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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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

(-)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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The present experiments investigated the effects of the specific alpha(2)-adrenoceptor antagonist atipamezole, alone and in combination with a dopamine agonist, on motor function in rats with a unilateral 6-hydroxydopamine lesion of the nigro-striatal pathway and on exploratory behaviour and cardiovascular function in rats equipped with telemetry transmitters. Dexmedetomidine, an alpha(2)-adrenoceptor agonist and the alpha(2)-adrenoceptor antagonists idazoxan and yohimbine were used as reference compounds. In the unilaterally lesioned animals, direct dopamine agonists, such as apomorphine, induce contralateral turning behaviour. Indirect agonists, such as amphetamine, induce ipsilateral circling in the animals. Atipamezole (0.3 mg/kg s.c) potentiated and dexmedetomidine (10 micro g/kg s.c.) decreased contralateral circling evoked by apomorphine (50 micro g/kg s.c.) and by l-3,4-dihydroxyphenylalanine (L-DOPA, 5 mg/kg i.p.). Atipamezole also prolonged the duration of action of L-DOPA. Atipamezole dose-dependently induced ipsilateral turning behaviour and potentiated turning induced by amphetamine (1 mg/kg i.p.). The alpha(1)-adrenoceptor antagonist prazosin (0.1 mg/kg i.p.) partially antagonised the effect of amphetamine and had a strong inhibitory effect on the atipamezole-induced potentiation of the amphetamine response. Prazosin did not have any major effect on either the apomorphine response itself or on the potentiation of the apomorphine response by atipamezole. This suggests that atipamezole can modulate motor function both indirectly, by stimulating the release of noradrenaline and directly, by blocking postsynaptic alpha(2)-adrenoceptors in neurones other than noradrenergic nerves. The alpha(2)-adrenoceptor antagonists, when tested at comparably effective central alpha(2)-adrenoceptor antagonising doses in a rat mydriasis model: atipamezole 0.3 mg/kg s.c., idazoxan 1 mg/kg s.c. and yohimbine 3 mg/kg s.c., all induced ipsilateral turning behaviour and potentiated apomorphine-induced contralateral circling. The effects of the alpha(2)-adrenoceptor antagonists were in general similar in these experiments. In habituated non-lesioned rats equipped with telemetry transmitters, apomorphine (50 micro g/kg s.c.) decreased blood pressure in the home cage and in an open-field test. It also decreased spontaneous motor activity in the open field. Neither atipamezole (0.3 mg/kg s.c.) nor idazoxan (1 mg/kg s.c.) had any effect on blood pressure when given alone, but reversed the apomorphine-induced decrease in blood pressure. Atipamezole also diminished apomorphine-induced sedation in the open-field test. In conclusion, atipamezole improved the efficacy of L-DOPA and apomorphine in an animal model of Parkinson's disease and also reduced adverse dopaminergic effects on vigilance and on cardiovascular function. These results suggest that an investigation of the effects of specific alpha(2)-adrenoceptor antagonists in Parkinson's disease patients is warranted.

The possible effect of atipamezole, a potent and specific alpha(2)-adrenoceptor antagonist, on the development and expression of d-amphetamine-induced behavioural sensitization was evaluated in mice. Male (C57Bl/6J) mice were given daily doses of d-amphetamine (2 mg/kg). In addition, groups of mice received injections of atipamezole (0.3 or 1 mg/kg) 20 min before d-amphetamine or vehicle administration. Idazoxan (1 mg/kg) was used in some experiments to extend the results to other alpha(2)-adrenoceptor antagonists. Challenge doses of d-amphetamine were administered to the mice on days 7-9 to evaluate the effects of alpha(2)-adrenoceptor antagonists on the d-amphetamine sensitization, evidenced by increased locomotor activation. Mice treated repeatedly with d-amphetamine developed strong locomotor sensitization that was reduced by pretreatment with alpha(2)-adrenoceptor antagonists. Acute atipamezole at both doses attenuated the expression of d-amphetamine-induced sensitization. Atipamezole at 1 mg/kg alone had no effect on locomotor activity, but the lower dose (0.3 mg/kg) increased locomotor activity after repeated administration. These results indicate that alpha(2)-adrenoceptor antagonists modulate the actions of d-amphetamine in a manner not explicable by their enhancing actions on noradrenaline and dopamine release, and may thus provide a novel approach to the treatment of motor complications caused by dopaminergic agents, such as dyskinesias, and perhaps also drug dependence.

