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ABSTRACT: A single administration of benzodiazepine-site ligands of the inhibitory GABA(A) receptors has been shown to lead to persistently potentiated AMPA receptor-mediated responses in dopaminergic neurons of the ventral tegmental area (VTA). This plasticity has been suggested to be a common property of different kinds of addictive drugs. We now wanted to test if the plasticity induced by diazepam would also affect behaviors elicited by other drugs of abuse. Activity and plasticity of the VTA dopaminergic neurons are known to be essential for the initiation and/or sensitization of the psychomotor responses to morphine and amphetamine. The effect of diazepam pre-treatment (a single dose of 5 mg/kg) was studied 24-72 h later in behaving C57BL/6J mice on locomotor activity induced by acute and repeated administration of morphine (5 mg/kg) and amphetamine (2.5 mg/kg). The pre-treatment attenuated the locomotor-activating effect of morphine. On the other hand, it reduced the amphetamine-induced locomotor sensitization in male mice in N-methyl-d-aspartate (NMDA) receptor-dependent manner. The acute amphetamine effect was not affected. The results indicate that benzodiazepine-induced neural plasticity transiently reduces the sensitivity to psychomotor stimulation by opioids and stimulants.
Neuroscience 07/2011; 192:312-21. · 3.38 Impact Factor
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ABSTRACT: LY341495 is a metabotropic glutamate receptor (mGluR) antagonist showing selectivity to mGluR2/3 but having measurable antagonist efficacy across all mGluR subtypes at 10-1000 fold higher concentrations. In vivo in rodents it increases locomotor activity and wakefulness, enhances cognition and modulates emotions. It also induces widespread neuronal activation measured as c-Fos expression. To further investigate the receptor subtypes through which LY341495 might act in vivo we analyzed how its effects are altered in mGluR2-knockout (KO) and mGluR3-KO brains. In most regions, LY341495 (3 mg/kg, i.p., 2.5 h) -induced c-Fos expression was not altered in either KO brain. However, in mGluR3-KO mice, LY341495 was almost inactive in the central extended amygdala [central nucleus of the amygdala, lateral (CeL) and bed nucleus of the stria terminalis, laterodorsal (BSTLD)], suggesting that acute blockade of mGluR3 is activating these neurons in wildtype brain. In the ventrolateral nucleus of the thalamus (VL), LY341495 produced a significantly enhanced response in mGluR3-KO mice and attenuated response in mGluR2-KO mice. We also analyzed locomotion in familiar environment and found that locomotor activity was dose-dependently increased by LY341495 (1-30 mg/kg, i.p.) regardless of the genotype. In unfamiliar environment, both KO strains showed enhanced sensitivity to LY341495 in reducing locomotor habituation. Together our results indicate that certain effects of LY341495 may not be mediated by a blockade of either mGluR2 or mGluR3, but may involve other mGluR subtypes. Alternatively, functions of mGluR2 and mGluR3 may be redundant, resulting similar effects irrespective the receptor subtype being antagonized in vivo by LY341495.
Neuropharmacology 06/2009; 57(2):172-82. · 4.81 Impact Factor
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ABSTRACT: Behavioral observations as a matrix of probabilistic changes of postures and acts are multiple measurements that could introduce variability to statistical analysis. We propose the multimetric statistical algorithm that supplements the linear analysis of variance by pair correlation, factor and discriminant function analyses. Although these methods were utilized mostly in behavioral studies, the combined use in frame of one behavioral test was not done before. In present study statistical techniques were applied to analyze social behavior in Turku aggressive (TA) and Turku non-aggressive (TNA) mouse lines, bidirectional selected for offensive aggression towards an unknown male. Each statistical technique amplified new details of mouse behavioral profiles that give possibility to describe TA and TNA subjects in terms of Cloninger's model of personality. Also, it was identified that TA mice displayed fighting-biting aggression while TNA mice demonstrated immobile defensive strategy. Hypothetical discriminant formula was found for each mouse behavioral genotype that might be used to identify behavioral profile and line affiliation of unknown subjects.
