Giuseppe Talani | Università degli Studi di Cagliari (original) (raw)

Papers by Giuseppe Talani

Proceedings of the National Academy of Sciences of the United States of America, Jan 2, 2014

Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in subst... more Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that "long thin" but not "mushroom" spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recor...

Molecular Pharmacology, 2003

Both benzodiazepines and ␥-hydroxybutyric acid (GHB) are used to treat alcohol withdrawal syndrom... more Both benzodiazepines and ␥-hydroxybutyric acid (GHB) are used to treat alcohol withdrawal syndrome. The molecular basis for this therapeutic efficacy was investigated with primary cultures of rat cerebellar granule cells. Long-term exposure of these cells to ethanol (100 mM, 5 days) reduced the abundance of mRNAs encoding the ␥ 2 L and ␥ 2 S subunits of the GABA type A receptor (Ϫ32 and Ϫ23%, respectively) but failed to affect that of ␣ 1 , ␣ 4 , or ␣ 6 subunit mRNAs. Subsequent ethanol withdrawal resulted in decreases in the amounts of ␣ 1 (Ϫ29%), ␣ 6 (Ϫ27%), ␥ 2 L (Ϫ64%), and ␥ 2 S (Ϫ76%),subunit mRNAs that were maximal after 6 to 12 h. In contrast, 3 h after ethanol withdrawal, the abundance of the ␣ 4 subunit mRNA was increased by 46%. Ethanol withdrawal did not affect neuronal This study was supported by Ministero dell'Istruzione dell'Universita e della Ricerca grant 2001055774.

SR141716 (1 mg/kg, i.p.) was administered 1 h before sacrifice; for FR rats, sacrifice c... more SR141716 (1 mg/kg, i.p.) was administered 1 h before sacrifice; for FR rats, sacrifice corresponded to the 5 min preceding food consumption. (A) Bar graph representing the effect of the administration of SR141716 on spontaneous AP firing recorded in VTA dopaminergic neurons. Data are expressed as absolute values (Hz) and were obtained from 3 different cells for each experimental group. (B) Bar graph representing the effect of SR141716 on the frequency of depolarization-induced APs in mPFC neurons. Data are expressed as absolute values (Hz) and were obtained from 4 to 9 different cells for each experimental groups. (C, D) Bar graphs representing the effect of SR141716 on the inhibitory action of (C) WIN 55212-2 (5 µM) and (D) baclofen (10 µM) on sIPSC frequency in mPFC neurons. Data are expressed as percentage of control and were calculated from 4 to 6 different cells. aP<0.0001 versus fed ad libitum rats treated with vehicle; bP<0.0001 versus FR treated with vehicle. For all experiments one way ANOVA and Newman Keuls post hoc test were performed.</p

Alcoholism-clinical and Experimental Research, 2004

Journal of Medicinal Chemistry, 2005

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 21, 2004

An interaction with the GABA type A (GABA(A)) receptor has long been recognized as one of the mai... more An interaction with the GABA type A (GABA(A)) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA(A) receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABA(A) receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3alpha,5alpha-THP as well as the amplitude of GABA(A) receptor-mediated IPSCs recorded from CA1 pyram...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 17, 2003

Changes in the expression of subunits of the GABA type A (GABA(A)) receptor are implicated in the... more Changes in the expression of subunits of the GABA type A (GABA(A)) receptor are implicated in the development of ethanol tolerance and dependence as well as in the central hyperexcitability associated with ethanol withdrawal. The impact of such changes on GABA(A) receptor function and pharmacological sensitivity was investigated with cultured rat hippocampal neurons exposed to ethanol for 5 d and then subjected to ethanol withdrawal. Both ethanol treatment and withdrawal were associated with a marked decrease in the maximal density of GABA-evoked Cl- currents, whereas the potency of GABA was unaffected. Ethanol exposure also reduced the modulatory efficacy of the benzodiazepine receptor agonists lorazepam, zolpidem, and zaleplon as well as that of the inverse agonists Ro 15-4513 and FG 7142, effects that were associated with a reduced abundance of mRNAs encoding the receptor subunits alpha1, alpha3, gamma2L, and gamma2S. Ethanol withdrawal restored the efficacy of lorazepam, but not...

