65 results on '"Korpi, Esa R."'
Search Results
2. Finnish neuroscience from past to present.
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Korpi, Esa R., Lindholm, Dan, Panula, Pertti, Tienari, Pentti J., and Haltia, Matti
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APOLIPOPROTEIN E4 , *NEUROSCIENCES , *APOLIPOPROTEIN E , *NEUROLOGICAL disorders , *SOMNOLOGY , *FETAL diseases , *SUBSTANCE-induced disorders - Published
- 2020
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3. S02-3PERSISTENT NEUROPLASTICITY IN VTA DA NEURONS INDUCED BY ALCOHOL AND GABA DRUGS.
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Korpi, Esa R
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BRAIN stem , *CONFERENCES & conventions , *ETHANOL , *NEURONS , *NEUROPLASTICITY , *GABA agents - Published
- 2017
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4. 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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5. 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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6. Evidence for a role of inhibition of orexinergic neurons in the anxiolytic and sedative effects of diazepam: A c-Fos study
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Panhelainen, Anne E. and Korpi, Esa R.
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TRANQUILIZING drugs , *SEDATIVES -- Overdose , *HYPNOTISM , *DIAZEPAM , *IMMUNOHISTOCHEMISTRY , *ANXIETY , *LABORATORY mice - Abstract
Abstract: The classical benzodiazepine diazepam (DZ) induces anxiolysis at low doses and sedation and hypnosis at higher doses. Different brain areas and neuronal populations most likely mediate these different behavioral effects. We used c-Fos immunohistochemistry as an indirect way to study neuronal activation or inhibition induced by DZ at anxiolytic and sedative doses (0.5 and 5mg/kg, respectively) in various brain areas involved in anxiety, arousal, sedation and addiction in C57BL/6J mice. We also focused on the two neuronal populations, orexinergic and dopaminergic neuronal populations, with the help of double-immunohistochemistry using c-Fos and orexin-A antibodies and c-Fos and tyrosine hydroxylase antibodies. We found that different brain areas of unhabituated mice reacted differently to the mild stress induced by vehicle injection. Also the response to anxiolytic or sedative doses of DZ differed between the areas, suggesting that distinct brain areas mediate the behavioral effects of low and high DZ doses. Our findings propose a role for inhibition of orexin neurons in the anxiolytic and sleep-promoting effects of DZ. In addition, the activation of central amygdala neurons by DZ treatment was associated with anxiolytic and sedative effects. On the other hand, the ventral hippocampus, basolateral amygdala, ventral tegmental area and prefrontal cortex were sensitive even to the mild injection stress, but not to the anxiolytic dose of DZ. [Copyright &y& Elsevier]
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- 2012
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7. Does ethanol act preferentially via selected brain GABAA receptor subtypes? the current evidence is ambiguous
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Korpi, Esa R., Debus, Fabian, Linden, Anni-Maija, Malécot, Cécile, Leppä, Elli, Vekovischeva, Olga, Rabe, Holger, Böhme, Ingo, Aller, M. Isabel, Wisden, William, and Lüddens, Hartmut
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GABA , *ALCOHOL , *AUDITORY pathways , *BENZODIAZEPINES - Abstract
Abstract: In rodent models, γ-aminobutyric acid A (GABAA) receptors with the α6 and δ subunits, expressed in the cerebellar and cochlear nucleus granule cells, have been linked to ethanol sensitivity and voluntary ethanol drinking. Here, we review the findings. When considering both in vivo contributions and data on cloned receptors, the evidence for direct participation of the α6-containing receptors to increased ethanol sensitivity is poor. The α6 subunit-knockout mouse lines do not have any changed sensitivity to ethanol, although these mice do display increased benzodiazepine sensitivity. However, in general the compensations occurring in knockout mice (regardless of which particular gene is knocked out) tend to fog interpretations of drug actions at the systems level. For example, the α6 knockout mice have increased TASK-1 channel expression in their cerebellar granule cells, which could influence sensitivity to ethanol in the opposite direction to that obtained with the α6 knockouts. Indeed, TASK-1 knockout mice are more impaired than wild types in motor skills when given ethanol; this might explain why GABAA receptor α6 knockout mice have unchanged ethanol sensitivities. As an alternative to studying knockout mice, we examined the claimed δ subunit-dependent/γ2 subunit-independent ethanol/[3H]Ro 15-4513 binding sites on GABAA receptors. We looked at [3H]Ro 15-4513 binding in HEK 293 cell membrane homogenates containing rat recombinant α6/4β3δ receptors and in mouse brain sections. Specific high-affinity [3H]Ro 15-4513 binding could not be detected under any conditions to the recombinant receptors or to the cerebellar sections of γ2(F77I) knockin mice, nor was this binding to brain sections of wild-type C57BL/6 inhibited by 1–100mM ethanol. Since ethanol may act on many receptor and channel protein targets in neuronal membranes, we consider the α6 (and α4) subunit-containing GABAA receptors unlikely to be directly responsible for any major part of ethanol''s actions. Therefore, we finish the review by discussing more generally alcohol and GABAA receptors and by suggesting potential future directions for this research. [Copyright &y& Elsevier]
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- 2007
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8. Alcohol drinking of alcohol-preferring AA rats is differentially affected by clozapine and olanzapine
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Ingman, Kimmo and Korpi, Esa R.
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ALCOHOL , *CLOZAPINE , *OLANZAPINE , *ANTIDEPRESSANTS - Abstract
Abstract: Clinical evidence suggests that atypical antipsychotic drugs might reduce alcohol drinking and help to maintain abstinence. This study aimed to compare the effects of two widely used atypical antipsychotic drugs clozapine and olanzapine on alcohol intake in alcohol-preferring AA (Alko, Alcohol) rats that were taught to drink 10% alcohol in a 4 h limited access paradigm. Effects of acute clozapine (0, 0.3, 1.0 and 5.0 mg/kg) and olanzapine (0, 0.1, 0.5 and 1.25 mg/kg) treatments on the limited access alcohol drinking were studied. In repeated treatment experiment, clozapine (1.0 mg/kg) or olanzapine (0.5 mg/kg) was administered once daily, before limited access alcohol drinking session, over 5 successive days. To reveal any effect of the drugs selective for alcohol drinking, alcohol was exchanged with 0.1% saccharin solution for the 4 h limited access, and acute treatments were repeated. Effects of the drugs on ambulatory locomotor activity were tested with doses that were used in the acute experiments. Acute clozapine treatment had no effect on either alcohol or saccharin drinking, but olanzapine significantly reduced 4 h alcohol drinking. Repeated olanzapine treatment significantly reduced 4 h alcohol drinking when compared with vehicle or clozapine, but a tolerance developed to this effect. Repeated clozapine treatment produced no significant effect compared with vehicle. Both drugs significantly reduced locomotor activity. In conclusion, the atypical antipsychotic olanzapine non-selectively reduced alcohol drinking, while clozapine failed to do so, even if both were administered at pharmacologically effective doses. [Copyright &y& Elsevier]
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- 2006
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9. GABAA receptor subtypes as targets for neuropsychiatric drug development
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Korpi, Esa R. and Sinkkonen, Saku T.
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GABA , *ALCOHOL drinking , *DRUG development , *GENETIC polymorphisms - Abstract
Abstract: The main inhibitory neurotransmitter system in the brain, the γ-aminobutyric acid (GABA) system, is the target for many clinically used drugs to treat, for example, anxiety disorders and epilepsy and to induce sedation and anesthesia. These drugs facilitate the function of pentameric A-type GABA (GABAA) receptors that are extremely widespread in the brain and composed from the repertoire of 19 subunit variants. Modern genetic studies have found associations of various subunit gene polymorphisms with neuropsychiatric disorders, including alcoholism, schizophrenia, anxiety, and bipolar affective disorder, but these studies are still at their early phase because they still have failed to lead to validated drug development targets. Recent neurobiological studies on new animal models and receptor subunit mutations have revealed novel aspects of the GABAA receptors, which might allow selective targeting of the drug action in receptor subtype-selective fashion, either on the synaptic or extrasynaptic receptor populations. More precisely, the greatest advances have occurred in the clarification of the molecular and behavioral mechanisms of action of the GABAA receptor agonists already in the clinical use, such as benzodiazepines and anesthetics, rather than in the introduction of novel compounds to clinical practice. It is likely that these new developments will help to overcome the present problems of the chronic treatment with nonselective GABAA agonists, that is, the development of tolerance and dependence, and to focus the drug action on the neurobiologically and neuropathologically relevant substrates. [Copyright &y& Elsevier]
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- 2006
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10. GABAA receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines.