Behavioural Processes 06/2007; 75(1):23-32. · 1.65 Impact Factor
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ABSTRACT: Kainic acid-induced status epilepticus leads to structural and functional changes in inhibitory GABAA receptors in the adult rat hippocampus, but whether similar changes occur in the developing rat is not known. We have used in situ hybridization to study status epilepticus-induced changes in the GABAAalpha1-alpha5, beta1-beta3, gamma1 and gamma2 subunit mRNA expression in the hippocampus of 9-day-old rats during 1 week after the treatment. Immunocytochemistry was applied to detect the alpha1, alpha2 and beta3 subunit proteins in the control and treated rats. In the saline-injected control rats, the alpha1 and alpha4 subunit mRNA expression significantly increased between the postnatal days 9-16, whereas those of alpha2, beta3 and gamma2 subunits decreased. The normal developmental changes in the expression of alpha1, alpha2, beta3 and gamma2 subunit mRNAs were altered after the treatment. The immunostainings with antibodies to alpha1, alpha2 and beta3 subunits confirmed the in situ hybridization findings. No neuronal death was detected in any hippocampal subregion in the treated rats. Our results show that status epilepticus disturbs the normal developmental expression pattern of GABAA receptor subunit in the rat hippocampus during the sensitive postnatal period of brain development. These perturbations could result in altered functional and pharmacological properties of GABAA receptors.
Journal of Neurochemistry 10/2005; 94(5):1384-94. · 4.06 Impact Factor
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D W Cope,
C Halbsguth,
T Karayannis,
P Wulff,
F Ferraguti,
H Hoeger,
E Leppä,
A-M Linden,
A Oberto,
W Ogris, E R Korpi,
W Sieghart,
P Somogyi,
W Wisden,
M Capogna
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ABSTRACT: Zolpidem is a hypnotic benzodiazepine site agonist with some gamma-aminobutyric acid (GABA)(A) receptor subtype selectivity. Here, we have tested the effects of zolpidem on the hippocampus of gamma2 subunit (gamma2F77I) point mutant mice. Analysis of forebrain GABA(A) receptor expression with immunocytochemistry, quantitative [(3)H]muscimol and [(35)S] t-butylbicyclophosphorothionate (TBPS) autoradiography, membrane binding with [(3)H]flunitrazepam and [(3)H]muscimol, and comparison of miniature inhibitory postsynaptic current (mIPSC) parameters did not reveal any differences between homozygous gamma2I77/I77 and gamma2F77/F77 mice. However, quantitative immunoblot analysis of gamma2I77/I77 hippocampi showed some increased levels of gamma2, alpha1, alpha4 and delta subunits, suggesting that differences between strains may exist in unassembled subunit levels, but not in assembled receptors. Zolpidem (1 microm) enhanced the decay of mIPSCs in CA1 pyramidal cells of control (C57BL/6J, gamma2F77/F77) mice by approximately 60%, and peak amplitude by approximately 20% at 33-34 degrees C in vitro. The actions of zolpidem (100 nm or 1 microm) were substantially reduced in gamma2I77/I77 mice, although residual effects included a 9% increase in decay and 5% decrease in peak amplitude. Similar results were observed in CA1 stratum oriens/alveus interneurons. At network level, the effect of zolpidem (10 microm) on carbachol-induced oscillations in the CA3 area of gamma2I77/I77 mice was significantly different compared with controls. Thus, the gamma2F77I point mutation virtually abolished the actions of zolpidem on GABA(A) receptors in the hippocampus. However, some residual effects of zolpidem may involve receptors that do not contain the gamma2 subunit.