Thiocolchicoside (TCC) is used clinically for its muscle relaxant, anti-inflammatory, and analges... more Thiocolchicoside (TCC) is used clinically for its muscle relaxant, anti-inflammatory, and analgesic properties, and it has been shown to interact with g-aminobutyric acid (GABA) type A receptors (GABA A Rs) and strychnine-sensitive glycine receptors in the rat central nervous system. In contrast to a proposed agonistic action at these two types of inhibitory receptors, pharmacological evidence has shown that, under certain conditions, TCC manifests convulsant activity in animals and humans. We now show that the phasic and tonic GABA A R-mediated currents recorded from Purkinje cells and granule neurons, respectively, in parasagittal cerebellar slices from adult male rats were inhibited by TCC in a concentration-dependent manner. The median inhibitory concentrations of TCC for these effects were w0.15 and w0.9 mM, respectively. TCC did not potentiate GABA B R-mediated currents in hippocampal slices, suggesting that its muscle relaxant action is not mediated by GABA B Rs. Intraperitoneal injection of TCC in rats either alone or in combination with negative modulators of GABAergic transmission revealed convulsant and proconvulsant actions of this drug. Our data, consistent with clinical observations of the epileptogenic effect of this compound, suggest that TCC is a potent competitive antagonist of GABA A R function.

The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition s... more The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition site of GABA A receptors. Zaleplon, like the hypnotic agent zolpidem but unlike classical benzodiazepines, exhibits preferential affinity for type I benzodiazepine (BZ 1 /N 1 ) receptors in binding assays. The modulatory action of zaleplon at GABA A receptors has now been compared with those of zolpidem and the triazolobenzodiazepine triazolam. Zaleplon potentiated GABA-evoked Cl À currents in Xenopus oocytes expressing human GABA A receptor subunits with a potency that was higher at a1h2g2 receptors than at a2or a3-containing receptors. Zolpidem, but not triazolam, also exhibited selectivity for a1-containing receptors. However, the potency of zaleplon at these various receptors was one-third to one-half that of zolpidem. Zaleplon and zolpidem also differed in their actions at receptors containing the a5 or g3 subunit. Zaleplon, zolpidem, and triazolam exhibited similar patterns of efficacy among the different receptor subtypes. The affinities of zaleplon for [ 3 H]flunitrazepam or t-[ 35 S]butylbicyclophosphorothionate ([ 35 S]TBPS) binding sites in rat brain membranes were lower than those of zolpidem or triazolam. Furthermore, zaleplon, unlike zolpidem, exhibited virtually no affinity for the peripheral type of benzodiazepine receptor. D

The International Journal of Neuropsychopharmacology, 2010

Several recent studies have expanded our conception of the role of astrocytes in neurogenesis, pr... more Several recent studies have expanded our conception of the role of astrocytes in neurogenesis, proposing that these cells may contribute to this phenomenon not only as a source of trophic substances, but also as stem cells themselves. We recently observed in vitro that human mature astrocytes can be induced to differentiate into cells with a neuronal phenotype. Antidepressant drugs have been shown to increase neurogenesis in the adult rodent hippocampus. In order to better understand the role of astroglia in antidepressant-induced neurogenesis, primary astrocyte cultures were treated with the antidepressant imipramine. Cell morphology was rapidly modified by treatment. In fact, whereas untreated astrocytes showed large, flat morphology, after a few hours of treatment cells exhibited a round-shaped cell body with long, thin processes. The expression of neuronal markers was analysed by immunocytochemistry, Western Blot and RT-PCR at different treatment times. Results showed an increase in neuronal markers such as neurofilament and neuron-specific enolase (NSE), whereas glial fibrillary acidic protein (GFAP) and nestin expression were not significantly modified by treatment. Similar results were obtained with fluoxetine and venlafaxine. Hes1 mRNA significantly increased after 2 h of treatment, suggesting involvement of this transcription factor in this process. These results confirm the role of astrocytes in neurogenesis and suggest that these cells may represent one of the targets of antidepressants.

