Esa R Korpi

Publications (84)257.84 Total impact

• Article: Brain regional mu-opioid receptor function in rat lines selected for differences in alcohol preference.

  Sanna L Soini, Petri Hyytiä, Esa R Korpi
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  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 mu-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 mu-opioid receptors to G proteins was determined autoradiographically using Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol-enkephalin-stimulated [35S]GTPgammaS 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 mu-opioid receptor function may correlate with innate differences in alcohol preference.
  European Journal of Pharmacology 08/2002; 448(2-3):157-63. · 2.52 Impact Factor
• Article: Drug interactions at GABA(A) receptors.

  Esa R Korpi, Gerhard Gründer, Hartmut Lüddens
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  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 gamma-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 GABA(A) 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 GABA(A) receptor properties and to gain insight into the biological function from fish to man and into evolutionary conserved GABA(A) 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 GABA(A) 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.
  Progress in Neurobiology 07/2002; 67(2):113-59. · 8.87 Impact Factor
• Article: Low brain histamine content affects ethanol-induced motor impairment.

  Minnamaija Lintunen, Kristiina Raatesalmi, Tina Sallmen, Oleg Anichtchik, Kaj Karlstedt, Jan Kaslin, Kalervo Kiianmaa, Esa R Korpi, Pertti Panula
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  ABSTRACT: The effect of ethanol on motor performance in humans is well established but how neural mechanisms are affected by ethanol action remains largely unknown. To investigate whether the brain histaminergic system is important in it, we used a genetic model consisting of rat lines selectively outbred for differential ethanol sensitivity. Ethanol-sensitive rats had lower levels of brain histamine and lower densities of histamine-immunoreactive fibers than ethanol-insensitive rats, although both rat lines showed no changes in histamine synthesizing neurons. Lowering the high brain histamine content of the ethanol-insensitive rats with alpha-fluoromethylhistidine before ethanol administration increased their ethanol sensitivity in a behavioral motor function test. Higher H3 receptor ligand binding and histamine-induced G-protein activation was detected in several brain regions of ethanol-naive ethanol-sensitive rats. Brain histamine levels and possibly signaling via H3 receptors may thus correlate with genetic differences in ethanol-induced motor impairment.
  Neurobiology of Disease 03/2002; 9(1):94-105. · 5.40 Impact Factor
• Article: Morphine withdrawal increases expression of GABAA receptor [small element of] subunit mRNA in locus coeruleus neurons

  Anu T. Heikkilä, Oxana Echenko, Mikko Uusi-Oukari, Saku T. Sinkkonen, Esa R. Korpi
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  ABSTRACT: An increase in the activity of brain stem locus coeruleus noradrenergic neurons has been hypothesised to be a major factor accounting for opiate withdrawal symptoms. These neurons are under GABAergic inhibition. Their GABAA receptors have unique pharmacological properties, most likely due to the enriched expression of GABAA receptor subtypes containing novel ∊ and θ subunits. Using in situ hybridisation of cryostat sections, we now report a significant increase in the ∊ subunit mRNA expression after precipitation of opioid withdrawal by naloxone. Similar changes were detected in tyrosine hydroxylase mRNA expression. The results suggest increased formation of unique GABAA receptor subtype(s) in the locus coeruleus neurons during increased neuronal activity.
  Neuroreport 09/2001; 12(13):2981-2985. · 1.66 Impact Factor
• Article: Magnesium potentiation of the function of native and recombinant GABAA receptors

  Tommi Möykkynen, Mikko Uusi-Oukari, Jari Heikkilä, David M. Lovinger, Hartmut Lüddens, Esa R. Korpi
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  ABSTRACT: Mg2+ decreased basal and GABA-inhibited t-butylbicyclophosphoro[35S]thionate binding to GABAA receptor ion channels in rat brain sections up to 1 mM, but increased the binding at 10 mM. The Mg2+-effect was detectable in the presence of a specific GABA site competitive antagonist. Two-electrode voltage clamp recordings of recombinant α1β2γ2S, α1β2, α2β2γ2S and α2β2 GABAA receptors revealed a potentiation by 0.1-1 mM Mg2+ of EC20 GABA-evoked ion currents. At 10 mM, Mg2+ decreased the currents. In the absence of GABA, Mg2+ did not evoke any currents. The results show that physiologically relevant Mg2+ concentrations affect the GABA responses on GABAA receptors in native and the main recombinant receptor subtypes, suggesting putative Mg2+ binding sites on the receptor complex.
  Neuroreport 07/2001; 12(10):2175-2179. · 1.66 Impact Factor
• Article: Coupling between agonist and chloride ionophore sites of the GABAA receptor: agonist/antagonist efficacy of 4-PIOL