European Journal of Neuroscience 07/2005; 21(11):3002-16. · 3.63 Impact Factor
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ABSTRACT: Affinity of the inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) to the benzodiazepine binding site of the GABA(A) receptor is abolished by a phenylalanine (F) to isoleucine (I) substitution at position 77 of the gamma2 subunit. We tested the effects of DMCM in gene knockin gamma2I77 mice carrying this mutation. Unlike in wild-type mice, DMCM was not able to reverse the GABA-induced reduction of the picrotoxin-sensitive t-butylbicyclophosphoro-[35S]thionate ([35S]TBPS) binding to GABA(A) receptor channels in the forebrain sections of gamma2I77 mice. Accordingly, DMCM was not convulsant in the mutant mice even at doses 20-fold higher (60mg/kg, i.p.) than those producing convulsions in wild-type littermate controls (3 mg/kg, i.p.). Neither did DMCM raise the c-Fos levels in gamma2I77 mouse brain. DMCM additionally exhibits a less well described agonistic effect on GABA(A) receptors that is normally masked by its strong inverse agonist effect. DMCM agonistically enhanced the GABA-induced reduction in [35S]TBPS binding to the cerebellar granule cell layer in control and mutant mice. In vivo DMCM (20-60 mg/kg i.p.) produced modest anxiolytic-like effects in gamma2I77 mice as assessed by elevated plus maze and staircase tests, but no motor impairment was found in the rotarod test. The results suggest only minor agonistic efficacy for the beta-carboline DMCM.
Neuropharmacology 04/2005; 48(4):469-78. · 4.81 Impact Factor
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ABSTRACT: The mammalian RFamide-related peptide RFRP1 was found to signal through the neuropeptide FF 2 receptor expressed in Xenopus oocytes. The peptide induced a dose-dependent outward current, which was dependent on the simultaneous expression of GIRK1 and GIRK4 potassium channels. In neuropathic rats, RFRP1 administered intrathecally induced tactile antiallodynia and thermal antinociception, whereas in the solitary tract nucleus it produced only mechanical antihyperalgesia. Expression of the RFamide-related peptide mRNA in the rat CNS was distinctly different from that of neuropeptide FF. Most notably, the gene was not expressed in the hindbrain or spinal cord at detectable levels. However, there was a prominent group of RFamide-related peptide mRNA-expressing neurons in the central hypothalamus, in the area in and between the dorsomedial and ventromedial nuclei. The results suggest that RFamide-related peptides are potentially involved in pain regulation through a hypothalamo-medullary projection system, and possibly via action on neuropeptide FF 2 receptors. In neuropathic animals, the pain suppressive effect of RFamide-related peptide varies depending on the submodality of noxious test stimulation and the site of RFamide-related peptide administration.
Neuroscience 02/2005; 134(3):1023-32. · 3.38 Impact Factor
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ABSTRACT: The importance of AMPA-type glutamate receptors has been demonstrated in neuronal plasticity and in adaptation to drugs of abuse. We studied the involvement of AMPA receptors in social interaction and anxiety and found that in several paradigms of agonistic behavior naïve male mice deficient for the GluR-A subunit- containing AMPA receptors are less aggressive than wild-type littermates. GluR-A deficient mice and wild-type littermates exhibited similar basic behavior and reflexes as monitored by observational Irwin's test, but they tended to be less anxious in elevated plus-maze and light-dark tests. Maternal aggression or male-female encounters were not affected which suggests that male hormones are involved in the expression of suppressed aggressiveness. However, testosterone levels and brain monoamines can be excluded and found to be similar between GluR-A deficient and wild-type littermates. The reduced AMPA receptor levels caused by the lack of the GluR-A subunit, and measured by a 30% reduction in hippocampal [3H]-S-AMPA binding, seem to be the reason for suppressed male aggressiveness. When we analyzed mice with reduced number of functional AMPA receptors mediated by the genomic introduced GluR-A(Q582R) channel mutation, we observed again male-specific suppressed aggression, providing additional evidence for GluR-A subunit-containing AMPA receptor involvement in aggression.
