, Markku Pelto-Huikko, Mika Scheinin, and Jukka Sallinen
- Subjects
Agonist ,medicine.medical_specialty ,medicine.drug_class ,Alpha (ethology) ,Motor Activity ,Pharmacology ,Body Temperature ,Mice ,chemistry.chemical_compound ,Neurochemical ,Idazoxan ,Receptors, Adrenergic, alpha-2 ,Dopamine ,Internal medicine ,medicine ,Animals ,Biogenic Monoamines ,RNA, Messenger ,Receptor ,Brain Chemistry ,Chemistry ,Homovanillic acid ,Imidazoles ,Medetomidine ,Mice, Inbred C57BL ,Endocrinology ,Adrenergic alpha-Agonists ,Mice, Inbred DBA ,Autoradiography ,Molecular Medicine ,medicine.drug - Abstract
alpha 2-Adrenergic receptors (alpha 2-ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding alpha 2-AR subtypes (alpha 2A, alpha 2B, and alpha 2C) have been cloned. We investigated the involvement of the alpha 2C-AR in alpha 2-adrenergic pharmacology by applying molecular genetic techniques to alter the expression of alpha 2C-AR in mice. The effects of dexmedetomidine, a subtype-nonselective alpha 2-AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the alpha 2C-AR gene and in their controls, but the hypothermic effect of the alpha 2-AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of alpha 2C-AR in striatum and other brain regions expressing alpha 2C-AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the alpha 2C-AR agonists was significantly accentuated. The hypothermic effect of alpha 2-AR agonists thus seems to be mediated in part by alpha 2C-AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of alpha 2C-AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased alpha 2C-AR expression had elevated concentrations of the dopamine metabolite compared with their controls.
- Published
- 1997
39. Enhancement of Intermediate-Term Memory by an Alpha-1 Agonist or a Partial Agonist at the Glycine Site of the NMDA Receptor
- Author
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Raimo Pussinen, Esa Koivisto, Antti Haapalinna, Paavo Riekkinen, Sakari Nieminen, and Jouni Sirviö
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Adrenergic receptor ,medicine.drug_class ,Cognitive Neuroscience ,Experimental and Cognitive Psychology ,Receptors, N-Methyl-D-Aspartate ,Partial agonist ,Behavioral Neuroscience ,Receptors, Glycine ,Memory ,Internal medicine ,medicine ,Animals ,Humans ,Learning ,Rats, Wistar ,Glycine receptor ,Communication ,business.industry ,Chemistry ,Glutamate receptor ,Retention, Psychology ,Rats ,Endocrinology ,Cycloserine ,NMDA receptor ,Intermediate-term memory ,business ,Indirect agonist ,Adrenergic alpha-Agonists ,Neuroscience - Abstract
The aim of the present study was to investigate whether the activation of alpha-1 adrenergic receptors can influence intermediate-term memory. Therefore, the effects of ST 587 (30 or 100 micrograms/kg), a putative alpha-1 agonist, on the retention of the radial arm task using non-matching to sample with a 4-h delay were investigated in rats. The results indicated that the administration of ST 587 (100 micrograms/kg) before a sampling phase increased the time to complete the sampling phase which was due to an increased number of errors of repetition (regarded as working memory errors) and a reduced number of arms visited in a given time (regarded as behavioral activity). However, this treatment increased the number of correct choices before the first error during the retention phase in this task. Since we were also interested in investigating the role of NMDA receptors in memory encoding, we investigated whether NMDA receptor modulation by d-cycloserine (1 or 10 mg/kg), a partial agonist of the glycine site on the NMDA receptor, had any influence on the performance of rats in this task. The results indicated that d-cycloserine (10 mg/kg) given before the sampling phase did not influence the performance of rats during the sampling phase, but it did improve their choice accuracy during the retention phase of this task. These data suggest that the systemic administration of either an alpha-1 agonist or an indirect agonist of NMDA receptors can facilitate intermediate-term retention of spatial information.