Frontiers in Endocrinology, 2011

Ethanol (EtOH) induced impairment of long-term potentiation (LTP) in the rat hippocampus is preve... more Ethanol (EtOH) induced impairment of long-term potentiation (LTP) in the rat hippocampus is prevented by the 5α-reductase inhibitor finasteride, suggesting that this effect of EtOH is dependent on the increased local release of neurosteroids such as 3α,5α-THP that promote GABA-mediated transmission. Given that social isolation (SI) in rodents is associated with altered plasma and brain levels of such neurosteroids as well as with an enhanced neurosteroidogenic action of EtOH, we examined whether the inhibitory effect of EtOH on LTP at CA3-CA1 hippocampal excitatory synapses is altered in C57BL/6J mice subjected to SI for 6 weeks in comparison with group-housed (GH) animals. Extracellular recording of field excitatory postsynaptic potentials (fEPSPs) as well as patch-clamp analysis were performed in hippocampal slices prepared from both SI and GH mice. Consistent with previous observations, recording of fEPSPs revealed that the extent of LTP induced in the CA1 region of SI mice was significantly reduced compared with that in GH animals. EtOH (40 mM) inhibited LTP in slices from SI mice but not in those from GH mice, and this effect of EtOH was abolished by co-application of 1 μM finasteride. Current-clamp analysis of CA1 pyramidal neurons revealed a decrease in action potential (AP) frequency and an increase in the intensity of injected current required to evoke the first AP in SI mice compared with GH mice, indicative of a decrease in neuronal excitability associated with SI. Together, our data suggest that SI results in reduced levels of neuronal excitability and synaptic plasticity in the hippocampus. Furthermore, the increased sensitivity to the neurosteroidogenic effect of EtOH associated with SI likely accounts for the greater inhibitory effect of EtOH on LTP in SI mice. The increase in EtOH sensitivity induced by SI may be important for the changes in the effects of EtOH on anxiety and on learning and memory associated with the prolonged stress attributable to SI.

Journal of Neuroscience, 2010

N-methyl-D-aspartate receptors (NMDARs) are key mediators of certain forms of synaptic plasticity... more N-methyl-D-aspartate receptors (NMDARs) are key mediators of certain forms of synaptic plasticity and learning. NMDAR complexes are heteromers composed of an obligatory GluN1 subunit and one or more GluN2 (GluN2A-GluN2D) subunits. Different subunits confer distinct physiological and molecular properties to NMDARs, but their contribution to synaptic plasticity and learning in the adult brain remains uncertain. Here, we generated mice lacking GluN2B in pyramidal neurons of cortex and CA1 subregion of hippocampus. We found that hippocampal principal neurons of adult GluN2B mutants had faster decaying NMDAR-mediated excitatory postsynaptic currents (EPSCs) than non-mutant controls, and were insensitive to GluN2B but not NMDAR antagonism. A subsaturating form of hippocampal long-term potentiation (LTP) was impaired in the mutants, whereas a saturating form of LTP was intact. A NMDAR-dependent form of long-term depression (LTD) produced by low-frequency stimulation combined with glutamate transporter inhibition was abolished in the mutants. Additionally, mutants exhibited decreased dendritic spine density in CA1 hippocampal neurons as compared to controls. On multiple assays for corticohippocampal-mediated learning and memory (hidden platform Morris water maze, T-maze spontaneous alternation, Pavlovian trace fear conditioning), mutants were impaired. These data further demonstrate the importance of GluN2B for synaptic plasticity in the adult hippocampus and suggest a particularly critical role in LTD, at least the form studied here. The finding that loss of GluN2B was sufficient to cause learning deficits illustrates the contribution of GluN2B-mediated forms of plasticity to memory formation, with implications for elucidating NMDAR-related dysfunction in disease-related cognitive impairment.

Journal of Neuroscience, 2004

An interaction with the GABA type A (GABA A ) receptor has long been recognized as one of the mai... more An interaction with the GABA type A (GABA A ) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3␣-hydroxy-5␣-pregnan-20-one (3␣,5␣-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA A receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABA A receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3␣,5␣-THP as well as the amplitude of GABA A receptor-mediated IPSCs recorded from CA1 pyramidal neurons in isolated hippocampal slices. These effects are shared by the neurosteroid precursor progesterone, the peripheral benzodiazepine receptor-selective agonist CB34, and ␥-hydroxybutyrate, all of which are known to increase the formation of neuroactive steroids in plasma and in the brain. The action of ethanol on GABA A receptormediated IPSC amplitude is biphasic, consisting of a rapid, direct effect on GABA A receptor activity and an indirect effect that appears to be mediated by neurosteroid synthesis. Furthermore, ethanol affects GABA A receptor activity through a presynaptic action, an effect that is not dependent on neurosteroid formation. These observations suggest that ethanol may modulate GABA A receptor function through an increase in de novo neurosteroid synthesis in the brain that is independent of the HPA axis. This novel mechanism may have a crucial role in mediating specific central effects of ethanol.