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Chandra, Dev, Korpi, Esa R., Miralles, Celia P., De Blas, Angel L., and Homanics, Gregg E.
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GABA , *BRAIN , *ANXIETY , *LABORATORY mice , *ANIMAL behavior , *HYPNOTICS , *BENZODIAZEPINES , *PHARMACODYNAMICS - Abstract
Background: Gamma-aminobutyric acid type A receptors (GABAA-Rs) are the major inhibitory receptors in the mammalian brain and are modulated by a number of sedative/hypnotic drugs including benzodiazepines and anesthetics. The significance of specific GABAA-Rs subunits with respect to behavior and in vivo drug responses is incompletely understood. The γ2 subunit is highly expressed throughout the brain. Global γ2 knockout mice are insensitive to the hypnotic effects of diazepam and die perinatally. Heterozygous γ2 global knockout mice are viable and have increased anxiety-like behaviors. To further investigate the role of the γ2 subunit in behavior and whole animal drug action, we used gene targeting to create a novel mouse line with attenuated γ2 expression, i.e., γ2 knockdown mice. Results: Knockdown mice were created by inserting a neomycin resistance cassette into intron 8 of the γ2 gene. Knockdown mice, on average, showed a 65% reduction of γ2 subunit mRNA compared to controls; however γ2 gene expression was highly variable in these mice, ranging from 10-95% of normal. Immunohistochemical studies demonstrated that γ2 protein levels were also variably reduced. Pharmacological studies using autoradiography on frozen brain sections demonstrated that binding of the benzodiazepine site ligand Ro15-4513 was decreased in mutant mice compared to controls. Behaviorally, knockdown mice displayed enhanced anxiety-like behaviors on the elevated plus maze and forced novelty exploration tests. Surprisingly, mutant mice had an unaltered response to hypnotic doses of the benzodiazepine site ligands diazepam, midazolam and zolpidem as well as ethanol and pentobarbital. Lastly, we demonstrated that the γ2 knockdown mouse line can be used to create γ2 global knockout mice by crossing to a general deleter cre-expressing mouse line. Conclusion: We conclude that: 1) insertion of a neomycin resistance gene into intron 8 of the γ2 gene variably reduced the amount of γ2, and that 2) attenuated expression of γ2 increased anxiety-like behaviors but did not lead to differences in the hypnotic response to benzodiazepine site ligands. This suggests that reduced synaptic inhibition can lead to a phenotype of increased anxiety-like behavior. In contrast, normal drug effects can be maintained despite a dramatic reduction in GABAA-R targets. [ABSTRACT FROM AUTHOR]
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- 2005
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11. Drug interactions at GABAA receptors
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Korpi, Esa R., Gründer, Gerhard, and Lüddens, Hartmut
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GABA receptors , *DRUG interactions - Abstract
Neurotransmitter receptor systems have been the focus of intensive pharmacological research for more than 20 years for basic and applied scientific reasons, but only recently has there been a better understanding of their key features. One of these systems includes the type A receptor for the γ-aminobutyric acid (GABA), which forms an integral anion channel from a pentameric subunit assembly and mediates most of the fast inhibitory neurotransmission in the adult vertebrate central nervous system. Up to now, depending on the definition, 16–19 mammalian subunits have been cloned and localized on different genes. Their assembly into proteins in a poorly defined stoichiometry forms the basis of functional and pharmacological GABAA receptor diversity, i.e. the receptor subtypes. The latter has been well documented in autoradiographic studies using ligands that label some of the receptors’ various binding sites, corroborated by recombinant expression studies using the same tools. Significantly less heterogeneity has been found at the physiological level in native receptors, where the subunit combinations have been difficult to dissect.This review focuses on the characteristics, use and usefulness of various ligands and their binding sites to probe GABAA receptor properties and to gain insight into the biological function from fish to man and into evolutionary conserved GABAA receptor heterogeneity. We also summarize the properties of the novel mouse models created for the study of various brain functions and review the state-of-the-art imaging of brain GABAA receptors in various human neuropsychiatric conditions.The data indicate that the present ligands are only partly satisfactory tools and further ligands with subtype-selective properties are needed for imaging purposes and for confirming the behavioral and functional results of the studies presently carried out in gene-targeted mice with other species, including man. [Copyright &y& Elsevier]
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- 2002
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12. 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]
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- 1999
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13. Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor.
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Korpi, Esa R. and Kleingoor, Claudia
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RATS - Abstract
Reports that the alpha6 gene of alcohol-non-tolerant (ANT) rats is expressed at wild-type levels but carries a point mutation generating an arginine-to-glutamine substitution at position 100. Suggestion that cerebellar motor control may be a distinct behavioral correlate of the alpha6-subunit-containing GABAA (gamma-aminobutyric acid) receptor subtype; Mutation in the alpha6 subunit of ANT rats; Analysis of the alpha6 subunit gene in ANT and control rats.
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- 1993
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14. Multiple actions of fenamates and other nonsteroidal anti-inflammatory drugs on GABAA receptors.
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Mansikkamäki, Salla, Sinkkonen, Saku T., Korpi, Esa R., and Lüddens, Hartmut
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NONSTEROIDAL anti-inflammatory agents , *GABA receptors , *TARGETED drug delivery , *PICROTOXININ , *BINDING sites - Abstract
The nonsteroidal anti-inflammatory drug (NSAID) niflumic acid, a fenamate in structure, has many molecular targets, one of them being specific subtypes of the main inhibitory ligand-gated anion channel, the GABA A receptor. Here, we report on the effects of other fenamates and other classes of NSAIDs on brain picrotoxinin-sensitive GABA A receptors, using an autoradiographic assay with [35S]TBPS as a ligand on mouse brain sections. We found that the other fenamates studied (flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid) affected the autoradiographic signal at low micromolar concentrations in a facilitatory-like allosteric fashion, i.e., without having affinity to the [35S]TBPS binding site. Unlike niflumic acid that shows clear preference for inhibiting cerebellar granule cell layer GABA A receptors, the other fenamates showed little brain regional selectivity, indicating that their actions are not receptor-subtype selective. Of the non-fenamate NSAIDs studied at 100 μM concentration, diclofenac induced the greatest inhibition of the binding, which is not surprising as it has close structural similarity with the potent fenamate meclofenamic acid. Using two-electrode voltage-clamp assays on Xenopus oocytes, the effect of niflumic acid was found to be dependent on the β subunit variant and the presence of γ2 subunit in rat recombinant α1β and α1βγ2 GABA A receptors, with the β1 allowing the niflumic acid inhibition and β3 the stimulation of the receptor-mediated currents. In summary, the fenamate NSAIDs constitute an interesting class of compounds that could be used for development of potent GABA A receptor allosteric agonists with other targets to moderate inflammation, pain and associated anxiety/depression. [ABSTRACT FROM AUTHOR]
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- 2019
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15. Effects of acute lysergic acid diethylamide on intermittent ethanol and sucrose drinking and intracranial self-stimulation in C57BL/6 mice.