  Holger Rabe, Raymonde Picard, Mikko Uusi-Oukari, Wulf Hevers, Hartmut Lüddens, Esa R. Korpi
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  ABSTRACT: Eight γ-aminobutyric acid (GABA) mimetics were tested on their ability to differentiate native GABAA receptor subtypes present in various rat brain regions. In rat brain cryostat sections, little regional variations by the agonistic actions of muscimol, thiomuscimol, 4,5,6,7-tetrahydroisoazolo(5,4-c)pyridin-3-ol, piperidine-4-sulphonic acid, taurine and β-alanine on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABAA receptor channels were found. They were very similar to those found for GABA itself and indicated no direct correlation with single subunit distributions for any of these compounds. Only the low-efficacy GABA mimetic 5-(4-piperidyl)isoxazol-3-ol (4-PIOL) acted like a weak partial agonist or antagonist depending on the brain area. As the cerebellar granule cell layer was relatively insensitive to both modes of action, we tested 4-PIOL in recombinant α1β2γ2 (widespread major subtype) and α6β2γ2 (cerebellar granule cell restricted) receptors where it had different effects on GABA-modulated [35S]TBPS binding and on electrophysiological responses. 4-PIOL may thus serve as a potential lead for receptor subtype selective compounds.
  European Journal of Pharmacology 01/2001; · 2.52 Impact Factor
• Article: Assembly of functional [alpha]6[beta]3[gamma]2[delta] GABAA receptors in vitro

  Wulf Hevers, Esa R. Korpi, Hartmut Lüddens
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  ABSTRACT: Transgenic mice deficient in the α6 subunit of the GABAA receptor show reduced levels of the δ subunit protein and an altered GABAA receptor pharmacology, suggesting selective assembly mechanisms. δ reduced the binding of [3H]Ro15-4513 or t-butylbicyclophosphoro[35S]thionate and, to a lesser extent, [3H]muscimol to recombinant α1β1γ2(δ), α4β1γ2(δ) and α6β1γ2(δ) receptors, paralleled by diminished GABA-evoked maximal currents in electrophysiological recordings for the latter one. The δ subunit gave rise to a lower EC50 for GABA and a slowed desensitization indicating its assembly in α6β2δ, α6β1γ2δ and α6β2γ2δ receptors. The data show that the δ subunits assemble in various functional GABAA receptor subtypes in vitro to reduce GABA-evoked maximal currents and ligand binding, but increase the potency for GABA.
  Neuroreport 12/2000; 11(18):4103-4106. · 1.66 Impact Factor
• Article: Ethanol: Novel Actions on Nerve Cell Physiology Explain Impaired Functions.

  Esa R. Korpi, Riikka Mäkelä, Mikko Uusi-Oukari
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  ABSTRACT: Molecular biological tools have revealed receptor proteins for excitatory and inhibitory neurotransmitters on cell membranes as targets of ethanol action. Behavioral and pharmacogenetic assays using rodent lines have supported this neurotransmitter theory of ethanol action and given a firm basis for future identification of the relevant genes and the central physiological processes vulnerable to ethanol.
  Physiology 09/1998; 13:164-170.
• Chapter: Methods for Transient Expression of Hetero-Oligomeric Ligand-Gated Ion Channels

  Hartmut Lüddens, Esa R. Korpi
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  ABSTRACT: Transient transfectron of mammalian cell lines with recombinant DNA has become a common tool for studying functional and structural properties of a wide variety of proteins (1–5). Transient transfections are especially practical for the expression of recombinant multisubunit complexes because their expression needs the prior knowledge and selection of which of a set of subunits are necessary to form functional heteromultrmers with distinct features. Subumt stoichiometry, mode of assembly, and the relative expression levels of individual cDNA vector constructs also have to be taken into account. The latter still poses an insurmountable problem, because no accurate predictions can be made.
  12/1996: pages 55-63;
• Article: Subtype specificity of γ-aminobutyric acid type A receptor antagonism by clozapine

