24 results on '"Korpi, Esa R."'
Search Results
2. GABAB receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine.
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Miguel, Elena, Vekovischeva, Olga, Kuokkanen, Katja, Vesajoki, Marja, Paasikoski, Nelli, Kaskinoro, Janne, Myllymäki, Mikko, Lainiola, Mira, Janhunen, Sanna K., Hyytiä, Petri, Linden, Anni‐Maija, Korpi, Esa R., de Miguel, Elena, and Linden, Anni-Maija
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TREATMENT of drug addiction ,COCAINE ,ALCOHOL ,COMPULSIVE behavior ,BINDING site assay ,BIOCHEMISTRY ,RODENTS ,GABA agonists ,QUINONE ,ANIMAL behavior ,RESEARCH ,NEURONS ,ANIMAL experimentation ,HETEROCYCLIC compounds ,RESEARCH methodology ,NEUROPLASTICITY ,CELL receptors ,EVALUATION research ,MEDICAL cooperation ,GABA modulators ,PHENOMENOLOGY ,SELF medication ,RATS ,COMPARATIVE studies ,REWARD (Psychology) ,BACLOFEN ,IMPACT of Event Scale ,RESEARCH funding ,ETHANOL ,DOPAMINE uptake inhibitors ,CENTRAL nervous system depressants ,BRAIN stem ,MICE ,PHARMACODYNAMICS - Abstract
Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABAB receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction. [ABSTRACT FROM AUTHOR]
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- 2019
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3. Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA‐A Receptor δ Subunit Knockout Mice.
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Siivonen, Milo S., Miguel, Elena, Aaltio, Juho, Manner, Aino K., Vahermo, Mikko, Yli‐Kauhaluoma, Jari, Linden, Anni‐Maija, Aitta‐aho, Teemu, and Korpi, Esa R.
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OPIOIDS ,NEUROPSYCHOPHARMACOLOGY ,DOPAMINE ,NEURONS ,MORPHINE - Abstract
Extrasynaptic δ subunit‐containing γ‐aminobutyric acid type A receptors (δ‐GABAARs) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ‐GABAARs are functionally expressed in the ventral tegmental area (VTA), the cell body region of mesocorticolimbic dopamine (DA) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo, by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ‐GABAAR knockout mice (δ‐KO). It is not known whether δ‐GABAARs are important for the effects of other drugs, such as opioids (that also inhibit GABA neurons) and stimulants (that primarily elevate monoamine levels). Here, we used δ‐KO mice and conditioned place preference (CPP) test to study the rewarding effects of morphine (20 mg/kg), methamphetamine (1 mg/kg) and mephedrone (5 mg/kg). Morphine‐induced nociception was also assessed using tail‐flick and hot‐plate tests. We found that the δ‐KO mice failed to express morphine‐induced CPP, but that they were more sensitive to morphine‐induced analgesia in the tail‐flick test. In contrast, stimulant‐induced CPP in the δ‐KO mice was similar to that in the wild‐type controls. Thus, the conditioned rewarding effect by opioids, but not that of stimulants, was impaired in the absence of δ‐GABAARs. Further studies are warranted to assess the potential of δ‐GABAAR antagonists as possible targets for reducing morphine reward and potentiating morphine analgesia. [ABSTRACT FROM AUTHOR]
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- 2018
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4. Addiction-related interactions of pregabalin with morphine in mice and humans: reinforcing and inhibiting effects.
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Vashchinkina, Elena, Piippo, Ossi, Vekovischeva, Olga, Krupitsky, Evgeny, Ilyuk, Ruslan, Neznanov, Nikholay, Kazankov, Kirill, Zaplatkin, Igor, and Korpi, Esa R.
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MORPHINE abuse ,PREGABALIN ,REINFORCEMENT (Psychology) ,RESPONSE inhibition ,TRANQUILIZING drugs ,LABORATORY mice - Abstract
The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors.
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Korpi, Esa R., Linden, Anni‐Maija, Hytönen, Heidi R., Paasikoski, Nelli, Vashchinkina, Elena, Dudek, Mateusz, Herr, Deron R., and Hyytiä, Petri
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NALTREXONE , *OPIOID receptors , *G protein coupled receptors , *PEOPLE with alcoholism , *HEALTH , *THERAPEUTICS , *ALCOHOLISM , *ANIMAL experimentation , *BIOLOGICAL models , *BRAIN , *CELL receptors , *ETHANOL , *NARCOTIC antagonists , *RATS , *PHARMACODYNAMICS ,ALCOHOL drinking prevention - Abstract
Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7 days either as daily injections or continuous osmotic minipump-driven infusions to alcohol-preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [35 S]GTPγS autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to μ-opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of κ-opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant κ-opioid receptors. The findings support the as-needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists. [ABSTRACT FROM AUTHOR]
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- 2017
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6. Acute Effects of Ethanol on Glutamate Receptors.