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Elsilä, Lauri V, Harkki, Juliana, Enberg, Emma, Martti, Alvar, Linden, Anni-Maija, and Korpi, Esa R
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LSD (Drug) , *BEVERAGES , *LABORATORY mice , *ETHANOL , *SUCROSE , *DRINKING (Physiology) , *NEUROBEHAVIORAL disorders - Abstract
Background: Psychedelics, like lysergic acid diethylamide (LSD), are again being studied as potential therapies for many neuropsychiatric disorders, including addictions. At the same time, the acute effects of psychedelics on rewarding behaviours have been scarcely studied. Aims: The current study aimed to clarify if LSD decreases binge-like ethanol drinking in mice, and whether the observed acute effects on ethanol consumption are generalizable to a natural reinforcer, sucrose, and if the effects resulted from aversive or reward-attenuating effects caused by LSD. Methods: The effects of acute LSD were examined using 2-bottle choice intermittent ethanol (20%) and sucrose drinking (10%), discrete-trial current-intensity threshold method of intracranial self-stimulation and short-term feeding behaviour assay in C57BL/6 male mice. Results: The results showed that acute 0.1 mg/kg, but not 0.05 mg/kg, dose (i.p.) of LSD reduced 2-h intermittent ethanol drinking transiently without any prolonged effects. No effects were seen in intermittent 2-h sucrose drinking. The tested LSD doses had neither effect on the intracranial self-stimulation current-intensity thresholds, nor did LSD affect the threshold-lowering, or rewarding, effects of simultaneous amphetamine treatment. Furthermore, LSD had small, acute diminishing effects on 2-h food and water intake. Conclusions: Based on these results, LSD decreases binge-like ethanol drinking in mice, but only acutely. This effect is not likely to stem from reward-attenuating effects but could be in part due to reduced consummatory behaviour. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission.
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Maksimovic, Milica, Aitta-aho, Teemu, and Korpi, Esa R.
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HIPPOCAMPUS (Brain) , *GENE expression , *CHRONIC disease treatment , *NEUROBEHAVIORAL disorders , *TARGETED drug delivery , *EXCITATORY amino acid agents , *LABORATORY mice - Abstract
Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. Gria1 −/ − mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood-stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M., Vekovischeva, O.Y., Aitta-Aho, T., Korpi, E.R., 2014. Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. PloS One. 9, e100188). Here, we complement our study by treating these mice chronically with perampanel, a novel non-competitive antagonist of AMPA receptors, for 4 weeks at the dose of 60 mg/kg diet, and found reduced locomotor hyperactivity in the Gria1 − / − animals, while not affecting the wild-type littermates. To study the cellular mechanism by which chronic treatments with glutamate-modulating mood-stabilizing drugs alleviate this hyperactivity, we used the immediate early gene c-Fos protein expression as a marker of neuronal activity in the brain. Chronic lithium, valproate and topiramate blunted the c-Fos expression especially in the dorsal hippocampus of the Gria1 − / − mice, with all of them reducing the number of c-Fos-positive cells in the CA3 region and valproate and topiramate also in the dentate gyrus (DG). Lamotrigine and perampanel treatments had the same effect in the all CA1, CA3 and DG subfields of the dorsal hippocampus of Gria1−/− mice. The results suggest that abnormal (hippocampal) glutamatergic transmission underlies the hyperactive phenotype of the Gria1−/− mice in a novel environment, and based on the efficacies of the present chronic drug treatments, this mouse model may serve as a predictive tool for studying novel mood-stabilisers. [ABSTRACT FROM AUTHOR]
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- 2014
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17. Activity of BKCa Channel Is Modulated by Membrane Cholesterol Content and Association with Na+/K+-ATPase in Human Melanoma IGR39 Cells.
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Tajima, Nobuyoshi, Itokazu, Yutaka, Korpi, Esa R., Somerharju, Pentti, and Käkelä, Reijo
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MELANOMA , *CELL proliferation , *CELL growth , *CELL division , *ISOPENTENOIDS , *NEUROENDOCRINE tumors , *ADENOSINE triphosphatase , *CHOLESTEROL - Abstract
Interaction of large conductance Ca2+- and voltage-activated K+ (BKCa) channels with Na+/K+-ATPase, caveolin-1, and cholesterol was studied in human melanoma IGR39 cells. Functional BKCa channels were enriched in caveolin-rich and detergent-resistant membranes, i.e. rafts, and blocking of the channels by a specific BKCa blocker paxilline reduced proliferation of the cells. Disruption of rafts by selective depletion of cholesterol released BKCa channels from these domains with a consequent increase in their activity. Consistently, cholesterol enrichment of the cells increased the proportion of BKCa channels in rafts and decreased their activity. Immunocytochemical analysis showed that BKCa channels co-localize with Na+/K+-ATPase in a cholesterol-dependent manner, thus suggesting their co-presence in rafts. Supporting this, ouabain, a specific blocker of Na+/K+-ATPase, inhibited BKCa whole-cell current markedly in control cells but not in cholesterol-depleted ones. This inhibition required the presence of external Na+. Collectively, these data indicate that the presence of Na+/K+-ATPase in rafts is essential for efficient functioning of BKCa channels, presumably because the pump maintains a low intracellular Na+ proximal to the BKCa channel. In conclusion, cholesterol could play an important role in cellular ion homeostasis and thus modulate many cellular functions and cell proliferation. [ABSTRACT FROM AUTHOR]
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- 2011
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18. Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons after a Single Dose of Benzodiazepine Agonists.
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Heikkinen, Anne E., Möykkynen, Tommi P., and Korpi, Esa R.
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DOPAMINERGIC neurons , *BENZODIAZEPINE agonists , *MORPHINE , *NEUROTRANSMITTERS , *DOPAMINERGIC mechanisms , *FLUMAZENIL , *NEUROPSYCHOPHARMACOLOGY - Abstract
Initial effects of drugs of abuse seem to converge on the mesolimbic dopamine pathway originating from the ventral tegmental area (VTA). Even after a single dose, many drugs of abuse are able to modulate the glutamatergic transmission activating the VTA dopamine neurons, which may represent a critical early stage in the development of addiction. Ligands acting on the benzodiazepine site of the inhibitory γ-aminobutyric acid type A (GABAA) receptors are known to be rewarding in animal models and have abuse liability in humans, but notably little evidence exists on the involvement of the mesolimbic dopamine system in their effects. Here we report that single in vivo doses of benzodiazepine-site agonists, similar to morphine and ethanol, induce a modulation in the glutamatergic transmission of VTA dopamine neurons. This is seen 24 h later as an increase in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory currents using whole-cell patch-clamp configuration in mouse VTA slices. The effect was due to increased frequency of spontaneous miniature AMPA receptor-mediated currents. It lasted at least 3 days after the injection of diazepam, and was prevented by coadministration of the benzodiazepine-site antagonist flumazenil or the NMDA receptor antagonist dizocilpine. A single injection of the GABAA receptor α1 subunit-preferring benzodiazepine-site ligand zolpidem also produced an increase in the AMPA/NMDA ratio in VTA dopamine neurons. These findings suggest a role for the mesolimbic dopamine system in the initial actions of and on neuronal adaptation to benzodiazepines.Neuropsychopharmacology (2009) 34, 290–298; doi:10.1038/npp.2008.89; published online 18 June 2008 [ABSTRACT FROM AUTHOR]
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- 2009
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19. Selective reduction of γ-aminobutyric acid type A receptor δ subunit mRNA levels by MK-801 in rat dentate gyrus
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Sinkkonen, Saku T., Lindén, Anni-Maija, Korpi, Esa R., and Wong, Garry
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GENE expression , *GENETIC regulation , *AMINO acids , *DECARBOXYLASES - Abstract
The influence of excitatory blockade elicited by uncompetitive N-methyl-d-aspartate (NMDA)/glutamate receptor antagonists on inhibitory GABAergic systems is not well understood. Adult male rats were injected i.p. with a single dose of the prototypical uncompetitive antagonist MK-801 (0.2–10 mg/kg) and in situ hybridization was performed to measure mRNA levels of γ-aminobutyric acid type A (GABAA) receptor subunits (α1–6, β1–3, γ1–3, δ, #x03B5;, and θ). A significant decrease in δ subunit mRNA levels, that reached ∼70% of saline-treated values, was observed in the hippocampal dentate gyrus following MK-801 administration. Other subunits did not display statistically significant alterations. These data demonstrate selective actions on GABAA receptor subunit levels that result from blockade of excitation by MK-801. [Copyright &y& Elsevier]
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- 2004
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20. Brain regional μ-opioid receptor function in rat lines selected for differences in alcohol preference
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Soini, Sanna L., Hyytiä, Petri, and Korpi, Esa R.