  Esa R. Korpi, Garry Wong, Hartmut Lüddens
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  ABSTRACT: Clozapine, an atypical neuroleptic, functionally antagonizes the -aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, -aminobutyric acid type A (GABAA) receptor, in brain vesicles. GABAA antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABAA antagonist 2-(3-carboxy-2,3-propyl)-3-amino-6-p-methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [35S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [3H]muscimol and [3H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [35S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant 622 receptors, the predominant 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 M. In contrast, recombinant 122 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant 622 and 632 receptors resulted in clozapine-insensitive receptors, whereas 612 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in 1x2 receptors decreased in the order of 112>122>132. The results indicate that clozapine antagonizes the function of most GABAA receptor subtypes, and that the interaction is determined by the interaction of the and subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.
  Archiv für Experimentelle Pathologie und Pharmakologie 01/1995; 352(4):365-373. · 2.65 Impact Factor
• Article: GABAA receptor subtypes as targets for neuropsychiatric drug development

  Esa R. Korpi, Saku T. Sinkkonen
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  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.
  Pharmacology & Therapeutics.
• Article: Autoradiographic imaging of altered synaptic αβγ2 and extrasynaptic αβ GABAA receptors in a genetic mouse model of anxiety

  Saku T Sinkkonen, Bernhard Lüscher, Hartmut Lüddens, Esa R Korpi
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  ABSTRACT: To image the possible alterations in brain regional GABAA receptor subtype properties in a genetic animal model of human anxiety, mice heterozygous for the deletion of GABAA receptor γ2 subunit (γ2+/−) were studied using ligand autoradiographic assays on brain cryostat sections. The []TBPS binding assay was designed to reveal impaired GABA and channel site coupling shown to be more prominent in recombinant α1/6β3 than in α1/2β3γ2 or β2 subunit-containing GABAA receptors expressed in HEK 293 cells. Increased GABA-insensitive []TBPS binding in the γ2+/− mouse brains was evident in the cerebral cortex and in subcortical regions, the alterations being regionally similar to the loss of γ2 subnunit-dependent benzodiazepine (BZ) sites as revealed by []Ro 15-4513 autoradiography. As the γ2 subunit protein is needed for synaptic clustering of GABAA receptors, these results indicate that the extrasynaptic αβ3 receptors can be visualized in vitro as atypical GABA-insensitive []TBPS binding sites.The results suggest that GABAAergic synaptic inhibition is widely decreased in the brains of anxiety-prone γ2+/− mice, while extrasynaptic GABAA receptors are increased. These autoradiographic imaging findings further demonstrate the need to develop GABAA receptor subtype-selective in vivo ligands to aid in assessing the contributions of various subcellular receptor populations in anxious and other patient groups.
  Neurochemistry International.
• Article: Structure–activity relationship of furosemide-derived compounds as antagonists of cerebellum-specific GABAA receptors

  Hartmut Lüddens, Hans-J Lang, Esa R Korpi
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  ABSTRACT: The Na+–K+–2Cl− cotransporter blocker furosemide inhibits γ-aminobutyric acid (GABA)-gated chloride currents and reverses GABA-mediated inhibition of []-t-butylbicyclophosphorothionate ([]TBPS) binding of the cerebellar α6 subunit-containing GABAA receptors much more potently than the cerebrocortical non-α6 subunit-containing receptors. Of the 44 compounds studied, all precursors or derivatives of diuretics, one compound [hydrazinosulfonyl-furosemide (PF 1885)] reversed 5-μM GABA-induced inhibition of []TBPS binding to cerebellar and cerebrocortical receptors. Three other compounds, all of which are structurally closely related to furosemide, were selective antagonists for the cerebellar receptors comparable to the lead compound. Still, the diuretic and GABAergic structure–activity relationships differ, since we found potent diuretic structures lacking GABA antagonistic activity. Further development of the GABAergic potency of furosemide derivatives can now focus on the modification of the carboxyl group, replaceable by tetrazole but not by sulfonic or phosphinic acids and the furanyl moiety which could be substituted by thienyl and benzyl groups.
  European Journal of Pharmacology.
• Article: Reduced benzodiazepine tolerance, but increased flumazenil-precipitated withdrawal in AMPA-receptor GluR-A subunit-deficient mice

  Teemu Aitta-aho, Olga Y. Vekovischeva, Pertti J. Neuvonen, Esa R. Korpi
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  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.
  Pharmacology Biochemistry and Behavior.
• Article: Effects of aripiprazole on alcohol intake in an animal model of high-alcohol drinking.