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Möykkynen, Tommi and Korpi, Esa R.
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ETHANOL , *GLUTAMATE receptors , *HIPPOCAMPUS (Brain) , *AMYGDALOID body , *LONG-term potentiation - Abstract
Several studies have revealed that acute ethanol inhibits the function of glutamate receptors. Glutamate receptor-mediated synaptic plasticity, such as N-methyl- d-aspartate-dependent long-term potentiation, is also inhibited by ethanol. However, the inhibition seems to be restricted to certain brain areas such as the hippocampus, amygdala and striatum. Ethanol inhibition of glutamate receptors generally requires relatively high concentrations and may therefore explain consequences of severe ethanol intoxication such as impairment of motor performance and memory. Effects of ethanol on glutamate system of developing nervous system may have a role in causing foetal alcohol syndrome. Newly found regulatory proteins of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA receptors seem to affect ethanol inhibition thus opening new lines of research. [ABSTRACT FROM AUTHOR]
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- 2012
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7. Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice.
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Procaccini, Chiara, Aitta‐aho, Teemu, Jaako‐Movits, Külli, Zharkovsky, Alexander, Panhelainen, Anne, Sprengel, Rolf, Linden, Anni‐Maija, and Korpi, Esa R.
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DEVELOPMENTAL neurobiology ,HIPPOCAMPUS (Brain) ,HYPERKINESIA ,SCHIZOPHRENIA ,MENTAL depression ,CIRCADIAN rhythms ,LABORATORY mice - Abstract
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit-deficient (GluA1−/−) mice display novelty-induced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression/mania. We used c-Fos expression in GluA1−/− mice to identify brain regions responsible for novelty-induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c-Fos expression in many brain regions in both wild-type and knockout mice. Interestingly, the clearest genotype effect was observed in the hippocampus and its main input region, the entorhinal cortex, where the novelty-induced c-Fos expression was more strongly enhanced in GluA1−/− mice. Their novelty-induced hyperlocomotion partly depended on the activity of AMPA receptors, as it was diminished by the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide (NBQX) and unaffected by the AMPA receptor potentiator 2,3-dihydro-1,4-benzodioxin-6-yl-1-piperidinylmethanone (CX546). The hyperlocomotion of GluA1−/− mice was normalised to the level of wild-type mice within 5-6 h, after which their locomotion followed normal circadian rhythm and was not affected by acute or chronic treatments with the selective serotonin reuptake inhibitor escitalopram. We propose that hippocampal dysfunction, as evidenced by the excessive c-Fos response to novelty, is the major contributor to novelty-induced hyperlocomotion in GluA1−/− mice. Hippocampal dysfunction was also indicated by changes in proliferation and survival of adult-born dentate gyrus cells in the knockout mice. These results suggest focusing on the functions of hippocampal formation, such as novelty detection, when using the GluA1−/− mouse line as a model for neuropsychiatric and cognitive disorders. [ABSTRACT FROM AUTHOR]
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- 2011
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8. Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic α6β GABAA receptors.
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Saarelainen, Kati S., Ranna, Martin, Rabe, Holger, Sinkkonen, Saku T., Möykkynen, Tommi, Uusi-Oukari, Mikko, Linden, Anni-Maija, Lüddens, Hartmut, and Korpi, Esa R.