- Published
- 1997
40. Dexmedetomidine Reduces Response Tendency, but Not Accuracy of Rats in Attention and Short-Term Memory Tasks
- Author
-
Paavo J. Riekkinen, Sirja Ruotsalainen, Jouni Sirviö, and Antti Haapalinna
- Subjects
Male ,Agonist ,Benzylamines ,medicine.medical_specialty ,medicine.drug_class ,media_common.quotation_subject ,Clinical Biochemistry ,Short-term memory ,Serial Learning ,Toxicology ,Biochemistry ,Behavioral Neuroscience ,Postsynaptic potential ,Internal medicine ,Adrenergic alpha-2 Receptor Agonists ,Reaction Time ,medicine ,Animals ,Attention ,Biogenic Monoamines ,Neurotransmitter Uptake Inhibitors ,Rats, Wistar ,Dexmedetomidine ,Adrenergic alpha-Antagonists ,Biological Psychiatry ,media_common ,Brain Chemistry ,Pharmacology ,Working memory ,Imidazoles ,Antagonist ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Medetomidine ,Rats ,Memory, Short-Term ,Endocrinology ,Anesthesia ,Psychology ,Adrenergic alpha-Agonists ,Psychomotor Performance ,medicine.drug ,Vigilance (psychology) - Abstract
The present study investigated the role of alpha 2-adrenergic mechanisms in the performance of motor responses, attention and short-term memory in rats. A low dose (3.0 micrograms/kg, s.c.) of dexmedetomidine, an alpha 2-adrenoceptor agonist, reduced response tendency in an attentional task and a working memory task, but it did not affect the choice accuracy of rats. Atipamezole (300 micrograms/kg), an alpha 2-adrenoceptor antagonist, increased anticipatory responding. Although atipamezole did not affect the number of omissions, it reversed the effects of dexmedetomidine on that parameter. We also investigated the effects of dexmedetomidine in rats with partial destruction of noradrenergic nerves induced by the neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride). On its own, DSP-4 treatment did not affect choice accuracy or behavioural activity of rats in the attentional task. The effects of dexmedetomidine (0.3-3.0 micrograms/kg) on anticipatory responses did not differ between controls and DSP-4 group. Furthermore, the effect on omissions was not consistently diminished in DSP-4 treated rats. These results suggest that the activation of postsynaptic alpha 2-adrenoreceptors may be responsible for dexmedetomidine-induced reduction of response tendency while attention and short-term memory are not markedly affected.
- Published
- 1997
41. Catechol 0-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats
- Author
-
Antti Haapalinna, Raija Liljequist, Maria Ahlander, Ying Hua Li, and Pekka T. Männistö
- Subjects
Catechol-O-methyl transferase ,Tolcapone ,Working memory ,Pharmacology ,Nucleus basalis ,Spatial memory ,Behavioral Neuroscience ,chemistry.chemical_compound ,chemistry ,Catecholamine ,medicine ,Entacapone ,Neurotransmitter ,Psychology ,Neuroscience ,medicine.drug - Abstract
Two catechol O-methyltransferase inhibitors, peripherally acting entacapone and also centrally acting tolcapone, were tested regarding their capacity to influence learning and memory in adult intact rats. Tolcapone was also studied in rats treated with scopolamine, in adult rats lesioned in the nuclei basalis magnocellularis, and in aged rats. Spatial working memory performance (radial-arm maze) of intact rats was facilitated following pretraining i.p. administration of tolcapone (10 mg/kg). Entacapone was ineffective at doses of 10 and 30 mg/kg. Senescent poor performers improved their accomplishment in the spatial memory task (linear-arm maze) under the influence of tolcapone. Scopolamine (1 mg/kg) impaired working memory performance. Bilateral lesions in the nucleus basalis magnocellularis reduced choline acetyltransferase activity in the frontal cortex by 26% and retarded the learning rate of spatial place task. Tolcapone was not able to counteract the performance deficits in these models. It is concluded that tolcapone can either slightly improve or impair the memory functions depending on task specific elements and performance factors.