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OPIOID receptors , *MORPHINE , *ALCOHOL - Abstract
It has been suggested that opioid peptides play a role in the reinforcing effects of alcohol. The present study was designed to examine the function of the μ-opioid receptor system in rat lines selectively bred for alcohol preference (AA [Alko, Alcohol] rat line) and alcohol avoidance (ANA [Alko, Non-Alcohol] rat line). The functional coupling of μ-opioid receptors to G proteins was determined autoradiographically using Tyr-d-Ala-Gly-N(Me)Phe-Gly-ol-enkephalin-stimulated [35S]GTPγS binding in brain cryostat sections. The binding was significantly increased in the striatal patches and substantia nigra reticulata of the AA rats in comparison with that of the ANA rats. Within the AA rat line, there was a significant positive correlation between 3 mg/kg morphine-induced locomotor activity and activation of G-proteins in the substantia nigra compacta and nucleus accumbens core. These results of the selective breeding experiment suggest that brain region-specific differences in μ-opioid receptor function may correlate with innate differences in alcohol preference. [Copyright &y& Elsevier]
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- 2002
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21. 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]
- Published
- 2000
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22. Enhanced morphine- and cocaine-induced behavioral sensitization in alcohol-preferring AA rats.
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Honkanen, A., Mikkola, Janne, Korpi, Esa R., Hyytiä, Petri, Seppälä, Timo, and Ahtee, Liisa
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ALCOHOL , *MORPHINE , *COCAINE , *RATS - Abstract
Abstract Locomotor stimulation and behavioral sensitization induced by acute and repeated treatment with alcohol, cocaine or morphine were studied in the alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-Alcohol) rats and non-selected Wistar rats. Daily treatment with alcohol (ethanol, 0.4 or 1.0 g/kg, IP) for 6 days had no effect on locomotor activity either in the AA or ANA rats. Acute cocaine (5, 10 or 20 mg/kg, IP) produced a locomotor stimulation in the animals of all lines studied, and there was no difference in this effect between the AA and ANA rats. During a 4-day repeated cocaine treatment, the AA rats became sensitized with the 10 mg/kg dose, while the ANA rats did not show any sensitization with this dose. With the 20 mg/kg cocaine dose, in addition to locomotor stimulation, the rats of all lines studied showed stereotyped behavior, which response was enhanced during repeated treatment. Morphine-induced locomotor stimulation was larger in the AA rats than in the ANA or Wistar rats both with 1.0 and 3.0 mg/kg doses and only the AA rats were sensitized during 4-day treatment with the 1 mg/kg dose. With the 3.0 mg/kg morphine dose, only the AA rats showed a weak sensitization evident only during the initial 30 min after morphine injection. As the drug-induced behavioral sensitization is an important factor in the development of drug addiction, it is possible that mechanisms underlying the enhanced susceptibility of the AA rats to morphine- and cocaine-induced sensitization contribute to the high intake of alcohol and other abused drugs by these animals. [ABSTRACT FROM AUTHOR]
- Published
- 1999
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23. Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area.
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Nagaeva, Elina, Zubarev, Ivan, Gonzales, Carolina Bengtsson, Forss, Mikko, Nikouei, Kasra, de Miguel, Elena, Elsilä, Lauri, Linden, Anni-Maija, Hjerling-Leffler, Jens, Augustine, George J., and Korpi, Esa R.
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REWARD (Psychology) , *NEURONS , *GABAERGIC neurons , *INTERNEURONS , *DOPAMINERGIC neurons , *MICE , *SOMATOSTATIN - Abstract
The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry. [ABSTRACT FROM AUTHOR]
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- 2020
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24. 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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25. Dopaminergic-GABAergic interplay and alcohol binge drinking.
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Leggio, Gian Marco, Di Marco, Roberta, Gulisano, Walter, D'Ascenzo, Marcello, Torrisi, Sebastiano Alfio, Geraci, Federica, Lavanco, Gianluca, Dahl, Kristiina, Giurdanella, Giovanni, Castorina, Alessandro, Aitta-aho, Teemu, Aceto, Giuseppe, Bucolo, Claudio, Puzzo, Daniela, Grassi, Claudio, Korpi, Esa R., Drago, Filippo, and Salomone, Salvatore
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DOPAMINERGIC mechanisms , *BINGE drinking , *NUCLEUS accumbens , *PHARMACOLOGY , *GABA - Abstract
Graphical abstract Abstract The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/−) mice and wild type littermates (D 3 R +/+). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R+/+, whereas it was robust in D 3 R−/−; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R+/+, but increased it in D 3 R−/−; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R−/− compared to D 3 R+/+; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R−/−, but not in D 3 R+/+. We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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26. 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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27. 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]
- Published
- 2018
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28. Chronic Treatment with Mood-Stabilizers Attenuates Abnormal Hyperlocomotion of GluA1-Subunit Deficient Mice.
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Maksimovic, Milica, Vekovischeva, Olga Y., Aitta-aho, Teemu, and Korpi, Esa R.
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MOOD stabilizers , *LABORATORY mice , *NEURAL transmission , *GLUTAMIC acid , *NEUROPLASTICITY , *GLUTAMATE receptors - Abstract
Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1−/− mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1−/− mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the Gria1−/− mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of Gria1−/− mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of Gria1−/− mice to the level shown by the wild-type Gria1+/+ mice. Gria1−/− mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the Gria1−/− mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the Gria1−/− mouse line can be utilized in screening for new therapeutics. [ABSTRACT FROM AUTHOR]
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- 2014
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29. Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons.
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Vashchinkina, Elena, Manner, Aino K, Vekovischeva, Olga, Hollander, Bjørnar den, Uusi-Oukari, Mikko, Aitta-aho, Teemu, and Korpi, Esa R
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RESPONSE inhibition , *AMPA receptors , *DOPAMINERGIC neurons , *LABORATORY mice , *NEUROPSYCHOPHARMACOLOGY - Abstract
The main fast-acting inhibitory receptors in the mammalian brain are γ-aminobutyric acid type-A (GABAA) receptors for which neurosteroids, a subclass of steroids synthesized de novo in the brain, constitute a group of endogenous ligands with the most potent positive modulatory actions known. Neurosteroids can act on all subtypes of GABAA receptors, with a preference for δ-subunit-containing receptors that mediate extrasynaptic tonic inhibition. Pathological conditions characterized by emotional and motivational disturbances are often associated with perturbation in the levels of endogenous neurosteroids. We studied the effects of ganaxolone (GAN)-a synthetic analog of endogenous allopregnanolone that lacks activity on nuclear steroid receptors-on the mesolimbic dopamine (DA) system involved in emotions and motivation. A single dose of GAN in young mice induced a dose-dependent, long-lasting neuroplasticity of glutamate synapses of DA neurons ex vivo in the ventral tegmental area (VTA). Increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate ratio and rectification of AMPA receptor responses even at 6 days after GAN administration suggested persistent synaptic targeting of GluA2-lacking AMPA receptors. This glutamate neuroplasticity was not observed in GABAA receptor δ-subunit-knockout (δ-KO) mice. GAN (500 nM) applied locally to VTA selectively increased tonic inhibition of GABA interneurons and triggered potentiation of DA neurons within 4 h in vitro. Place-conditioning experiments in adult wild-type C57BL/6J and δ-KO mice revealed aversive properties of repeated GAN administration that were dependent on the δ-subunits. Prolonged neuroadaptation to neurosteroids in the VTA might contribute to both the physiology and pathophysiology underlying processes and changes in motivation, mood, cognition, and drug addiction. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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30. Gene Expression Alterations in the Cerebellum and Granule Neurons of Cstb−/− Mouse Are Associated with Early Synaptic Changes and Inflammation.