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GABA agonists ,TRANSGENIC mice ,HIPPOCAMPUS (Brain) ,GABA receptors ,NEURAL transmission - Abstract
The behavioral and functional significance of the extrasynaptic inhibitory GABA
A receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABAA receptor α6 subunit gene in the forebrain under the Thy-1.2 promoter (Thy1α6) mice ectopically expressing α6 subunits especially in the hippocampus to study how extrasynaptically enriched αβ(γ2)-type receptors alter animal behavior and receptor responses. In these mice extrasynaptic α6β receptors make up about 10% of the hippocampal GABAA receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA-site competitive agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; 3 mg/kg) induced remarkable anxiolytic-like response in the light : dark exploration and elevated plus-maze tests in Thy1α6 mice, while being almost inactive in wild-type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild-type mice. In hippocampal sections of Thy1α6 mice, the α6β receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [35 S]TBPS binding to the GABAA receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABAA receptors revealed that GABA was a partial agonist at α6β3 and α6β3δ receptors, but a full agonist at α6β3γ2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic αβ GABAA receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition. [ABSTRACT FROM AUTHOR]- Published
- 2008
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9. Methadone increases intracellular calcium in SH-SY5Y and SH-EP1-hα7 cells by activating neuronal nicotinic acetylcholine receptors.
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Pakkanen, Jukka S., Nousiainen, Heli, Yli-Kauhaluoma, Jari, Kylänlahti, Irene, Möykkynen, Tommi, Korpi, Esa R., Jian-Hong Peng, Lukas, Ronald J., Ahtee, Liisa, and Tuominen, Raimo K.
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OPIOID receptors ,DRUG receptors ,CELL receptors ,ACETYLCHOLINE ,NEUROTRANSMITTERS ,NEUROCHEMISTRY ,NEUROSCIENCES - Abstract
(–)-Methadone acts as an agonist at opioid receptors. Both (+)- and (–)-enantiomers of methadone have been suggested to be potent non-competitive antagonists of α3β4 neuronal nicotinic acetylcholine receptors (nAChRs). In the present study, we have examined interactions of methadone with nAChRs by using receptor binding assays, patch-clamp recording and calcium fluorometry imaging with SH-SY5Y cells naturally expressing α7 and α3* nAChR subtypes and SH-EP1-hα7 cells heterologously expressing human α7 nAChRs. Methadone potently inhibited binding of [
3 H]methyllycaconitine to α7 nAChRs and that of [3 H]epibatidine to α3* nAChRs. Methadone pretreatment induced up-regulation of epibatidine binding sites in SH-SY5Y cells. Using whole-cell patch-clamp recording, both isomers of methadone activated cation currents via mecamylamine-sensitive nAChRs in SH-SY5Y cells. Nicotine and both (+)- and (–)-methadone evoked increases in [Ca2+ ]i in both fluo-3AM loaded cell lines, and these effects were blocked by mecamylamine and by the α7 selective antagonist methyllycaconitine, suggesting effects of methadone as α7-nAChR agonist. Sensitivity of sustained nicotine and methadone effects to blockade by CdCl2 , ryanodine and xestospongin-c implicates voltage-operated Ca2+ channels and intracellular Ca2+ stores as downstream modulators of elevated [Ca2+ ]i . Collectively, our results suggest that methadone engages in complex and potentially pharmacologically significant interactions with nAChRs. [ABSTRACT FROM AUTHOR]- Published
- 2005
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10. Maturation of cultured hippocampal slices results in increased excitability in granule cells
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Lindroos, Markus M., Soini, Sanna L., Kukko-Lukjanov, Tiina-Kaisa, Korpi, Esa R., Lovinger, David, and Holopainen, Irma E.
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HIPPOCAMPUS (Brain) ,CELLS ,MATURATION (Psychology) ,AXONS - Abstract
Abstract: The preparation of hippocampal slices results in loss of input neurons to dentate granule cells, which leads to the reorganization of their axons, the mossy fibers, and alters their functional properties in long-term cultures, but its temporal aspects in the immature hippocampus are not known. In this study, we have focused on the early phase of this plastic reorganization process by analyzing granule cell function with field potential and whole cell recordings during the in vitro maturation of hippocampal slices (from 1 to 17 days in vitro, prepared from 6 to 7-day-old rats), and their morphology using extracellular biocytin labelling technique. Acute slices from postnatal 14–22-day-old rats were analyzed to detect any differences in the functional properties of granule cells in these two preparations. In field potential recordings, small synaptically-evoked responses were detected at 2 days in vitro, and their amplitude increased during the culture time. Whole cell voltage clamp recordings revealed intensive spontaneous excitatory postsynaptic currents, and the susceptibility to stimulus-evoked bursting increased with culture time. In acutely prepared slices, neither synaptically-evoked responses in field potential recordings nor any bursting in whole cell recordings were detected. The excitatory activity was under the inhibitory control of γ-aminobutyric acid type A receptor. Extracellularily applied biocytin labelled dentate granule cells, and revealed sprouting and aberrant targeting of mossy fibers in cultured slices. Our results suggest that reorganization of granule cell axons takes place during the early in vitro maturation of hippocampal slices, and contributes to their increased excitatory activity resembling that in the epileptic hippocampus. Cultured immature hippocampal slices could thus serve as an additional in vitro model to elucidate mechanisms of synaptic plasticity and cellular reactivity in response to external damage in the developing hippocampus. [Copyright &y& Elsevier]
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- 2005
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11. Behavioural correlates of an altered balance between synaptic and extrasynaptic GABAAergic inhibition in a mouse model.