Journal of Neuroscience, 2009

Pregnancy is associated with changes in mood and anxiety level as well as with marked hormonal fl... more Pregnancy is associated with changes in mood and anxiety level as well as with marked hormonal fluctuations. Increases in the brain concentrations of neuroactive steroids during pregnancy in rats are accompanied by changes in expression of subunits of the GABA type A receptor (GABA A -R) in the brain. Granule cells of the dentate gyrus (DGGCs) exhibit two components of inhibitory GABAergic transmission: a phasic component mediated by synaptic GABA A -Rs, and a tonic component mediated by extrasynaptic GABA A -Rs. Recordings of GABAergic currents were obtained from hippocampal slices prepared from rats in estrus, at pregnancy day 15 (P15) or P19, or at 2 d after delivery. Exogenous GABA or 3␣,5␣-THP induced an increase in tonic current in DGGCs that was significantly greater at P19 than in estrus. Neither tonic nor phasic currents were affected by pregnancy in CA1 pyramidal cells. Immunohistochemical analysis revealed a marked increase in the abundance of the ␦ subunit of the GABA A -R and a concomitant decrease in that of the ␥ 2 subunit in the hippocampus at P19. Expression of the ␣ 4 subunit did not change during pregnancy but was increased 2 d after delivery. Treatment of rats from P12 to P18 with the 5␣-reductase inhibitor finasteride prevented the changes in tonic current and in ␦ and ␥ 2 subunit expression normally apparent at P19. These data suggest that the number of extrasynaptic GABA A -Rs is increased in DGGCs during late pregnancy as a consequence of the associated marked fluctuations in the brain levels of neuroactive steroids.

Psychopharmacology, 2006

Rationale: Changes in the expression of type A receptors for γ-aminobutyric acid (GABA) represent... more Rationale: Changes in the expression of type A receptors for γ-aminobutyric acid (GABA) represent one of the mechanisms implicated in the development of tolerance to and dependence on ethanol. The impact of such changes on the function and pharmacological sensitivity of GABA A receptors (GABA A Rs) has remained unclear, however. Certain behavioral and electrophysiological actions of ethanol are mediated by an increase in the concentration of neuroactive steroids in the brain that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Such steroids include potent modulators of GABA A R function. Objectives: We have investigated the effect of ethanol exposure and withdrawal on subunit expression and receptor function evaluated by subunit selective compounds, as well as the effects of short-term exposure to ethanol on both neurosteroid synthesis and GABA A R function, in isolated neurons and brain tissue. Results: Chronic treatment with and subsequent withdrawal from ethanol alter the expression of genes for specific GABA A R subunits in cultured rat neurons, and these changes are associated with alterations in receptor function and pharmacological sensitivity to neurosteroids, zaleplon, and flumazenil. Acute ethanol exposure increases the amount of 3α-hydroxy-5αpregnan-20-one (allopregnanolone) in hippocampal slices by a local action independent of the activity of the HPA axis. This effect of ethanol was associated with an increased amplitude of GABA A R-mediated miniature inhibitory postsynaptic currents recorded from CA1 pyramidal neurons in such slices. Conclusions: Chronic ethanol exposure elicits changes in the subunit composition of GABA A Rs, which, in turn, likely contribute to changes in receptor function associated with the altered pharmacological and behavioral sensitivity characteristic of ethanol tolerance and dependence. Ethanol may also modulate GABA A R function by increasing the de novo synthesis of neurosteroids in the brain in a manner independent of the HPA axis. This latter mechanism may play an important role in the central effects of ethanol.

PLoS ONE, 2014

Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) ... more Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1 cannabinoid receptor in this brain region.