Previous studies suggest that enhanced noradrenergic neurotransmission promotes functional recovery following cerebral lesions. The present study investigated whether systemic administration of an α 2 -adrenergic antagonist, atipamezole, facilitates recovery following transient focal cerebral ischemia in rats. The effect of atipamezole therapy on recovery from ischemia was compared with the effect of enriched-environment housing in rats. Ischemia was induced by occlusion of the right middle cerebral artery (MCA) for 120 min using the intraluminal filament model. Daily atipamezole treatment (1 mg/kg, subcutaneously) was started on day 2 after ischemia induction and drug administration stopped after 10 days. Another group of rats was housed in an enriched environment from day 2 following ischemia induction until the end of the experiment. Several different behavioral tests were used to measure functional recovery during the 26 days following the induction of focal cerebral ischemia. There was improved performance in the limb-placing test from the beginning of atipamezole treatment to day 8, and in wheel-running in the foot-slip test on days 2 and 4. Enriched-environment housing facilitated recovery in the foot-slip test in a later phase of the test period (days 8 to 10). Discovery of a hidden platform in a water-maze task was also facilitated in rats housed in the enriched environment, but this was probably due to the increased swimming speed of these rats. The present data suggest that the α 2 -adrenergic antagonist, atipamezole, facilitates sensorimotor recovery after focal ischemia, but has no effect on subsequent water-maze tests assessing spatial learning and memory, when assessed 11 days after the cessation of drug administration.

The present study investigated the effect of postischaemic infusion of an irreversible monoamine oxidase B (MAO-B) inhibitor, l-deprenyl, an equipotent dose of a reversible MAO-B inhibitor, lazabemide, or 0.9% NaCl on infarct volumes following focal cerebral ischaemia in rats. The drug doses (0.3 mg/kg) were selected to induce selective MAO-B inhibition (45-55%), but not MAO-A inhibition. The infarct volumes in the cortex or in the striatum did not differ between the experimental groups 72 hr after transient occlusion of the middle cerebral artery, which suggests that during ischaemia/reperfusion, suppressed oxidative stress by partial MAO-B inhibition or MAO-B independent mechanisms such as induction of trophic factors, does not protect against ischaemia/reperfusion damage.

Neuroleptics are known to cause anhedonia and attenuate sexual behaviour at therapeutic doses in humans. These effects are assumed to result from the dopamine antagonism of the drugs. It has been observed that a mixed dopamine D1/D2 antagonist, haloperidol, may cause a reduction in the number of intromissions required to achieve ejaculation. On the other hand, dopamine antagonists are considered unable to modify sexual behaviour once the copulatory sequence is initiated. In this study, male rats received low doses of haloperidol (30 or 60 microg/kg) before the investigation of sexual behaviour in five consecutive days and the mating test was repeated after withdrawal periods of four and five days. Haloperidol dose-dependently reduced intromission frequency, and this effect was maintained for four days after withdrawal. Ejaculation latency was reduced in all groups, including controls. The results indicate that at low doses haloperidol dose-dependently reduces intromission frequency, and the effect of a repeated dosage may persist several days after cessation of medication.