Genes Brain and Behavior 11/2004; 3(5):253-65. · 3.48 Impact Factor
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D W Cope,
P Wulff,
A Oberto,
M I Aller,
M Capogna,
F Ferraguti,
C Halbsguth,
H Hoeger,
H E Jolin,
A Jones,
A N J McKenzie,
W Ogris,
A Poeltl,
S T Sinkkonen,
O Y Vekovischeva, E R Korpi,
W Sieghart,
E Sigel,
P Somogyi,
W Wisden
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ABSTRACT: Agonists of the allosteric benzodiazepine site of GABAA receptors bind at the interface of the alpha and gamma subunits. Here, we tested the in vivo contribution of the gamma2 subunit to the actions of zolpidem, an alpha1 subunit selective benzodiazepine agonist, by generating mice with a phenylalanine (F) to isoleucine (I) substitution at position 77 in the gamma2 subunit. The gamma2F77I mutation has no major effect on the expression of GABAA receptor subunits in the cerebellum. The potency of zolpidem, but not that of flurazepam, for the inhibition of [3H]flunitrazepam binding to cerebellar membranes is greatly reduced in gamma2I77/I77 mice. Zolpidem (1 microM) increased both the amplitude and decay of miniature inhibitory postsynaptic currents (mIPSCs) in Purkinje cells of control C57BL/6 (34% and 92%, respectively) and gamma2F77/F77 (20% and 84%) mice, but not in those of gamma2F77I mice. Zolpidem tartrate had no effect on exploratory activity (staircase test) or motor performance (rotarod test) in gamma2I77/I77 mice at doses up to 30 mg/kg (i.p.) that strongly sedated or impaired the control mice. Flurazepam was equally effective in enhancing mIPSCs and disrupting performance in the rotarod test in control and gamma2I77/I77 mice. These results show that the effect of zolpidem, but not flurazepam, is selectively eliminated in the brain by the gamma2F77I point mutation.
Neuropharmacology 08/2004; 47(1):17-34. · 4.81 Impact Factor
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ABSTRACT: Angelman syndrome is a severe neurodevelopmental disorder with cognitive impairment and neurological deficits. It results from a maternal deletion of human chromosome 15q11-13 containing two candidate genes E6-P ubiquitin-protein ligase (UBE3A) and GABA(A) receptor beta3 subunit (GABRB3), the latter of which has been also linked to autism. To clarify the potential role of GABA(A) beta3 subunit-containing inhibitory receptors in these disorders, we applied ligand autoradiography on brain sections from mice with inactivated GABRB3 or maternal UBE3A genes. Binding of GABA(A) receptor channel ([(35)S]t-butylbicyclophosphorothionate) and benzodiazepine ([(3)H]Ro 15-4513) site ligands was reduced in selected brain regions of the beta3-deficient mice as compared to controls, while the UBE3A-deficient mice failed to show reduced GABA(A) receptors. The results, suggesting two different pathophysiological mechanisms, are in agreement with positron emission tomography results from Angelman syndrome patients of the corresponding genetic backgrounds.
Neuroscience Letters 05/2003; 340(3):205-8. · 2.11 Impact Factor
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W Wisden,
D Cope,
T Klausberger,
B Hauer,
S T Sinkkonen,
V Tretter,
R Lujan,
A Jones, E R Korpi,
I Mody,
W Sieghart,
P Somogyi
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ABSTRACT: We generated transgenic (Thy1alpha6) mice in which the GABA(A) receptor alpha6 subunit, whose expression is usually confined to granule cells of cerebellum and cochlear nuclei, is ectopically expressed under the control of the pan-neuronal Thy-1.2 promoter. Strong Thy1alpha6 subunit expression occurs, for example, in deep cerebellar nuclei, layer V iscocortical and hippocampal pyramidal cells and dentate granule cells. Ligand binding and protein biochemistry show that most forebrain alpha6 subunits assemble as alpha6betagamma2-type receptors, and some as alpha1alpha6betagamma2 and alpha3alpha6betagamma2 receptors. Electron microscopic immunogold labeling shows that most Thy1-derived alpha6 immunoreactivity is in the extrasynaptic plasma membrane of dendrites and spines in both layer V isocortical and CA1pyramidal cells. Synaptic immunolabeling is rare. Consistent with the alpha6 subunits' extrasynaptic localization, Thy1alpha6 CA1 pyramidal neurons have a five-fold increased tonic GABA(A) receptor-mediated current compared with wild-type cells; however, the spontaneous IPSC frequency and the mIPSC amplitude in Thy1alpha6 mice decrease 37 and 30%, respectively compared with wild-type. Our results strengthen the idea that GABA(A) receptors containing alpha6 subunits can function as extrasynaptic receptors responsible for tonic inhibition and further suggest that a homeostatic mechanism might operate, whereby increased tonic inhibition causes a compensatory decrease in synaptic GABA(A) receptor responses.