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Joensuu, Tarja, Tegelberg, Saara, Reinmaa, Eva, Segerstråle, Mikael, Hakala, Paula, Pehkonen, Heidi, Korpi, Esa R., Tyynelä, Jaana, Taira, Tomi, Hovatta, Iiris, Kopra, Outi, and Lehesjoki, Anna-Elina
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GENE expression , *CEREBELLUM , *NEURONS , *INFLAMMATION , *LABORATORY mice , *NEURODEGENERATION - Abstract
Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited neurodegenerative disease, manifesting with myoclonus, seizures and ataxia, caused by mutations in the cystatin B (CSTB) gene. With the aim of understanding the molecular basis of pathogenetic events in EPM1 we characterized gene expression changes in the cerebella of pre-symptomatic postnatal day 7 (P7) and symptomatic P30 cystatin B -deficient (Cstb−/−) mice, a model for the disease, and in cultured Cstb−/− cerebellar granule cells using a pathway-based approach. Differentially expressed genes in P7 cerebella were connected to synaptic function and plasticity, and in cultured cerebellar granule cells, to cell cycle, cytoskeleton, and intracellular transport. In particular, the gene expression data pinpointed alterations in GABAergic pathway. Electrophysiological recordings from Cstb−/− cerebellar Purkinje cells revealed a shift of the balance towards decreased inhibition, yet the amount of inhibitory interneurons was not declined in young animals. Instead, we found diminished number of GABAergic terminals and reduced ligand binding to GABAA receptors in Cstb−/− cerebellum. These results suggest that alterations in GABAergic signaling could result in reduced inhibition in Cstb−/− cerebellum leading to the hyperexcitable phenotype of Cstb−/− mice. At P30, the microarray data revealed a marked upregulation of immune and defense response genes, compatible with the previously reported early glial activation that precedes neuronal degeneration. This further implies the role of early-onset neuroinflammation in the pathogenesis of EPM1. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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31. Long-term cognitive and neurochemical effects of “bath salt” designer drugs methylone and mephedrone
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den Hollander, Bjørnar, Rozov, Stanislav, Linden, Anni-Maija, Uusi-Oukari, Mikko, Ojanperä, Ilkka, and Korpi, Esa R.
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DESIGNER drugs , *PSYCHOTROPIC plants , *DIAGNOSIS of brain diseases , *DRUG efficacy , *NEUROCHEMISTRY , *LABORATORY mice , *NEUROTOXICOLOGY - Abstract
Abstract: Introduction/aims: The use of cathinone-derivative designer drugs methylone and mephedrone has increased rapidly in recent years. Our aim was to investigate the possible long-term effects of these drugs on a range of behavioral tests in mice. Further, we investigated the long-term effects of these drugs on brain neurochemistry in both rats and mice. Methods: We treated animals with a binge-like regimen of methylone or mephedrone (30mg/kg, twice daily for 4days) and, starting 2weeks later, we performed behavioral tests of memory, anxiety and depression and measured brain levels of dopamine (DA), serotonin (5-HT), their metabolites and norepinephrine (NE). 5-HT and DA transporter (5-HTT and DAT) levels were also measured in rats by [3H]paroxetine and [3H]mazindol binding. Results: Mephedrone reduced working memory performance in the T-maze spontaneous alternation task but did not affect neurotransmitter levels aside from a 22% decrease in striatal homovanillic acid (HVA) levels in mice. Methylone had little effect on behavior or neurotransmitter levels in mice but produced a widespread depletion of 5-HT and 5-HTT levels in rats. Conclusions: Both methylone and mephedrone appeared to have a long-term effect on either behavioral or biochemical gauges of neurotoxicity in rodents. [Copyright &y& Elsevier]
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- 2013
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32. Autoinactivation of the Stargazin--AMPA Receptor Complex: Subunit-Dependency and Independence from Physical Dissociation.
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Semenov, Artur, Möykkynen, Tommi, Coleman, Sarah K., Korpi, Esa R., and Keinänen, Kari
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COHESINS , *CHROMATIDS , *GENE expression , *ONCOGENES , *CELL proliferation , *CANCER - Abstract
Agonist responses and channel kinetics of native a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are modulated by transmembrane accessory proteins. Stargazin, the prototypical accessory protein, decreases desensitization and increases agonist potency at AMPA receptors. Furthermore, in the presence of stargazin, the steady-state responses of AMPA receptors show a gradual decline at higher glutamate concentrations. This "autoinactivation" has been assigned to physical dissociation of the stargazin-AMPA receptor complex and suggested to serve as a protective mechanism against overactivation. Here, we analyzed autoinactivation of GluA1-A4 AMPA receptors (all flip isoform) expressed in the presence of stargazin. Homomeric GluA1, GluA3, and GluA4 channels showed pronounced autoinactivation indicated by the bell-shaped steady-state dose response curves for glutamate. In contrast, homomeric GluA2i channels did not show significant autoinactivation. The resistance of GluA2 to autoinactivation showed striking dependence on the splice form as GluA2-flop receptors displayed clear autoinactivation. Interestingly, the resistance of GluA2-flip containing receptors to autoinactivation was transferred onto heteromeric receptors in a dominant fashion. To examine the relationship of autoinactivation to physical separation of stargazin from the AMPA receptor, we analyzed a GluA4-stargazin fusion protein. Notably, the covalently linked complex and separately expressed proteins expressed a similar level of autoinactivation. We conclude that autoinactivation is a subunit and splice form dependent property of AMPA receptor-stargazin complexes, which involves structural rearrangements within the complex rather than any physical dissociation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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33. Importance of GluA1 Subunit-Containing AMPA Glutamate Receptors for Morphine State-Dependency.
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Aitta-aho, Teemu, Möykkynen, Tommi P., Panhelainen, Anne E., Vekovischeva, Olga Yu., Bäckström, Pia, and Korpi, Esa R.
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GLUTAMIC acid , *MORPHINE , *LABORATORY mice , *NEUROPLASTICITY , *OPIOIDS , *INFORMATION retrieval - Abstract
In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.c. during eight sessions over four days) using an unbiased procedure, followed by testing for conditioned place preference at morphine states that were the same as or different from the one the mice were conditioned to. In GluA1 wildtype littermate mice the same-state morphine dose produced the greatest expression of place preference, while in the knockout mice no place preference was then detected. Both wildtype and knockout mice expressed moderate morphine-induced place preference when not at the morphine state (saline treatment at the test); in this case, place preference was weaker than that in the same-state test in wildtype mice. No correlation between place preference scores and locomotor activity during testing was found. Additionally, as compared to the controls, the knockout mice showed unchanged sensitization to morphine, morphine drug discrimination and brain regional m-opioid receptor signal transduction at the G-protein level. However, the knockout mice failed to show increased AMPA/NMDA receptor current ratios in the ventral tegmental area dopamine neurons of midbrain slices after a single injection of morphine (10 mg/kg, s.c., sliced prepared 24 h afterwards), in contrast to the wildtype mice. The results indicate impaired druginduced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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34. GABA Site Agonist Gaboxadol Induces Addiction-Predicting Persistent Changes in Ventral Tegmental Area Dopamine Neurons But Is Not Rewarding in Mice or Baboons.
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Vashchinkina, Elena, Panhelainen, Anne, Vekovischevac, Olga Yu., Aitta-aho, Teemu, Ebert, Bjarke, Ator, Nancy A., and Korpi, Esa R.