- Published
- 1997
42. Monoamine oxidase B inhibitor selegiline protects young and aged rat peripheral sympathetic neurons against 6-hydroxydopamine-induced neurotoxicity
- Author
-
Antti Hervonen, Jaana Suhonen, Esa Heinonen, T. Salonen, and Antti Haapalinna
- Subjects
Male ,Aging ,medicine.medical_specialty ,Monoamine Oxidase Inhibitors ,Tyrosine 3-Monooxygenase ,Superior Cervical Ganglion ,Adrenergic Neurons ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,stomatognathic system ,Internal medicine ,Selegiline ,medicine ,Animals ,Neurotoxin ,Rats, Wistar ,Oxidopamine ,business.industry ,MPTP ,Neurotoxicity ,Peripheral Nervous System Diseases ,medicine.disease ,Immunohistochemistry ,Rats ,Monoamine neurotransmitter ,Endocrinology ,Microscopy, Fluorescence ,nervous system ,chemistry ,Catecholamine ,Catecholaminergic cell groups ,Neurology (clinical) ,business ,medicine.drug - Abstract
Selegiline is a selective and irreversible monoamine B inhibitor with the capacity to increase the level of several antioxidative enzymes in rat brain. It can protect adrenergic neurons against injury induced by neurotoxins such as MPTP, DSP-4 and AF64A in animal studies. In addition, the protective action is not limited to catecholaminergic cells, as selegiline can also minimize the loss of developing motoneurons after axotomy. The aim of this study was to determine whether selegiline can protect peripheral catecholaminergic neurons against the neurotoxic effect of 6-OHDA. This kind of protective effect against 6-OHDA neurotoxicity has not been reported before. Wistar albino male rats aged 4 or 24 months were treated with selegiline or saline solution 1 h before 6-OHDA injection. At 2 weeks after the 6-OHDA injection, the superior cervical ganglia (SCG) and submandibular glands (SMG) were studied using catecholamine histofluorescence and immunohistochemistry for tyrosine hydroxylase (TH). The number of TH-positive cells in the SCG and the length and number of adrenergic nerve fibers in the SMG were quantified. Our findings showed that 6-OHDA caused a reduction of TH immunoreactivity and catecholamine histofluorescence in neuronal somata, as well as a decrease in the number and length of adrenergic nerve fibers in the submandibular gland. Selegiline pretreatment protected SCG neurons and their postganglionic nerve fibers in SMG against these changes in a dose-dependent manner. The mechanism through which selegiline exerts its neuroprotective effect is as yet unknown.
- Published
- 1996
43. Effect of α2-adrenergic drugs dexmedetomidine and atipamezole on extracellular amino acid levels in vivo
- Author
-
Paavo Riekkinen, Pirjo Valtonen, Toivo Halonen, and Antti Haapalinna
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Microdialysis ,medicine.drug_class ,Glutamic Acid ,Biology ,Hippocampus ,chemistry.chemical_compound ,Seizures ,Internal medicine ,Adrenergic alpha-2 Receptor Agonists ,medicine ,Extracellular ,Animals ,Amino Acids ,Rats, Wistar ,Dexmedetomidine ,Neurotransmitter ,Adrenergic alpha-Antagonists ,gamma-Aminobutyric Acid ,Pharmacology ,chemistry.chemical_classification ,Aspartic Acid ,Epilepsy ,Imidazoles ,Glutamate receptor ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Medetomidine ,Rats ,Amino acid ,Spectrometry, Fluorescence ,Endocrinology ,chemistry ,Potassium ,Calcium ,Extracellular Space ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
alpha 2-Adrenoceptors are known to be involved in a variety of physiological functions and pathological conditions, including epilepsy and the extent of excitotoxin-induced cell death. In this study we evaluated whether selective alpha 2-adrenergic drugs can modulate the release of neurotransmitter amino acids. The effect of the alpha 2-adrenoceptor agonist dexmedetomidine (5 micrograms/kg, s.c.) and the alpha 2-adrenoceptor antagonist atipamezole (0.1 mg/kg and 1 mg/kg, s.c.) on the release of extracellular glutamate, aspartate and gamma-aminobutyric acid (GABA) was studied with microdialysis in the hippocampus of freely moving rats under basal and K(+)-evoked conditions. Atipamezole (1 mg/kg) decreased K(+)-evoked glutamate efflux by 30% compared to the control group (P0.05) but did not affect significantly the effluxes of aspartate and GABA. Dexmedetomidine and the lower dose of atipamezole (0.1 mg/kg) did not significantly alter the evoked overflow of amino acids. The results suggest that alpha 2-adrenergic drugs have only modest effects on the K(+)-stimulated overflow of extracellular neurotransmitter amino acids in rat hippocampus.