  Kimmo Ingman, Johanna Kupila, Petri Hyytiä, Esa R Korpi
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  ABSTRACT: This study examined the effects of aripiprazole, a novel atypical antipsychotic drug with partial agonist properties at dopamine D2 receptors, on the voluntary limited access alcohol drinking of alcohol-preferring AA (Alko, Alcohol) rats. AA rats were taught to drink 10% alcohol in a 4 h limited access paradigm. Effects of acute aripiprazole (0, 0.3, 1.0, and 3.0 mg/kg) on the limited access alcohol drinking were studied. In repeated treatment experiment, aripiprazole (0, 1.0, and 6.0 mg/kg) was administered once daily over five successive days. To reveal any effect by aripiprazole not selective for alcohol drinking, 0.025% saccharin solution was substituted for alcohol during the 4 h limited access, and acute treatments were repeated. The effects of aripiprazole on ambulatory locomotor activity were tested with doses that were used in the acute experiments. Acute aripiprazole at the doses of 0.3, 1.0, and 3.0 mg/kg had no effect on alcohol drinking. Repeated treatment with the aripiprazole dose of 6.0 mg/kg significantly diminished alcohol drinking at the 1 h time point. This dose had no effect on saccharin drinking when given acutely. Acute aripiprazole at the doses of 1.0, 3.0, and 6.0 mg/kg significantly suppressed locomotor activity. Aripiprazole decreased limited access alcohol drinking in AA rats, but only at a high dose that also strongly suppressed locomotor activity.
  Alcohol and Alcoholism 41(4):391-8. · 2.95 Impact Factor
• Article: Characterization of novel ligands for wild-type and natural mutant diazepam-insensitive benzodiazepine receptors

  Garry Wong, Mikko Uusi-Oukari, Holger C. Hansen, Peter D. Suzdak, Esa R. Korpi
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  ABSTRACT: A series of benzodiazepine receptor ligands with different chemical structures were evaluated for their affinities at diazepam-sensitive and diazepam-insensitive binding sites for [3H]Ro 15-4513 (ethyl-8-azido-5,60dihydro-5-methyl-6-oxo-4H-imidazo-[1,5a][1,4]benzodiazepine-3-carboxylate) in cerebellar GABAA receptors. Rats of Wistar strain and of alcohol-sensitive (ANT) and alcohol-insensitive (AT) lines were used. The ANT rats possess a single point mutation in their GABAA receptor α6 subunit, which makes their diazepam-insensitive sites sensitive to benzodiazepine agonists, unlike those of AT and Wistar rats. All compounds evaluated displayed high-affinity binding to diazepam-sensitive sites (Ki < 50 nM). In contrast, a wider range of affinities were observed at diazepam-insensitive sites which depended upon the basic structure and substitutions. The 7- and 8-halogen substituted imidazobenzodiazepines and 12-halogen substituted diimidazoquinazolines displayed the highest affinities (Ki < 15 nM), while intermediate to low affinities (100 < Ki < 4000 nM) were displayed by imidazoquinazolines, thienopyrimidines, one oxoimidazoquinoxaline, and some cyclopyrrolones. The imidazoquinoxalines evaluated displayed the lowest affinity (Ki > 10000 nM). The oxoimidazoquinoxaline, 6-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-isopropyl-4-oxo-imidazol[1,5-a]quinoxaline (NNC 14-0578) and suriclone represent the first benzodiazepine receptor full agonists to bind with relatively high affinity (Ki ∼ 100 nM) to diazepam-insensitive sites. The 5 position substituted methoxybenzyl, dimethylallyl, and 4-fluorobenzyl oxoimidazoquinoxaline analogs demonstrated a 58–336-fold higher affinity for ANT than AT diazepam-insensitive sites. Classical benzodiazepines having a 5-phenyl substituent have demonstrated a similar preference for ANT sites, suggesting that all these structures bind to diazepam-insensitive sites in the same orientation. The other compounds evaluated demonstrated only a more modest selectivity (1–12-fold), indicating different structural requirements for binding to mutant ANT and wild-type AT and Wistar receptors. These results expand the range of ligands which display high affinity for diazepam-insensitive sites. Such compounds shoudl be helpful in determining intrinsic actions of high-affinity ligands at these sites and in assessing the contribution of these sites in enhanced sedative sensitivity of cerebellar function in the ANT rats.
  European Journal of Pharmacology: Molecular Pharmacology.
• Article: Brain regional μ-opioid receptor function in rat lines selected for differences in alcohol preference