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GABA agonists , *BRAIN anatomy , *DOPAMINERGIC neurons , *BABOONS as laboratory animals , *DRUG addiction , *GLUTAMATE receptors , *BENZODIAZEPINES - Abstract
Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABAA receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism. Here, we have tested a non-benzodiazepine direct GABA site agonist 4,5,6,7-tetrahydroisoxazolol[4,5-c]pyridine-3-ol (THIP) (also known as gaboxadol) that acts preferentially via highaffinity extrasynaptic GABAA receptors. A single sedative dose of THIP (6 mg/kg) to mice induced glutamate receptor plasticity for at least 6 d after administration. Increased AMPA/NMDA receptor current ratio and increased frequency, amplitude, and rectification of AMPA receptor responses suggested persistent targeting of GluA2-lacking AMPA receptors in excitatory synapses of VTA dopamine neurons ex vivo after THIP administration. This effect was abolished in GABAA receptor mice, which have a loss of extrasynaptic GABAA receptors. In behavioral experiments, we found neither acute reinforcement in intravenous selfadministration sessions with THIP at relevant doses using a yoked control paradigm in mice nor in baboons using a standard paradigm for assessing drug abuse liability; nor was any place preference found after conditioning sessions with various doses of THIP but rather a persistent aversion in 6 mg/kg THIP-conditioned mice. In summary, we found that activation of extrasynaptic -subunit-containing GABAA receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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35. Actions of two GABAA receptor benzodiazepine-site ligands that are mediated via non-γ2-dependent modulation
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Leppä, Elli, Linden, Anni-Maija, Rabe, Holger, Vekovischeva, Olga Yu., Wulff, Peer, Lüddens, Hartmut, Wisden, William, and Korpi, Esa R.
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GABA receptors , *BENZODIAZEPINES , *LIGANDS (Biochemistry) , *SEDATIVES , *HYPNOTICS , *ZOLPIDEM , *AMINOBUTYRIC acid , *NEUROTRANSMITTER receptors , *LABORATORY mice - Abstract
Abstract: The potent sedative-hypnotic zolpidem and the convulsant methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) act primarily by binding to the benzodiazepine site of the main inhibitory neurotransmitter receptor, the pentameric γ-aminobutyric acid type A receptor (GABAA). This binding depends critically on the wild-type F77 residue of the GABAA receptor γ2 subunit. Mice with γ2 subunit F77I point mutation (γ2I77 mouse line) lose the high-affinity nanomolar binding of these ligands as well as their most robust behavioral actions at low doses. Interestingly, the γ2I77 mice offer a tool to study the actions of these substances mediated via other possible binding sites of the GABAA receptor. In ligand autoradiographic experiments, we discovered in γ2I77 mouse brain sections a significant amount of residual non-γ2 subunit-dependent benzodiazepine site binding enriched to the striatum and septum. Zolpidem only weakly affected this residual binding at micromolar concentrations, and only a high zolpidem dose (≥40mg/kg) caused sedation and deficits in motor coordination in γ2I77 mice. DMCM had an agonistic action through a secondary, low-affinity non-benzodiazepine binding site of the GABAA receptor in the forebrain of γ2I77 mice, and this drug also fully displaced the residual benzodiazepine-site labeling. In behavioral tests, a high dose (20mg/kg) of DMCM was sedative and modulated fear learning. DMCM, but not zolpidem, acted as an agonist in recombinant GABAA α1/6β3 receptors studied using ligand binding and electrophysiological assays. Our results highlight the less well-known actions of high doses of DMCM and zolpidem that are not mediated via the γ2 subunit-containing benzodiazepine site of the GABAA receptor. [Copyright &y& Elsevier]
- Published
- 2011
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36. Removal of GABAA Receptor γ2 Subunits from Parvalbumin Neurons Causes Wide-Ranging Behavioral Alterations.
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Leppä, Elli, Linden, Anni-Maija, Vekovischeva, Olga Y., Swinny, Jerome D., Rantanen, Ville, Toppila, Esko, Höger, Harald, Sieghart, Werner, Wulff, Peer, Wisden, William, and Korpi, Esa R.
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GABA receptors , *PARVALBUMINS , *SYNAPSES , *GENETIC recombination , *CENTRAL nervous system diseases , *RESPONSE inhibition , *AUTORADIOGRAPHY , *MORTALITY , *SENSORIMOTOR integration - Abstract
We investigated the behavioral significance of fast synaptic inhibition by αβγ2-type GABAA receptors on parvalbumin (Pv) cells. The GABAA receptor γ2 subunit gene was selectively inactivated in Pv-positive neurons by Cre/loxP recombination. The resulting Pv-δγ2 mice were relatively healthy in the first postnatal weeks; but then as Cre started to be expressed, the mice progressively developed wide-ranging phenotypic alterations including low body weight, motor deficits and tremor, decreased anxiety levels, decreased pain sensitivity and deficient prepulse inhibition of the acoustic startle reflex and impaired spatial learning. Nevertheless, the deletion was not lethal, and mice did not show increased mortality even after one year. Autoradiography with t-butylbicyclophosphoro[35S]thionate suggested an increased amount of GABAA receptors with only a and b subunits in central nervous system regions that contained high levels of parvalbumin neurons. Using BACtransgenesis, we reduced some of the Pv-δγ2 phenotype by selectively re-expressing the wild-type γ2 subunit back into some Pv cells (reticular thalamic neurons and cerebellar Pv-positive neurons). This produced less severe impairments of motor skills and spatial learning compared with Pv-δγ2 mice, but all other deficits remained. Our results reveal the widespread significance of fast GABAergic inhibition onto Pv-positive neurons for diverse behavioral modalities, such as motor coordination, sensorimotor integration, emotional behavior and nociception. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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37. 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]
- Published
- 2011
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38. Ligand-binding Domain Determines Endoplasmic Reticulum Exit of AMPA Receptors.
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Coleman, Sarah K., Möykkynen, Tommi, Hinkkuri, Sami, Vaahtera, Lauri, Korpi, Esa R., Pentikäinen, Olli T., and Keinänen, Kari
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ION channels , *GLUTAMIC acid , *NEURONS , *CELL membranes , *ENDOPLASMIC reticulum , *CELL membrane formation - Abstract
AMPA receptors (AMPARs) are tetrameric ion channels that mediate rapid glutamate signaling in neurons and many non-neuronal cell types. Endoplasmic reticulum (ER) quality control mechanisms permit only correctly folded functional receptors to be delivered to the cell surface. We analyzed the biosynthetic maturation and transport of all 12 GluA1-4 subunit splice variants as homomeric receptors and observed robust isoform-dependent differences in ER exit competence and surface expression. In contrast to inefficient ER exit of both GluA3 splice forms and the flop variants of GluA1 and GluA4, prominent plasma membrane expression was observed for the other AMPAR isoforms. Surprisingly, deletion of the entire N-terminal domain did not alter the transport phenotype, nor did the different cytosolic C-terminal tail splice variants. Detailed analysis of mutant receptors led to the identification of distinct residues in the ligand-binding domain as primary determinants for isoform-specific maturation. Considered together with the essential role of bound agonist, our findings reveal the ligand-binding domain as the critical quality control target in AMPAR biogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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39. Human locus coeruleus neurons express the GABAA receptor γ2 subunit gene and produce benzodiazepine binding
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Hellsten, Kati S., Sinkkonen, Saku T., Hyde, Thomas M., Kleinman, Joel E., Särkioja, Terttu, Maksimow, Anu, Uusi-Oukari, Mikko, and Korpi, Esa R.
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LOCUS coeruleus , *GENE expression , *GABA receptors , *BENZODIAZEPINES , *NORADRENERGIC neurons , *VIGILANCE (Psychology) - Abstract
Abstract: Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for γ-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABAA receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The γ2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABAA receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the γ2 subunit''s expression and participation in the functional GABAA receptors in the mammalian locus coeruleus. We report here that the γ2 subunit is transcribed and participates in the assembly of functional GABAA receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific γ2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [3H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the α1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the α1 and γ2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects. [Copyright &y& Elsevier]
- Published
- 2010
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- View/download PDF
40. Prototypic GABAA Receptor Agonist Muscimol Acts Preferentially Through Forebrain High-Affinity Binding Sites.
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Chandra, Dev, Halonen, Lauri M., Linden, Anni-Maija, Procaccini, Chiara, Hellsten, Kati, Homanics, Gregg E., and Korpi, Esa R.