- Published
- 1995
44. The effects of selective alpha-2 adrenergic agents on the performance of rats in a 5-choice serial reaction time task
- Author
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Maria Mazurkiewicz, Paavo J. Riekkinen, Hannele Lahtinen, Jouni Sirviö, Paavo Riekkinen, and Antti Haapalinna
- Subjects
Male ,Agonist ,medicine.drug_class ,medicine.medical_treatment ,Arousal ,Discrimination Learning ,Adrenergic alpha-2 Receptor Agonists ,Reaction Time ,medicine ,Animals ,Attention ,Rats, Wistar ,Latency (engineering) ,Dexmedetomidine ,Adrenergic Agent ,Analysis of Variance ,General Neuroscience ,Imidazoles ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Medetomidine ,Rats ,Stimulant ,Anesthesia ,Alpha-2 adrenergic receptor ,Psychology ,Psychomotor Performance ,medicine.drug - Abstract
The present study investigated how the systemic administration of alpha-2 adrenergic agents that modulate the function of the noradrenergic system in brain, affect rousal and sustained attention. Food-deprivated rats were trained to detect and respond to brief flashes of light presented randomly in one of five spatially diverse locations. The effects of single-dose administrations of dexmedetomidine, an alpha-2 agonist, and atipamezole, an alpha-2 antagonists, on the choice accuracy, errors of omissions, speed of responding, and collection of the reward could be assessed in this task. Dexmedetomidine increased the amount of omissions, speed of response, and decreased the number of premature responses, although it did not markedly lengthen response latencies and food collection latency. Atipamezole increased the number of premature responses. Neither dexmedetomidine nor atipamezole had any effect on choice accuracy of rats in this task. The results suggest that dexmedetomidine decreased behavioral activity and arousal of rats, whereas atipamezole had mild stimulant effect on behavior.
- Published
- 1994
45. Dose- and parameter-dependent effects of atipamezole, an α2-antagonist, on the performance of rats in a five-choice serial reaction time task
- Author
-
Pekka Jäkälä, Paavo Riekkinen, Jouni Sirviö, Antti Haapalinna, Paavo J. Riekkinen, and Maria Mazurkiewicz
- Subjects
Male ,Serial reaction time ,medicine.medical_specialty ,Visual perception ,Clinical Biochemistry ,Stimulus (physiology) ,Toxicology ,Choice Behavior ,Biochemistry ,Arousal ,Norepinephrine ,Behavioral Neuroscience ,Discrimination, Psychological ,Internal medicine ,Reaction Time ,medicine ,Animals ,Attention ,Rats, Wistar ,Adrenergic alpha-Antagonists ,Biological Psychiatry ,Pharmacology ,Dose-Response Relationship, Drug ,Imidazoles ,Antagonist ,Atipamezole ,Rats ,Endocrinology ,Space Perception ,Anesthesia ,Systemic administration ,Food Deprivation ,Psychology ,Photic Stimulation ,Psychomotor Performance ,Parameter dependent ,medicine.drug - Abstract
The present study investigated whether atipamezole (ATI), a potent α 2 -adrenoceptor antagonist that increases the release of noradrenaline in brain, improves attention in rats. Thus, the effects of ATI on the performance of adult male rats in the five-choice serial reaction time task were studied. Food-deprived rats were trained to detect and respond to brief flashes of light presented randomly in one of five spatially diverse locations. The effects of single-dose administration of ATI (0.03–3.0 mg/kg) on the performance of rats under different parametric manipulations of the task were tested: 1) the visual stimuli were presented at unpredictable intertrial intervals (ITIs) or b) the intensity (brightness) of visual stimuli was reduced, thus placing an additional load on attentional processing for animals. Presenting the stimuli earlier than normally or reducing its intensity markedly impaired the choice accuracy of rats. At doses of 0.03, 0.3, and 1.0 mg/kg, ATI improved the choice accuracy of rats when tested using reduced stimulus intensity. ATI 3.0 mg/kg did not affect accuracy performance when tested using reduced stimulus intensity but impaired it when tested using unpredictable ITIs. The other doses of ATI (0.03, 0.3, and 1.0 mg/kg) did not markedly affect choice accuracy of rats tested using unpredictable ITI. Our results could be explained by the assumption that an acute, systemic administration of ATI affects arousal mechanisms and facilities the processing of visual stimuli related to reward.