Neuropharmacology 10/2002; 43(4):530-49. · 4.81 Impact Factor
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ABSTRACT: A GABA(A) receptor delta subunit-deficient mouse line was created by homologous recombination in embryonic stem cells to investigate the role of the subunit in the brain GABA(A) receptors. High-affinity [(3)H]muscimol binding to GABA sites as studied by ligand autoradiography was reduced in various brain regions of delta(-/-) animals. [(3)H]Ro 15-4513 binding to benzodiazepine sites was increased in delta(-/-) animals, partly due to an increment of diazepam-insensitive receptors, indicating an augmented forebrain assembly of gamma 2 subunits with alpha 4 subunits. In the western blots of forebrain membranes of delta(-/-) animals, the level of gamma 2 subunit was increased and that of alpha 4 decreased, while the level of alpha1 subunits remained unchanged. In the delta(-/-) forebrains, the remaining alpha 4 subunits were associated more often with gamma 2 subunits, since there was an increase in the alpha 4 subunit level immunoprecipitated by the gamma 2 subunit antibody. The pharmacological properties of t-butylbicyclophosphoro[(35)S]thionate binding to the integral ion-channel sites were slightly altered in the forebrain and cerebellum, consistent with elevated levels of alpha 4 gamma 2 and alpha 6 gamma 2 subunit-containing receptors, respectively.The altered pharmacology of forebrain GABA(A) receptors and the decrease of the alpha 4 subunit level in delta subunit-deficient mice suggest that the delta subunit preferentially assembles with the alpha 4 subunit. The delta subunit seems to interfere with the co-assembly of alpha 4 and gamma 2 subunits and, therefore, in its absence, the gamma 2 subunit is recruited into a larger population of alpha 4 subunit-containing functional receptors. These results support the idea of subunit competition during the assembly of native GABA(A) receptors.
Neuroscience 02/2002; 109(4):733-43. · 3.38 Impact Factor
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ABSTRACT: Changes in magnesium ion (Mg(2+)) concentration may be implicated in alcohol-related behaviors through modulation of neuronal excitability by actions on ligand-gated ion channels. To study whether putative Mg(2+)-binding sites differ between two rat lines, alcohol-insensitive (AT) and alcohol-sensitive (ANT) rats, selectively outbred for differential sensitivity to the motor-impairing effect of ethanol, we compared the effect of Mg(2+) on [35S]tert-butylbicyclophosphorothionate ([35S]TBPS) binding to GABA(A) receptors with the use of ligand autoradiographic analyses of brain sections from these rats. There were some slight differences between the rat lines in modulation of the binding in the forebrain. A low concentration of Mg(2+) (0.1 mM) inhibited basal [35S]TBPS binding more efficiently in the central gray matter and hippocampus in the ANT rats than in the AT rats. In the presence of gamma-aminobutyric acid, the effect of a low concentration of Mg(2+) was higher in the caudate-putamen and inner layer of the cerebral cortex in the AT rats than in the ANT rats. No difference between the rat lines was found at a higher (3 mM) Mg(2+) concentration. Furosemide, a GABA(A) antagonist selective for cerebellar granule cell-specific alpha6beta2/3 subunit-containing receptors, was less efficient in antagonizing the Mg(2+)-induced inhibition of [35S]TBPS binding in the ANT rats than in the AT rats. Another divalent cation, zinc ion, was less efficient in displacing [35S]TBPS binding from the cerebellar granule cell layer in the ANT rats than in the AT rats, whereas a trivalent cation, lanthanum ion, produced identical modulation of the binding in the two rat lines. The results indicate that the alcohol-sensitive ANT rats have altered cerebellar granule cell--specific alpha6 subunit--containing GABA(A) receptors and seem to indicate that these receptors might be implicated in the sensitivity difference of the rat lines to ethanol and sedative drugs.
Alcohol 11/2001; 25(2):69-75. · 2.47 Impact Factor
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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 GABA(A) receptors have unique pharmacological properties, most likely due to the enriched expression of GABA(A) receptor subtypes containing novel epsilon and straight theta subunits. Using in situ hybridisation of cryostat sections, we now report a significant increase in the epsilon 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 GABA(A) receptor subtype(s) in the locus coeruleus neurons during increased neuronal activity.