The effects of an alpha2-adrenoceptor antagonist, atipamezole, on exploratory behaviour in a novel environment, spontaneous motor activity and active avoidance learning were studied after acute injection and continuous infusion (0.1 mg/kg h) for 24 h and 6-9 days in rats. The effects of atipamezole on biogenic amines and their main metabolites in brain were studied after an acute injection (0.3 mg/kg s.c.) and continuous infusion (0.1 mg/kg h) for 24 h and 10 days. The level of central alpha2-adrenoceptor antagonism and the drug concentration in blood and in the brain were measured after continuous infusion for 24 h and 10 days. In behavioural tests, atipamezole had no effect on spontaneous motor activity at any of the doses studied. However, after both acute administration and continuous 24-h infusion, atipamezole decreased exploratory behaviour in a staircase test, but no longer after 6 days of continuous infusion. Acute administration of atipamezole impaired performance in active avoidance learning tests causing a learned helplessness-like behaviour. When the training was started after 7 days of continuous infusion, atipamezole significantly improved active avoidance learning. There was a significant increase in the metabolite of noradrenaline (NA), 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4), after 24 h but not any longer after 10 days of continuous atipamezole infusion, although the extent of central alpha2-adrenoceptor antagonism was unchanged and the atipamezole concentration present in brain was even elevated at 10 days compared to levels after 24-h infusion. In conclusion, these results reveal that acute and subchronic atipamezole treatments have different and even opposite effects on behaviour in novel, stressful situations. After acute treatment, atipamezole potentiates reaction to novelty and stress, causing a decrease in exploratory activity and impairment in shock avoidance learning. After subchronic treatment, there was no longer any effect on exploratory behaviour and, in fact, there was an improvement in the learning of a mildly stressful active avoidance test. The changes in behaviour occurred in parallel with attenuation in the MHPG-SO4-increasing effect, thus the suppressed behaviour in the present test conditions after acute atipamezole injection is associated with a major increase in central NA release. The results support the role of alpha2-adrenoceptors and noradrenergic system in reactions both to novelty and stress and have possible implications in cognitive functions as well as in depression.

Three human and mouse genes encoding alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) have been cloned. The alpha2C-adrenoceptor is the most abundant alpha2-adrenoceptor subtype in the striatum and modulates metabolism of both dopamine and serotonin. To investigate the possible involvement of the alpha2C-adrenoceptor subtype in behaviours regulated by dopamine and serotonin, two strains of genetically-engineered mice were examined. One had a targeted inactivation of the alpha2C-adrenoceptor gene, and the other had tissue-specific over-expression of alpha2C-adrenoceptors. The locomotor activity of the mice was evaluated after stimulation with D-amphetamine, and the behavioural serotonin syndrome and head twitches were investigated after L-5-hydroxytryptophan treatment. In addition, the effects of D-amphetamine and L-5-hydroxytryptophan were studied after pretreatment with dexmedetomidine, a subtype-nonselective alpha2-adrenoceptor agonist. The lack of alpha2C-adrenoceptor expression increased and the over-expression of alpha2C-adrenoceptors decreased the response to D-amphetamine stimulation. The effect of alpha2C-adrenoceptor gene inactivation was more prominent in D-amphetamine-treated males than in females. Dexmedetomidine inhibited D-amphetamine-induced hyperlocomotion and the L-5-hydroxytryptophan-induced serotonin syndrome, but the inhibition was attenuated in mice lacking alpha2C-adrenoceptors. However, the head twitches induced by L-5-hydroxytryptophan were effectively inhibited by dexmedetomidine in all studied mice, which suggests that alpha2A-adrenoceptors mediate the inhibition of the head twitch response. The results lend further support to the proposed existence of functionally distinct alpha2-adrenoceptor subtypes that can serve as new and specific therapeutic targets in various neuropsychiatric diseases.

The effects of the alpha2-adrenoceptor drugs, medetomidine and atipamezole, on dopamine overflow evoked by low (6 Hz-10 s) and high (50 Hz-4 s) frequency electrical stimulation of the median forebrain bundle were studied in striatum of BALB/C mice anaesthetized with chloral hydrate with fast in vivo voltammetry techniques. The effects of these drugs on the basal concentrations of dopamine metabolites were also investigated by means of differential pulse voltammetry. Medetomidine dose dependently decreased dopamine overflow in nucleus accumbens in the dose range 5-100 microg/kg, s.c. This effect was seen only at low frequency stimulation and reached 85% at a dose of 100 microg/kg. Medetomidine also decreased the basal concentration of striatal homovanillic acid. This effect did not exceed 35%. Atipamezole antagonized the inhibitory effects of medetomidine on the dopamine overflow. but showed no effect itself. We suggest that alpha2-adrenoceptors in dopaminergic terminal fields in the mouse striatum are involved in the regulation of dopamine release at physiological stimulation frequencies.