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Sinkkonen, Saku T., Vekovischeva, Olga Y., Möykkynen, Tommi, Ogris, Waltraud, Sieghart, Werner, Wisden, William, and Korpi, Esa R.
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GABA ,LABORATORY mice ,PHARMACOLOGY ,FUROSEMIDE ,AUTORADIOGRAPHY ,SPASMS - Abstract
GABA
A receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1α6 mice with ectopic forebrain expression of GABAA receptorα6 subunits exhibit increased extrasynaptic GABAA receptor-mediated background conductance and reduced synaptic GABAA receptor currents in hippocampal CA1 neurons[W. Wisdenet al. (2002)Neuropharmacology43, 530–549]. Here we demonstrate that isolated CA1 neurons of these mice showed furosemide-sensitivity of GABA-evoked currents, confirming the functional expression ofα6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1α6 brain sections revealed pharmacological features that are unique forα6βγ2 andα6β receptors. The existence of atypicalα6β receptors was confirmed after completely eliminating GABAA receptors containingγ1,γ2,γ3 orδ subunits using serial immunoaffinity chromatography on subunit-specific GABAA receptor antibodies. Behaviourally, the Thy1α6 mice showed normal features with slightly enhanced startle reflex and struggle-escape behaviours. However, they were more sensitive to GABAA antagonists DMCM (shorter latency to writhing clonus) and picrotoxinin (shorter latency to generalized convulsions). Tiagabine, an antiepileptic GABA-uptake inhibitor that increases brain GABA levels, delayed picrotoxinin-induced convulsions at a low dose of 3.2 mg/kg in Thy1α6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1α6 mice. Altered balance between extrasynaptic and synaptic receptors thus affects seizure sensitivity to GABAergic convulsants. Importantly, the increased extrasynaptic inhibition, even when facilitated in the presence of tiagabine, was not able fully to counteract enhanced seizure induction by GABAA antagonists. [ABSTRACT FROM AUTHOR]- Published
- 2004
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12. Reduced Adrenal Activation in a Rat Line Selected for High Alcohol Sensitivity.
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Raatesalmi, Kristina, Virtanen, Antti, Sarviharju, Maija, Pelto-Huikko, Markku, and Korpi, Esa R.
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Background A rat line developed by selective breeding for high alcohol sensitivity has blunted corticosterone responses to alcohol and stress. In the present study, we determined possible differences in adrenal activation after alcohol and motor performance testing between the alcohol-sensitive alcohol-nontolerant and alcohol-insensitive alcohol-tolerant rats. Methods The animals received ethanol (2 g/kg, intraperitoneally), and 30 min later they were subjected to a motor function test (i.e., normal selection test used in the breeding of the lines); the control animals for both rat lines received no treatment and minimal handling. Blood corticosterone and ACTH levels at the single time point were determined by radioimmunoassay, and adrenal activation was determined by in situ hybridization of the immediate early gene c-fos, nor1, nurr1, and NGFI-B mRNA expression. Results The alcohol nontolerant rats had lower corticosterone but normal ACTH levels after ethanol and motor testing. Adrenal early gene expression of all of the genes studied was strongly induced by the treatment in both rat lines, but the inductions of c-fos, nor1, and nurr1 were significantly lower in the alcohol-sensitive animals. Acute treatment with a high dose of ACTH also induced less adrenal gene expression in the alcohol-sensitive animals. Conclusions The results suggest that the reduced adrenal activation is associated with high alcohol sensitivity in a genetic animal model, which is in agreement with the human findings of alcohol insensitivity during glucocorticoid treatment. [ABSTRACT FROM AUTHOR]
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- 2002
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13. Uncompetitive Antagonists of the N-Methyl-D-aspartate (NMDA) Receptors Alter the mRNA Expression of Proteins Associated with the NMDA Receptor Complex.