- Published
- 1993
46. Comparative effects of alpha-2 receptor agents and THA on the performance of adult and aged rats in the delayed non-matching to position task
- Author
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Maija Harju, Paavo Riekkinen, Antti Haapalinna, Paavo J. Riekkinen, and Jouni Sirviö
- Subjects
Male ,Aging ,medicine.medical_specialty ,Reinforcement Schedule ,Short-term memory ,Adrenergic ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Adrenergic alpha-2 Receptor Agonists ,medicine ,Animals ,Rats, Wistar ,Dexmedetomidine ,Adrenergic alpha-Antagonists ,Brain Chemistry ,Pharmacology ,Imidazoles ,Antagonist ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Medetomidine ,Rats ,Memory, Short-Term ,Endocrinology ,Space Perception ,Anesthesia ,Tacrine ,Conditioning, Operant ,Alpha-2 adrenergic receptor ,Psychology ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The present study investigated the effects of dexmedetomidine (an alpha-2 adrenoceptor agonist), atipamezole (an alpha-2 adrenoceptor antagonist) and tacrine (an inhibitor of acetylcholinesterase) on the performance of adult and aged rats in a delayed non-matching to position task assessing spatial short-term memory. Most of the aged rats were impaired in the pretraining phases and in the acquisition of the non-delayed version of the task. After a substantial training period of the delayed version of the task, both adult and aged rats reached their asymptotic level of performance. Both adult and aged rats showed a decline in the percent correct responses at the longest delays in this task, and a delay independent decrease in the percent correct responses across the delays (0-30 s) was found in the group of aged rats (25-month-old) as compared to the adults (10-month-old). Dexmedetomidine (0.3, 1.0 or 3.0 micrograms/kg), atipamezole (0.03, 0.3 or 3.0 mg/kg) and tacrine (1.0 or 3.0 mg/kg) did not increase the percent correct responses in adult or aged rats. The highest doses of dexmedetomidine and tacrine decreased behavioural activity of rats during this short-term memory testing. Atipamezole (0.03 mg/kg) increased behavioural activity of rats. The results suggest that acute, systemic administrations of alpha-2 drugs or an anticholinesterase do not improve short-term memory in rats.
- Published
- 1992
47. Effects of atipamezole, an α2-adrenoceptor antagonist, on the performance of rats in a five-choice serial reaction time task
- Author
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Pekka Jäkälä, Jouni Sirviö, Paavo Riekkinen, and Antti Haapalinna
- Subjects
Male ,Serial reaction time ,Adult male ,Adrenergic receptor ,Clinical Biochemistry ,Serial Learning ,Pharmacology ,Toxicology ,Biochemistry ,Behavioral Neuroscience ,Discrimination, Psychological ,α2 adrenoceptor ,Reaction Time ,medicine ,Animals ,Selective attention ,Adrenergic alpha-Antagonists ,Biological Psychiatry ,Imidazoles ,Antagonist ,Atipamezole ,Rats, Inbred Strains ,Behavioral activation ,Rats ,Anesthesia ,Food Deprivation ,Psychology ,Photic Stimulation ,Psychomotor Performance ,medicine.drug - Abstract
The present study investigates whether pharmacological activation of the noradrenergic system improves attention. The effects of atipamezole, a potent α 2 -adrenoceptor antagonist, on the performance of adult male rats in the five-choice serial reaction time task were studied. Before drug testings, food-deprived rats were trained to detect and respond to brief flashes of light presented randomly by the computer in one of five spatially diverse locations until a stable level of performance had been reached (about 3 months). Single-dose administration of atipamezole (0.03–3.0 mg/kg) slightly increased the number of premature and preservative responses during the intertrial interval and slightly decreased the reaction times to incorrect responses, indicating increased behavioral activation. Atipamezole did not affect discriminative accuracy. However, in a subpopulation of rats with the poorest discriminative accuracy according to pretest performance seven of eight rats improved their discriminative accuracy when treated with 0.3 mg/kg atipamezole as compared to controls. At the other doses tested, no improvement was found. The present results suggest that acute administration of atipamezole, an α 2 -adrenoceptor antagonist, slightly increases behavioral activation, although the effects on baseline performance in the task measuring selective attention are modest.