Neuroreport 10/2001; 12(13):2981-5. · 1.66 Impact Factor
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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 alpha1beta2gamma2S, alpha1beta2, alpha2beta2gamma2S and alpha2beta2 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 08/2001; 12(10):2175-9. · 1.66 Impact Factor
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ABSTRACT: AMPA-type glutamate receptors have been suggested to be involved in the neurobiological mechanisms of drug addiction. We have made use of two mouse lines, which both have modulated AMPA receptor responses. The first line is entirely deficient in glutamate receptor-A (GluR-A) subunits (A-/- knock-out line) and, in the second one, the Q582 residue of GluR-A subunits is replaced by an arginine residue (R/R mutants), which reduces the calcium permeability and channel conductance of the receptors containing this mutated subunit. Mice of both lines are healthy, but they show slightly increased locomotor activity. Acute morphine administration enhanced locomotor activity of the GluR-A-/- and GluR-A(R/R) mice, at least as much as that of their wild-type littermates. Only in the GluR-A-/- mice did we observe reduced tolerance development in tail-flick antinociception and less severe naloxone-precipitated withdrawal symptoms after treatment with increasing morphine doses, without differences in plasma and brain morphine levels when compared with wild type. Repeated daily morphine administration sensitized the locomotor activity responses in the GluR-A-/- and GluR-A(R/R) mice only when given in the measuring cages, whereas the wild-type mice showed slightly increased responses also when the repeated treatment was given in their home cages. Normal or even enhanced context-dependent sensitization was observed also with repeated amphetamine administration in the GluR-A subunit-deficient mice. The results indicate that AMPA receptors are involved in the acute and chronic effects of morphine, including context-independent sensitization, and that the GluR-A subunit itself is important for morphine tolerance and dependence.
Journal of Neuroscience 07/2001; 21(12):4451-9. · 7.11 Impact Factor
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ABSTRACT: Acute administration of a neurosteroid 5beta-pregnan-3alpha-ol-20-one induced a greater impairment in motor performance of the selectively bred alcohol-sensitive (ANT) than alcohol-insensitive (AT) rats. This difference was not associated with the sensitivity of gamma-aminobutyrate type A (GABA(A)) receptors, as 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone) decreased the autoradiographic signals of t-butylbicyclophosphoro[35S]thionate binding to GABA(A) receptor-associated ionophores more in the brain sections of AT than ANT rats. Nor was the difference associated with baseline levels of neuroactive progesterone metabolites, as 5alpha-pregnan-3,20-dione (5alpha-DHP) and 5alpha-pregnan-3alpha-ol-20-one were lower in the ANT rats. After ethanol (2 g/kg, i.p.) administration and the subsequent motor performance test, the increased brain concentrations of these metabolites were still lower in the ANT than AT rats, although especially in the cerebellum the relative increases were greater in the ANT than AT rats. The present data suggest that the mechanisms mediating neurosteroid-induced motor impairment are susceptible to genetic variation in rat lines selected for differences in ethanol intoxication.
European Journal of Pharmacology 07/2001; 421(1):31-8. · 2.52 Impact Factor
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The FASEB Journal 05/2001; 15(6):1074-6. · 5.71 Impact Factor
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ABSTRACT: N-methyl-D-aspartate (NMDA) receptor function appears to be under complex control during physiological and pharmacological states. We have investigated the effects of acute administration of uncompetitive NMDA receptor antagonists on mRNA levels of NMDA receptor subunits and on molecules known to cluster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK-801) decreased mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal and parietal cortices, respectively. MK-801 increased mRNA levels of synapse-associated protein-90/postsynaptic density-95 (SAP90/PSD-95) and a gamma-isoform of protein kinase C (PKCgamma) in cortical regions. Synapse-associated protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK-801 or phencyclidine. NMDA receptor uncompetitive antagonists alter the expression of multiple receptor components and such events may ultimately play a role in adaptation or toxic responses.
Pharmacology & Toxicology 03/2001; 88(2):98-105.
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Duodecim; lääketieteellinen aikakauskirja 02/2001; 117(4):383-7.