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Lindén, Anni-Maija, Väisänen, Jussi, Storvik, Markus, Lakso, Merja, Korpi, Esa R., Wong, Garry, and Castrén, Eero
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N-methyl-D-aspartate (NMDA) receptor function appears to be under complex control during physiological and pharmacological states. We have investigated the effects of acute administration of uncompetitive NMDA receptor antagonists on mRNA levels of NMDA receptor subunits and on molecules known to cluster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK-801) decreased mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal and parietal cortices, respectively. MK-801 increased mRNA levels of synapse-associated protein-90/postsynaptic density-95 (SAP90/PSD-95) and a γ-isoform of protein kinase C (PKCγ) in cortical regions. Synapse-associated protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK-801 or phencyclidine. NMDA receptor uncompetitive antagonists alter the expression of multiple receptor components and such events may ultimately play a role in adaptation or toxic responses. [ABSTRACT FROM AUTHOR]
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- 2001
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14. Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA(A) receptor beta3 subunit deletions.
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Holopainen, Irma E., Metsähonkala, E.-Liisa, Kokkonen, Hannaleena, Parkkola, Riitta K., Manner, Tuula E., Någren, Kjell, Korpi, Esa R., Holopainen, I E, Metsähonkala, E L, Kokkonen, H, Parkkola, R K, Manner, T E, Någren, K, and Korpi, E R
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- 2001
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15. Chronic ethanol treatment and GABAAreceptor α6 subunit gene expression: a study using α6 subunit-deficient mice.
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Vekovischeva, Olga Y., Uusi-Oukari, Mikko, and Korpi, Esa R.
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PHYSIOLOGICAL effects of alcohol ,GABA ,RAT physiology ,ALCOHOLISM ,BIOCHEMICAL mechanism of action ,GENETICS - Abstract
Chronic alcohol administration increases the expression of cerebellum-specific GABA[sub A] receptor alpha 6 subunit mRNA, protein and selective autoradiographical finger print on rat and mouse brain sections. We have tested whether the alpha 6 gene is activated by chronic alcohol administration (daily p.o. injection of 2 g/kg during the first 3 days and 2.5 g/kg during the next 17 days) that produced tolerance in the rotarod test to motor impairment by acute challenge of ethanol (2 g/kg, i.p.). We utilized a mouse line engineered to express E. coli beta-galactosidase enzyme and an unfunctional truncated alpha 6 subunit under the control of the alpha 6 gene promoter. Chronic ethanol treatment failed to alter the cerebellar beta-galactosidase activity when compared with no treatment and isocaloric sucrose treatment in groups of alpha 6 subunit-deficient mice. The results suggest that tolerance to motor-impairing effects of ethanol can be achieved in the absence of alpha 6 subunit-containing GABA[sub A] receptors, but that the reported upregulation of alpha 6 gene transcription by ethanol treatment requires functional alpha 6 subunits. [ABSTRACT FROM AUTHOR]
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- 2000
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16. Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from α6-subunit-deficient mice.
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Korpi, Esa R., Koikkalainen, Paula, Vekovischeva, Olga Y., Mäkelä, Riikka, Kleinz, Raymonde, Uusi‐Oukari, Mikko, and Wisden, William
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GABA receptors , *ATAXIA , *BENZODIAZEPINES , *MICE physiology , *PHYSIOLOGY - Abstract
Abstract Benzodiazepine- and alcohol-induced ataxias in rodents have been proposed to be affected by the γ-aminobutyric acid type A (GABAA) receptor α6 subunit, which contributes to receptors specifically expressed in cerebellar granule cells. We have studied an α6 –/– mouse line for motor performance and drug sensitivity. These mice, as a result of a specific genetic lesion, carry a precise impairment at their Golgi-granule cell synapses. On motor performance tests (rotarod, horizontal wire, pole descending, staircase and swimming tests) there were no robust baseline differences in motor function or motor learning between α6 –/– and α6 +/+ mice. On the rotarod test, however, the mutant mice were significantly more impaired by diazepam (5–20 mg/kg, i.p.), when compared with α6 +/+ control and background C57BL/6J and 129/SvJ mouse lines. Ethanol (2.0–2.5 g/kg, i.p.) produced similar impairment in the α6 –/– and α6 +/+ mice. Diazepam-induced ataxia in α6 –/– mice could be reversed by the benzodiazepine site antagonist flumazenil, indicating the involvement of the remaining α1β2/3γ2 GABAA receptors of the granule cells. The level of activity in this synapse is crucial in regulating the execution of motor tasks. We conclude that GABAA receptor α6 subunit-dependent actions in the cerebellar cortex can be compensated by other receptor subtypes; but if not for the α6 subunit, patients on benzodiazepine medication would suffer considerably from ataxic side-effects. [ABSTRACT FROM AUTHOR]
- Published
- 1999
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17. Effects of Ethanol on Recombinant Rat GABAA Receptors: [35S] t-Butylbicyclophosphorothionate ([35S]TBPS) Binding Study.