- Published
- 1992
48. alpha(2A)-Adrenoceptors regulate d-amphetamine-induced hyperactivity and behavioural sensitization in mice
- Author
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Aapo Honkanen, Jukka Sallinen, Juuso Juhila, Mika Scheinin, Esa R. Korpi, and Antti Haapalinna
- Subjects
Male ,medicine.medical_specialty ,Dextroamphetamine ,Genotype ,Alpha (ethology) ,Pharmacology ,Motor Activity ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Dopamine ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Drug Sensitization ,Conditioning, Psychological ,medicine ,Animals ,Amphetamine ,Sensitization ,Adrenergic alpha-Antagonists ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Analysis of Variance ,Adrenergic Uptake Inhibitors ,Behavior, Animal ,business.industry ,Dopaminergic ,Imidazoles ,Atipamezole ,Adrenergic alpha-2 Receptor Antagonists ,Conditioned place preference ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Stimulants, such as d-amphetamine, enhance the release of dopamine in the central nervous system (CNS) and induce locomotor activation in mice. When amphetamine is administered repeatedly, the locomotor activation is progressively increased. This behavioural sensitization may be associated with the development of drug craving, addiction and dependence. Also noradrenergic mechanisms participate in the mediation of the effects of psychostimulants. In this study we show that mice lacking the alpha(2)-adrenoceptor subtype A (alpha(2A)-AR knock-out (KO) on C57Bl/6J background) are supersensitive to the acute locomotor effects of d-amphetamine (5 mg/kg) in a novel environment compared to wild-type (WT) control mice. When both genotypes were treated repeatedly with d-amphetamine (2 mg/kg) they developed locomotor hyperactivation (sensitization), but its amplitude was lower in alpha(2A)-AR KO mice. Development of hyperactivation was reduced in both genotypes by pretreatment with the selective alpha(2)-adrenoceptor antagonist, atipamezole (1 mg/kg). Acute atipamezole also attenuated the expression of d-amphetamine-induced behavioural sensitization especially in WT mice. Interestingly, alpha(2A)-AR KO mice failed to exhibit persistent sensitization after 2 weeks of abstinence from repeated d-amphetamine. Rewarding properties of d-amphetamine, measured by conditioned place preference, were similar in both genotypes. These findings indicate that d-amphetamine-induced acute and sensitized locomotor effects are controlled by alpha(2)-adrenoceptors. Drugs antagonizing the alpha(2A)-adrenoceptor subtype may provide a novel approach for reducing drug sensitization and motor complications caused by dopaminergic agents.