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ANIMAL models in research , *AMINOBUTYRIC acid , *HIPPOCAMPUS (Brain) , *BINDING sites , *CEREBRAL cortex - Abstract
Muscimol has been regarded as a universal agonist for all γ-aminobutyric acid type A receptor (GABAA-R) subtypes. However, brain regional distribution of muscimol's high-affinity binding sites greatly differs from those of other binding sites of the GABAA-R. To test whether behavioral effects of muscimol correlated with the density of high-affinity [3H]muscimol binding, we examined several GABAA-R subunit gene-modified mouse lines: α1, α4, or δ-knockouts (KO), α4+δ-double KO, and Thy1.2 promoter-driven α6 transgenic mice (Thy1α6). We determined the high-affinity [3H]muscimol binding in brain sections by quantitative autoradiography and sedative/ataxic effects induced in vivo by muscimol using a constant speed rotarod. α4-KO mice had reduced [3H]muscimol binding in the caudate-putamen, thalamus, and hippocampus, and were less sensitive to the behavioral impairment by muscimol. Similarly, δ-KO mice also had reduced binding to forebrain regions and a lower behavioral sensitivity to muscimol than their wild-type controls. In contrast, α1-KO mice had unaltered behavioral sensitivity to muscimol and unaltered [3H]muscimol binding, even though previous studies have demonstrated dramatically reduced binding to various other GABAA-R sites in these mice. Finally, Thy1α6 mice exhibited increased behavioral sensitivity to muscimol, and to another direct GABA-site agonist gaboxadol, and increased [3H]muscimol binding in the cerebral cortex and hippocampus. Thus, the differences in sedative and motor-impairing actions of muscimol in various mouse models correlated with the level of forebrain high-affinity [3H]muscimol binding. These data suggest that a small special population of GABAA-Rs, most likely extrasynaptic non-α1-containing receptors, strongly contributes to the in vivo pharmacological effects of muscimol. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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41. Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice.
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Nuutinen, Saara, Karlstedt, Kaj, Aitta-aho, Teemu, Korpi, Esa R., and Panula, Pertti
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HISTAMINE , *SLEEP , *ALCOHOL , *HOMEOSTASIS , *PHYSIOLOGICAL control systems , *GABA , *LABORATORY mice - Abstract
Neuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward. The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice. Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity. The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABAA receptor ligand [3H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward. Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
42. Analysis of the Potential Role of GluA4 Carboxyl- Terminus in PDZ Interactions.
- Author
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Coleman, Sarah K., Cai, Chunlin, Kalkkinen, Nisse, Korpi, Esa R., and Keinänen, Kari
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CARBOXYLIC acids , *SYNAPSES , *PROTEINS , *ORGANIC acids , *ACRYLIC acid , *NERVE endings , *NERVES , *BIOMOLECULES , *ORGANIC compounds - Abstract
Background: Specific delivery to synapses of a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors with long-tailed subunits is believed to be a key event in many forms of activity-dependent changes in synaptic strength. GluA1, the best characterized long-tailed AMPA receptor subunit, contains a C-terminal class I PDZ binding motif, which mediates its interaction with scaffold and trafficking proteins, including synapse-associated protein 97 (SAP97). In GluA4, another long-tailed subunit implicated in synaptic plasticity, the PDZ motif is blocked by a single proline residue. This feature is highly conserved in vertebrates, whereas the closest invertebrate homologs of GluA4 have a canonical class I PDZ binding motif. In this work, we have examined the role of GluA4 in PDZ interactions. Methodology/Principal Findings: Deletion of the carboxy-terminal proline residue of recombinant GluA4 conferred avid binding to SAP97 in cultured cells as shown by coimmunoprecipitation, whereas wild-type GluA4 did not associate with SAP97. Native GluA4 and SAP97 coimmunoprecipitated from mouse brain independently of the GluA1 subunit, supporting the possibility of in vivo PDZ interaction. To obtain evidence for or against the exposure of the PDZ motif by carboxyterminal processing of native GluA4 receptors, we generated an antibody reagent specific for proline-deleted GluA4 C-terminus. Immunoprecipitation and mass spectrometric analyses indicated that the carboxyl-terminus of native GluA4 AMPA receptors is intact and that the postulated single-residue cleavage does not occur to any significant extent. Conclusion/Significance: We conclude that native GluA4 receptors are not capable of canonical PDZ interactions and that their association with SAP97 is likely to be indirect. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
43. Brain regional distribution of GABAA receptors exhibiting atypical GABA agonism: Roles of receptor subunits
- Author
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Halonen, Lauri M., Sinkkonen, Saku T., Chandra, Dev, Homanics, Gregg E., and Korpi, Esa R.
- Subjects
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GABA receptors , *CHEMICAL inhibitors , *THIOSULFATES , *BINDING sites , *BRAIN imaging , *AUTORADIOGRAPHY - Abstract
Abstract: The major inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), has only partial efficacy at certain subtypes of GABAA receptors. To characterize these minor receptor populations in rat and mouse brains, we used autoradiographic imaging of t-butylbicyclophosphoro[35S]thionate ([35S]TBPS) binding to GABAA receptors in brain sections and compared the displacing capacities of 10mM GABA and 1mM 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a competitive GABA-site agonist. Brains from GABAA receptor α1, α4, δ, and α4+δ subunit knockout (KO) mouse lines were used to understand the contribution of these particular receptor subunits to “GABA-insensitive” (GIS) [35S]TBPS binding. THIP displaced more [35S]TBPS binding than GABA in several brain regions, indicating that THIP also inhibited GIS-binding. In these regions, GABA prevented the effect of THIP on GIS-binding. GIS-binding was increased in the cerebellar granule cell layer of δ KO and α4+δ KO mice, being only slightly diminished in that of α1 KO mice. In the thalamus and some other forebrain regions of wild-type mice, a significant amount of GIS-binding was detected. This GIS-binding was higher in α4 KO mice. However, it was fully abolished in α1 KO mice, indicating that the α1 subunit was obligatory for the GIS-binding in the forebrain. Our results suggest that native GABAA receptors in brain sections showing reduced displacing capacity of [35S]TBPS binding by GABA (partial agonism) minimally require the assembly of α1 and β subunits in the forebrain and of α6 and β subunits in the cerebellar granule cell layer. These receptors may function as extrasynaptic GABAA receptors. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
44. Ethanol increases desensitization of recombinant GluR-D AMPA receptor and TARP combinations
- Author
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Möykkynen, Tommi P., Coleman, Sarah K., Keinänen, Kari, Lovinger, David M., Korpi, Esa R., Möykkynen, Tommi P, and Keinänen, Kari
- Subjects
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PSYCHOLOGY of alcoholism , *DESENSITIZATION (Psychotherapy) , *RECOMBINANT proteins , *PROPIONIC acid , *CELL receptors , *CELLULAR control mechanisms , *EMBRYONIC stem cells , *CELL membranes , *PATCH-clamp techniques (Electrophysiology) , *BIOLOGICAL transport , *CALCIUM , *CELL lines , *COMPARATIVE studies , *ETHANOL , *RESEARCH methodology , *MEDICAL cooperation , *MEMBRANE proteins , *RESEARCH , *EVALUATION research , *EXCITATORY amino acid agonists , *EXCITATORY amino acid antagonists , *PHYSIOLOGY - Abstract
Abstract: Glutamate receptors are important target molecules of the acute effect of ethanol. We studied ethanol sensitivity of homomeric GluR-D receptors expressed in human embryonic kidney 293 cells and examined whether recently discovered transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory proteins (TARPs) affect ethanol sensitivity. Coexpression of the TARPs, stargazin, and γ4 increased the time constant (τ-value) of current decay in the presence of agonist, thus slowing the onset of desensitization and increasing the steady-state current. Ethanol produced less inhibition of the peak current than the steady-state current for all types of the GluR-D receptors. In addition, ethanol concentration-dependently accelerated the rate of desensitization, measured as the τ-value of fast decay of peak current. This effect was enhanced with coexpression of TARPs. The recovery from desensitization was slowed down by coexpression of γ4 but ethanol did not affect this process in any GluR-D combination. The results support the idea that increased desensitization is an important mechanism in the ethanol inhibition of AMPA receptors and indicate that coexpression of TARPs can alter this effect of ethanol. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
45. Reduced benzodiazepine tolerance, but increased flumazenil-precipitated withdrawal in AMPA-receptor GluR-A subunit-deficient mice
- Author
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Aitta-aho, Teemu, Vekovischeva, Olga Y., Neuvonen, Pertti J., and Korpi, Esa R.