  Sanna L Soini, Petri Hyytiä, Esa R Korpi
  [show abstract] [hide abstract]
  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.
  European Journal of Pharmacology.
• Article: Cerebellar GABAA receptors and anxiolytic action of diazepam

  Olga Y. Vekovischeva, Antti Haapalinna, Maija Sarviharju, Aapo Honkanen, Esa R. Korpi
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  ABSTRACT: Alcohol-sensitive ANT rats have a point mutation in the cerebellum-enriched GABAA receptor α6 subunit, which makes this subunit and the ANT rats in vivo highly sensitive to benzodiazepine agonists. In the elevated plus maze test of anxiety, diazepam produced a greater anxiolytic response in the ANT rats than in the control, alcohol-insensitive AT rats. The ANT rats were less sensitive to the sedative effect of diazepam in the staircase test of exploration. The results thus suggest that the mutant cerebellar granule cell layer receptors can participate in GABAA receptor-activation-induced anxiolysis.
  Brain Research.
• Article: Loreclezole and La3+ differentiate cerebellar granule cell GABAA receptor subtypes

  Riikka Mäkelä, William Wisden, Esa R Korpi
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  ABSTRACT: The effects of loreclezole and La3+ on native cerebellar GABAA receptors were compared between GABAA receptor α6 subunit-deficient (α6−/−) and wildtype mouse lines, produced through homologous recombination, using t-[]butylbicyclophosphorothionate ([]TBPS) autoradiography in brain sections. In the α6 subunit-deficient mice, the GABA receptor antagonistic ability of La3+ was abolished in the cerebellar granule cell layer, consistent with its opposite actions on α6- and α1 subunit-containing receptors. La3+ significantly potentiated the action of GABA in the molecular layer of the α6−/− mice, but not in that of the wildtype mice. The potentiation of agonistic GABA inhibition of []TBPS binding by loreclezole in α6−/− granule cells was reduced, suggesting an emergence of low-affinity GABAA receptors. The present results thus identified two ligands that may be useful in studying functional roles of cerebellar α1 and α6 subunit-containing GABAA receptor subtypes.
  European Journal of Pharmacology.
• Article: α2A-Adrenoceptors regulate d-amphetamine-induced hyperactivity and behavioural sensitization in mice

  Juuso Juhila, Aapo Honkanen, Jukka Sallinen, Antti Haapalinna, Esa R. Korpi, Mika Scheinin
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  ABSTRACT: Stimulants, such as d-amphetamine, enhance the release of dopamine in the central nervous system (CNS) and induce locomotor activation in mice. When amphetamine is administered repeatedly, the locomotor activation is progressively increased. This behavioural sensitization may be associated with the development of drug craving, addiction and dependence. Also noradrenergic mechanisms participate in the mediation of the effects of psychostimulants. In this study we show that mice lacking the α2-adrenoceptor subtype A (α2A-AR knock-out (KO) on C57Bl/6J background) are supersensitive to the acute locomotor effects of d-amphetamine (5 mg/kg) in a novel environment compared to wild-type (WT) control mice. When both genotypes were treated repeatedly with d-amphetamine (2 mg/kg) they developed locomotor hyperactivation (sensitization), but its amplitude was lower in α2A-AR KO mice. Development of hyperactivation was reduced in both genotypes by pretreatment with the selective α2-adrenoceptor antagonist, atipamezole (1 mg/kg). Acute atipamezole also attenuated the expression of d-amphetamine-induced behavioural sensitization especially in WT mice. Interestingly, α2A-AR KO mice failed to exhibit persistent sensitization after 2 weeks of abstinence from repeated d-amphetamine. Rewarding properties of d-amphetamine, measured by conditioned place preference, were similar in both genotypes. These findings indicate that d-amphetamine-induced acute and sensitized locomotor effects are controlled by α2-adrenoceptors. Drugs antagonizing the α2A-adrenoceptor subtype may provide a novel approach for reducing drug sensitization and motor complications caused by dopaminergic agents.
  European Journal of Pharmacology.