- Published
- 2005
49. Uptake of 6-[18F]fluoro-L-dopa and [18F]CFT reflect nigral neuronal loss in a rat model of Parkinson's disease
- Author
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Sarita, Forsback, Riitta, Niemi, Päivi, Marjamäki, Olli, Eskola, Jörgen, Bergman, Tove, Grönroos, Merja, Haaparanta, Antti, Haapalinna, Juha, Rinne, and Olof, Solin
- Subjects
Male ,Brain Mapping ,Apomorphine ,Behavior, Animal ,Tyrosine 3-Monooxygenase ,Brain ,Parkinson Disease ,Immunohistochemistry ,Functional Laterality ,Dihydroxyphenylalanine ,Rats ,Levodopa ,Rats, Sprague-Dawley ,Substantia Nigra ,Amphetamine ,Disease Models, Animal ,Radioligand Assay ,Dopamine Agonists ,Sympatholytics ,Animals ,Autoradiography ,Central Nervous System Stimulants ,Propionates ,Stereotyped Behavior ,Oxidopamine - Abstract
In order to characterize the sensitivity of an analog of levodopa and a dopamine transporter ligand to detect defects in nigrostriatal function, the uptake of [(18)F]FDOPA and [(18)F]CFT was studied ex vivo in a rat model of Parkinson's disease. The brains of these rats were unilaterally lesioned with an intranigral injection of 6-hydroxydopamine. The lesioned animals were divided into three groups subject to their behavior after pharmacological challenges. Circling behavior was recorded after amphetamine, apomorphine, and L-DOPA challenge in order to predict lesion size. The spatial distribution of radioactivity after [(18)F]FDOPA or [(18)F]CFT injection in brain sections was determined with digital autoradiography. Regions of interest were left/right striatum, left/right substantia nigra, and cerebellum. The degree of unilateral lesion for each animal was confirmed by counting of nigral tyrosine hydroxylase-positive cell bodies. With both tracers the uptake in the lesioned side was lower than in the intact side in the striatum and in the substantia nigra. In conclusion, both tracers clearly demonstrated nigrostriatal dopaminergic hypofunction and correlated with the number of nigral dopaminergic neurons. However, [(18)F]FDOPA showed a much higher unspecific uptake of radioactivity, due to extensive metabolism; therefore, this tracer was less sensitive than the transporter tracer [(18)F]CFT to detect these defects.
- Published
- 2003
50. Atipamezole, an alpha(2)-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats
- Author
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Asla Pitkänen, Jari Nissinen, Antti Haapalinna, Zinayida Bezvenyuk, and Susanna Narkilahti
- Subjects
Male ,Emotions ,Morris water navigation task ,Brain damage ,Status epilepticus ,Pharmacology ,Epileptogenesis ,Rats, Sprague-Dawley ,Epilepsy ,Status Epilepticus ,medicine ,Kindling, Neurologic ,Animals ,Learning ,Maze Learning ,Diazepam ,Behavior, Animal ,Kindling ,Antagonist ,Imidazoles ,Atipamezole ,Electroencephalography ,Infusion Pumps, Implantable ,medicine.disease ,Electric Stimulation ,Electrodes, Implanted ,Rats ,Electrophysiology ,Neurology ,Epilepsy, Temporal Lobe ,Anesthesia ,Disease Progression ,Anticonvulsants ,Neurology (clinical) ,medicine.symptom ,Psychology ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
Stimulation of alpha(2)-adrenoceptors delays the development of kindling, a model of epileptogenesis in humans. Blocking alpha(2)-adrenoceptors is proconvulsant, but has beneficial effects on somatomotor recovery after experimental stroke. We investigated whether atipamezole, a selective alpha(2)-adrenoceptor antagonist, affects the recovery process from status epilepticus (SE)-induced brain damage, which affects the risk of epileptogenesis. Vehicle or atipamezole (100 microg/kg/h) treatment was started 1 week after the induction of SE and continued for 9 weeks using Alzet minipumps (n = 70). Development and severity of epilepsy, spatial and emotional learning, and histologic analysis were used as outcome measures. There were no differences in the percentage of animals with epilepsy in the different treatment groups. In the atipamezole group, however, daily seizure frequency was lower (P0.01), a higher percentage of epileptic animals had mild epilepsy (1 seizure/day; P0.01), and seizure frequency did not increase over time compared with the vehicle group. The atipamezole group had milder hilar cell damage (P0.05) and less intense mossy fiber sprouting (P0.05). Behavioral impairments were similar between groups. Our data indicate that chronic treatment with atipamezole does not prevent epileptogenesis. There is, however, a disease-modifying effect; that is, the epilepsy that develops is milder and non-progressive. These data warrant further studies.
- Published
- 2003
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