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Korpi, Esa R., Herb, A., and Lüddens, H.
- Abstract
To determine the roles of the alternatively spliced short and long forms of the γ2 subunit in the effect of ethanol on the GABA
A receptor function, picrotoxin-sensitive [35 S] t-butylbicyclophosphorothionate ([35 S]TBPS) binding was studied in recombinant rat α1β2γ2 and α6β2γ2 receptors expressed in human embryonic kidney 293 cells. Ethanol (10-500 mM) in the absence of added GABA had only minor effects on [35 S]TBPS binding irrespective of the γ2 splice variant, its effects being greater in α6β2γ2 than in α1β2γ2 receptors. Ethanol (100 mM) decreased the binding in all four subunit combinations at various concentrations of GABA, again an effect independent of the γ2 variant. The two γ2 variants had different effects on GABA modulation of the binding, with the long γ2 variant decreasing the efficiency of GABA inhibition in α6β2γ2 receptors and enhancing the biphasic GABA stimulation and inhibition in α1β2γ2 receptors. The findings confirm the importance of the α subunits in the allosteric interactions between the convulsant binding site and other effector sites, which can be modified only to a minor extent by the type of the γ2 splice variant. [ABSTRACT FROM AUTHOR]- Published
- 1995
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18. Furosemide interactions with brain GABAA receptors.
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Korpi, Esa R and Lüddens, Hartmut
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- 1997
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19. Rapid Formation of Reduced Haloperidol in Guinea Pigs Following Haloperidol Administration.
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Korpi, Esa R., Costakos, Dennis T., and Wyatt, Richard Jed
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- 1985
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20. Phenotypic and Genotypic Analysis of Rats with Cerebellar GABAA Receptors Composed from Mutant and Wild-Type α6 Subunits.
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Mäkelä, Riikka, Wong, Garry, Lüddens, Hartmut, and Korpi, Esa R.
- Published
- 1995
- Full Text
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21. A Liquid Chromatographic Assay for 5-Hydroxytryptophan, Serotonin and 5-Hydroxyindoleacetic Acid in Human Body Fluids.
- Author
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Petruccelli, Bruno, Bakris, George, Miller, Tom, Korpi, Esa R., and Linnoila, Markku
- Published
- 1982
- Full Text
- View/download PDF
22. GABA B receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine.
- Author
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de Miguel E, Vekovischeva O, Kuokkanen K, Vesajoki M, Paasikoski N, Kaskinoro J, Myllymäki M, Lainiola M, Janhunen SK, Hyytiä P, Linden AM, and Korpi ER
- Subjects
- Allosteric Regulation, Animals, Baclofen pharmacology, Behavior, Animal drug effects, Benzofurans pharmacology, CHO Cells, Cricetulus, GABA-B Receptor Agonists pharmacology, Humans, Mice, Quinazolinones pharmacology, Rats, Receptors, Glutamate drug effects, Receptors, Glutamate metabolism, Reward, Self Administration, Ventral Tegmental Area cytology, Ventral Tegmental Area drug effects, Central Nervous System Depressants pharmacology, Cocaine pharmacology, Dopamine Uptake Inhibitors pharmacology, Dopaminergic Neurons drug effects, Ethanol pharmacology, GABA Modulators pharmacology, Neuronal Plasticity drug effects, Receptors, GABA-B drug effects
- Abstract
Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABA
B receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction., (© 2018 Society for the Study of Addiction.)- Published
- 2019
- Full Text
- View/download PDF
23. Behavioural correlates of an altered balance between synaptic and extrasynaptic GABAAergic inhibition in a mouse model.