- Subjects
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PHARMACODYNAMICS , *DRUG tolerance , *BENZODIAZEPINES , *GLUTAMIC acid , *MUSCLE relaxants , *FLURAZEPAM , *LABORATORY mice - Abstract
Abstract: Pharmacotherapy with benzodiazepines is compromised by rapid sedative tolerance and diverse withdrawal symptoms. To assess the role of AMPA-type glutamate receptor GluR-A subunits in neuroadaptation to subchronic benzodiazepine treatment, GluR-A subunit-deficient mice were rendered tolerant by a high-dose seven-day flurazepam treatment (40 mg/kg, s.c., twice a day for 4 days, 60 mg/kg twice a day for 3 days). The acute effects to flurazepam were not changed in the GluR−/− mice compared with their littermate control mice. GluR-A−/− mice developed less tolerance than their controls as demonstrated in behavioral tests for muscle relaxation and sensory functions. Actually, the knockout mice exhibited slower recovery than their littermates from impaired gait and pelvic position after an acute 40 mg/kg dose of flurazepam. The apparent elimination of flurazepam was similarly increased in the knockout and control mice as assessed by blood and brain concentrations 2 h after acute and chronic treatments, but the active metabolite desalkylflurazepam cumulated similarly in both mouse lines. Withdrawal symptoms, precipitated by flumazenil (20 mg/kg, s.c.) 48 h after discontinuation of the flurazepam treatment, were enhanced in the GluR-A−/− mice. The results stress the importance of the AMPA-receptor system in neuroadaptation to acute and chronic effects of benzodiazepines. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
46. Agonist Occupancy Is Essential for Forward Trafficking of AMPA Receptors.
- Author
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Coleman, Sarah K., Möykkynen, Tommi, Jouppila, Annukka, Koskelainen, Susanna, Rivera, Claudio, Korpi, Esa R., and Keinänen, Kari
- Subjects
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CELL receptors , *GLUTAMIC acid , *SYNAPSES , *NEUROPLASTICITY , *ENDOPLASMIC reticulum , *CELL transplantation - Abstract
Regulated trafficking of AMPA receptors to cell surface and to synapses is an important determinant of neuronal excitability. In the present study, we have addressed the role of agonist binding and desensitization in the early trafficking of glutamate receptor-D (GluR-D) AMPA receptors. Analysis of point-mutated GluR-D receptors, via electrophysiology and immunofluorescence, revealed that agonistbinding activity is essential for efficient delivery to cell surface in transfected cell lines and in neurons. Cotransfection with stargazin could fully rescue the surface expression of nonbinding mutant receptors in cell lines, indicating that stargazin is able to interact with and promote exit of AMPA receptors from endoplasmic reticulum (ER) independently of agonist binding. Secretion of separately expressed ligand-binding domain constructs showed a similar dependency of agonist binding to that observed with full-length GluR-D, supporting the idea that glutamate-induced closure of the binding site cleft is registered by ER quality control as a necessary priming step for transport competence. In contrast to agonist binding, the ability of the receptor to undergo desensitization had only a minor influence on trafficking. Our results are consistent with the hypothesis that AMPA receptors are synthesized as intrinsically unstable molecules, which require glutamate binding for structural stability and for transport-competence. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
47. Morphine–nicotine interaction in conditioned place preference in mice after chronic nicotine exposure
- Author
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Vihavainen, Tanja, Piltonen, Marjo, Tuominen, Raimo K., Korpi, Esa R., and Ahtee, Liisa
- Subjects
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MORPHINE , *NICOTINE , *OPIOID receptors , *BIOCHEMISTRY - Abstract
Abstract: Previously we found that morphine''s effects on locomotor activity and brain dopamine metabolism were enhanced in mice after cessation of 7-week oral nicotine treatment. In the present experiments we show that such chronic nicotine exposure cross-sensitizes NMRI mice to the reinforcing effect of morphine in the conditioned place preference paradigm. The nicotine-treated mice developed conditioned place preference after being conditioned twice with morphine 5 mg/kg s.c. whereas in control mice a higher dose (10 mg/kg) of morphine was required. Since the reinforcing effect of morphine is mediated via µ-opioid receptors we used [3H]DAMGO autoradiography to study whether the number (B max) or affinity (K D) of µ-opioid receptors in the mouse brain are affected following chronic nicotine exposure. However, no changes were found in the number or affinity of µ-opioid receptors in any of the brain areas studied. Neither did we find alterations in the functional activity of µ-opioid receptors studied by [35S]GTPγS-binding. In conclusion, chronic oral nicotine treatment augments the reinforcing effects of morphine in mice, and this cross-sensitization does not seem to be mediated by µ-opioid receptors. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
48. Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic α6β GABAA receptors.
- Author
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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.
- Subjects
- *
GABA agonists , *TRANSGENIC mice , *HIPPOCAMPUS (Brain) , *GABA receptors , *NEURAL transmission - Abstract
The behavioral and functional significance of the extrasynaptic inhibitory GABAA 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 [35S]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
- Full Text
- View/download PDF
49. From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors.
- Author
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Wulff, Peer, Goetz, Thomas, Leppä, Elli, Linden, Anni-Maija, Renzi, Massimiliano, Swinny, Jerome D, Vekovischeva, Olga Y, Sieghart, Werner, Somogyi, Peter, Korpi, Esa R, Farrant, Mark, and Wisden, William
- Subjects
- *
SYNAPSES , *BEHAVIOR , *NEURONS , *GABA , *ZOLPIDEM , *PHENYLALANINE , *PURKINJE cells - Abstract
In mammals, identifying the contribution of specific neurons or networks to behavior is a key challenge. Here we describe an approach that facilitates this process by enabling the rapid modulation of synaptic inhibition in defined cell populations. Binding of zolpidem, a systemically active allosteric modulator that enhances the function of the GABAA receptor, requires a phenylalanine residue (Phe77) in the γ2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase–induced swapping of the γ2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABAA receptors in chosen cell types. We demonstrate the power of this method in the cerebellum, where zolpidem rapidly induces significant motor deficits when Purkinje cells are made uniquely sensitive to its action. This combined molecular and pharmacological technique has demonstrable advantages over targeted cell ablation and will be invaluable for investigating many neuronal circuits. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
50. Lifelong ethanol consumption and brain regional GABAA receptor subunit mRNA expression in alcohol-preferring rats
- Author
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Sarviharju, Maija, Hyytiä, Petri, Hervonen, Antti, Jaatinen, Pia, Kiianmaa, Kalervo, and Korpi, Esa R.
- Subjects
- *
MESSENGER RNA , *RNA , *GABA , *ALCOHOL - Abstract
Abstract: Brain regional γ-aminobutyric acid type A (GABAA) receptor subunit mRNA expression was studied in ethanol-preferring AA (Alko, Alcohol) rats after moderate ethanol drinking for up to 2 years of age. In situ hybridization with oligonucleotide probes specific for 13 different subunits was used with coronal cryostat sections of the brains. Selective alterations were observed by ethanol exposure and/or aging in signals for several subunits. Most interestingly, the putative highly ethanol-sensitive α4 and β3 subunit mRNAs were significantly decreased in several brain regions. The age-related alterations in α4 subunit expression were parallel to those caused by lifelong ethanol drinking, whereas aging had no significant effect on β3 subunit expression. The results suggest that prolonged ethanol consumption leading to blood concentrations of about 10mM may downregulate the mRNA expression of selected GABAA receptor subunits and that aging might have partly similar effects. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
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