Neuroscience, 2008

T h e cerebellar cortex contributes to the control of movement, coordination, and certain cogniti... more T h e cerebellar cortex contributes to the control of movement, coordination, and certain cognitive functions. The cerebellar network is composed of five different types of neurons that are wired together in a repetitive module. Given that four of these five neurons synthesize and release GABA, this inhibitory neurotransmitter plays a central role in regulation of the excitability and correct functioning of the cerebellar cortex. We have now used isoniazid, an inhibitor of glutamic acid decarboxylase, the enzyme responsible for the synthesis of GABA, to evaluate the contribution of GABAergic transmission in different types of cerebellar cortical neurons to the functioning of the cerebellar circuit. Parasagittal cerebellar slices were prepared from 28-to 40-day-old male rats and were subjected to patch-clamp recording in the voltageor current-clamp mode. Exposure of the tissue slices to isoniazid (10 mM) resulted in a decrease in the level of GABAergic transmission in Purkinje cells and a consequent increase in the firing rate of spontaneous action potentials that was apparent after 40 min. In granule neurons, isoniazid reduced both tonic and phasic GABAergic currents and thereby altered the flow of information across the cerebellar cortex. Our data support the notion that the amount of GABA at the synaptic level is a major determinant of the excitability of the cerebellar cortex, and they suggest that isoniazid may be a useful tool with which to study the function of the cerebellar network. inhibitory postsynaptic current; EPSP, excitatory postsynaptic potential; GABA A , GABA type A; GAD, glutamic acid decarboxylase; Hepes, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; INH, isonicotinic acid hydrazide; mIPSC, miniature inhibitory postsynaptic current; MPA, 3-mercaptopropionic acid.

Neurochemical Research, 2014

Social isolation (SI) is a notable model of prolonged mild stress, characterized by multiple neur... more Social isolation (SI) is a notable model of prolonged mild stress, characterized by multiple neurochemical and behavioral alterations, that appears particularly suitable for studying different aspects of the interplay between stress and ethanol (EtOH) consumption in order to characterize potential molecular mechanisms, including changes in the function of inhibitory GABAergic synapses, underlying such interaction. In C57BL/6J mice, SI is associated with an altered hippocampal concentration of the neuroactive steroids 3α-hydroxy-5α-pregnan-20-one (3α-5α-THP), an increased expression of the α4 and δ subunit of γ-aminobutyric acid type A receptors (GABAARs) in the dentate gyrus (DG), and a parallel enhancement of the stimulatory action of 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) on GABAergic tonic currents recorded in voltage-clamped DG granule cells (DGGCs). In addition, SI in C57BL/6J mice determines an increase in voluntary EtOH consumption and EtOH preference when compared to group-housed (GH) control animals. Furthermore, in hippocampal slices of SI mice we also observed a marked reduction of both cellular excitability and long term potentiation (LTP) in pyramidal neurons of the CA1 hippocampal sub-region, effects that were prevented by the long term treatment of SI mice with the neuroactive steroid precursor progesterone. In this article, we summarize some of our recent findings on the effects of SI in C57BL/6J mice on voluntary EtOH intake, regulation of GABAARs gene expression and function and hippocampal long term synaptic plasticity.

Journal of Neurochemistry, 2006

Previously we have demonstrated that social isolation of rats reduces both the cerebrocortical an... more Previously we have demonstrated that social isolation of rats reduces both the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG), and potentiates the positive effects of acute ethanol administration on the concentrations of this neurosteroid. We now show that the ethanol-induced increase in 3a,5a-TH PROG is more pronounced in the brain than in the plasma of isolated rats. The ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect is prevented by treatment with finasteride. Social isolation modified the effects of ethanol on the amounts of steroidogenic regulatory protein mRNA and protein in the brain. Moreover, ethanol increased the amplitude of GABA A receptor-mediated miniature inhibitory postsynaptic currents recorded from CA1 pyramidal neurones with greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed rats, an effect inhibited by finasteride. The amounts of the a 4 and d subunits of the GABA A receptor in the hippocampus were increased in isolated rats as were GABA A receptor-mediated tonic inhibitory currents in granule cells of the dentate gyrus. These results suggest that social isolation results in changes in GABA A receptor expression in the brain, and in an enhancement of the stimulatory effect of ethanol on brain steroidogenesis, GABA A receptor function and associated behaviour. evoked miniature inhibitory postsynaptic current; EtOH, ethanol; GAPDH, glyceraldehyde-3-phopshate dehydrogenase; HPA, hypothalamic-pituitary-adrenal; mIPSC, miniature inhibitory postsynaptic current; PBR, peripheral benzodiazepine receptor; PBS, phosphate-buffered saline; PBS-T, PBS containing 0.2% Triton X-100; StAR, steroidogenic regulatory protein.