- Author
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Sinkkonen ST, Vekovischeva OY, Möykkynen T, Ogris W, Sieghart W, Wisden W, and Korpi ER
- Subjects
- Animals, Dose-Response Relationship, Drug, Female, Hippocampus metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Neural Inhibition drug effects, Nipecotic Acids metabolism, Nipecotic Acids pharmacology, Protein Binding drug effects, Protein Binding physiology, Receptors, GABA-A genetics, Seizures chemically induced, Seizures genetics, Synapses drug effects, Synapses genetics, Tiagabine, gamma-Aminobutyric Acid metabolism, gamma-Aminobutyric Acid pharmacology, Neural Inhibition physiology, Receptors, GABA-A metabolism, Reflex, Startle physiology, Seizures metabolism, Synapses metabolism
- Abstract
GABAA receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1alpha6 mice with ectopic forebrain expression of GABAA receptor alpha6 subunits exhibit increased extrasynaptic GABAA receptor-mediated background conductance and reduced synaptic GABAA receptor currents in hippocampal CA1 neurons [W. Wisden et al. (2002) Neuropharmacology 43, 530-549]. Here we demonstrate that isolated CA1 neurons of these mice showed furosemide-sensitivity of GABA-evoked currents, confirming the functional expression of alpha6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1alpha6 brain sections revealed pharmacological features that are unique for alpha6betagamma2 and alpha6beta receptors. The existence of atypical alpha6beta receptors was confirmed after completely eliminating GABAA receptors containing gamma1, gamma2, gamma3 or delta subunits using serial immunoaffinity chromatography on subunit-specific GABAA receptor antibodies. Behaviourally, the Thy1alpha6 mice showed normal features with slightly enhanced startle reflex and struggle-escape behaviours. However, they were more sensitive to GABAA antagonists DMCM (shorter latency to writhing clonus) and picrotoxinin (shorter latency to generalized convulsions). Tiagabine, an antiepileptic GABA-uptake inhibitor that increases brain GABA levels, delayed picrotoxinin-induced convulsions at a low dose of 3.2 mg/kg in Thy1alpha6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1alpha6 mice. Altered balance between extrasynaptic and synaptic receptors thus affects seizure sensitivity to GABAergic convulsants. Importantly, the increased extrasynaptic inhibition, even when facilitated in the presence of tiagabine, was not able fully to counteract enhanced seizure induction by GABAA antagonists.
- Published
- 2004
- Full Text
- View/download PDF
24. Selective delta-opioid receptor antagonist N,N(CH3)2-Dmt-Tic-OH does not reduce ethanol intake in alcohol-preferring AA rats.
- Author
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Ingman K, Salvadori S, Lazarus L, Korpi ER, and Honkanen A
- Subjects
- Animals, Behavior, Animal physiology, Brain drug effects, Brain metabolism, Dipeptides administration & dosage, Drug Administration Schedule, Enkephalin, D-Penicillamine (2,5)- metabolism, Enkephalin, D-Penicillamine (2,5)- therapeutic use, Ethanol administration & dosage, Locomotion drug effects, Male, Naltrexone therapeutic use, Narcotic Antagonists administration & dosage, Rats, Alcoholism rehabilitation, Choice Behavior, Dipeptides pharmacology, Dipeptides therapeutic use, Ethanol adverse effects, Narcotic Antagonists pharmacology, Narcotic Antagonists therapeutic use, Receptors, Opioid, delta antagonists & inhibitors, Tetrahydroisoquinolines
- Abstract
We studied the effect of a novel delta-opioid receptor antagonist N,N(CH(3))(2)Dmt-Tic-OH (Me(2)-Dmt-Tic-OH) on voluntary ethanol intake in an alcohol-preferring AA (Alko, Alcohol) rat line using a 4-hour limited access paradigm. Acute injections of Me(2)-Dmt-Tic-OH (10 and 30 mg/kg, i.p.) did not reduce 1-hour or 4-hour ethanol intake. Subtype non-selective opioid receptor antagonist naltrexone [0.1 and 0.3 mg/kg, subcutaneously (s.c.)] significantly reduced 1-hour ethanol drinking but had no effect on 4-hour ethanol consumption. Locomotor stimulation induced by the delta-opioid receptor agonist Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; 15 microg, intracerebroventricularly) was significantly attenuated by Me(2)-Dmt-Tic-OH (10 and 30 mg/kg, i.p.), which confirmed its efficacy as a delta-opioid receptor antagonist in rat brain. Our results support the idea that delta-opioid receptors do not mediate alcohol reward in AA rats.
- Published
- 2003
- Full Text
- View/download PDF
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