In this study, the effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms, were compared with those of diazepam and propranolol. The rats were given highly intoxicating doses of ethanol for 4 days. After the intoxication period, rats were divided into four equal groups: a dexmedetomidine-treated group (30 micrograms/kg, sc), a diazepam-treated group (2 mg/kg, sc), a propranolol-treated group (5 mg/kg, sc), and a control group with no medication. Medication was given in the withdrawal phase-2, 8, 14, and 20 hr after the onset of the withdrawal symptoms. The severity of the ethanol withdrawal symptoms (rigidity, tremor, irritability, and hypoactivity) was observed up to 33 hr after the onset of the ethanol withdrawal symptoms. Both dexmedetomidine and diazepam significantly relieved tremor compared with the control group. Diazepam reduced irritability significantly, compared with the control group. When measured as the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability), dexmedetomidine and diazepam significantly relieved the ethanol withdrawal reaction. Propranolol attenuated tremor, but was inefficient against other withdrawal symptoms. Dexmedetomidine may thus represent a new effective drug in the treatment of the ethanol withdrawal syndrome.

The dose-response curves for a number of alpha-adrenergic drugs were investigated to estimate a possible role of the alpha 2/alpha 1 selectivity of these drugs on the incidence of cortical high voltage spindles (HVS), reflecting level of vigilance. The alpha 2 antagonists yohimbine (0.25-4 mg/kg) and idazoxan (0.5-4 mg/kg), but not atipamezole induced a biphasic effect on the incidence of HVS in rats. This effect of relatively small doses of yohimbine and idazoxan should be taken into consideration when using these drugs as alpha 2 antagonists in behavioral and neurophysiological tests. On the other hand the linearity of the dose-response curve for atipamezole (0.01-4 mg/kg) indicates that this drug is a good candidate for use in such tests.

The present study investigated whether an alpha 2-adrenoceptor antagonist (atipamezole) can influence hyperactivity induced by the systemic administration of scopolamine. In the water maze (WM) task, scopolamine (scop) 0.25 mg/kg treatment significantly increased swimming speed during the acquisition phase of this task. Atipamezole (ati) 30 micrograms/kg slightly reduced swimming speed both in saline- and in scop-treated rats. Ati 300 micrograms/kg slightly reduced swimming speed in saline-treated rats, and it prevented the scop-induced increase in swimming speed, because ati300-scop treated rats swam more slowly than the saline-saline group. In addition, ati 300 micrograms/kg reduced the total distance swum in scop-treated rats during a free swim trial (the platform was removed from the pool) performed 1 day after the acquisition phase of the WM test, even though it did not affect this parameter when administered alone. In the open arena task, which assessed the ambulation of rats when the pool was covered with a solid floor, scopolamine dose-dependently increased locomotor activity. The rats ambulated more when treated with scop 0.50 mg/kg compared to vehicle treatment, whereas the effect of scop 0.25 mg/kg treatment did not reach significance. In a test investigating the effects of ati 300 micrograms/kg and scop 0.50 mg/kg given singly or combined, the rats ambulated more during both ati 300 micrograms/kg and scop 0.50 mg/kg treatments given alone, but when combined, the rats ambulated less than during scop-saline treatment even though this was more than during control (saline-saline) treatment. These results indicate that the systemic administration of an alpha 2-antagonist can reduce hyperactivity induced by scopolamine.

The effects of levosimendan on cerebrovascular lesions and mortality were investigated in models of primary and secondary stroke. We aimed to determine whether the effects of levosimendan are comparable to and/or cumulative with those of valsartan, and to investigate whether levosimendan-induced vasodilation has a role in its effects on stroke. In a primary stroke Dahl/Rapp rat model, mortality rates were 70% and 5% for vehicle and levosimendan, respectively. Both stroke incidence (85% vs. 10%, P