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PubMed2000

Benzodiazepine-sensitive GABA(A) receptors limit the activity of the NMDA/NO/cyclic GMP pathway: a microdialysis study in the cerebellum of freely moving rats.

In the cerebellum, infusion of NMDA (200 microM) for 20 min evoked a marked (200%) increase of extracellular cyclic GMP (cGMP) levels. The selective GABA(A) receptor agonist muscimol (0.01-100 microM) was able to counteract the NMDA effect with an EC(50) of 0.65 microM; the inhibitory effect of muscimol (10 microM) was prevented by bicuculline (50 microM). Diazepam (10 microM) significantly potentiated the muscimol (1 microM) inhibition; furthermore, when coinfused with 0.1 microM muscimol (a concentration not affecting, on its own, the cGMP response to NMDA), diazepam (10 microM) reduced the NMDA effect. Similar results were obtained with zolpidem (0.1-1 microM). Finally, local infusion of the benzodiazepine site antagonist flumazenil (10 microM), together with muscimol and diazepam, almost completely restored the effect of NMDA on extracellular cGMP levels. It is concluded that GABA(A) receptors potently control the NMDA/nitric oxide/cGMP pathway in the cerebellum in vivo. In terms of the alpha subunit composition, we can deduce that the cerebellar GABA(A) receptor does not contain alpha(6) or beta(4) subunits because it is diazepam-sensitive. Moreover, the observation that zolpidem is active at a rather low concentration, in combination with localization studies present in the literature, tend to exclude the presence of alpha(5) subunits in the receptor composition and suggest the involvement of an alpha(1) subunit.

Animals↗
PubMed1989

cAMP and forskolin decrease gamma-aminobutyric acid-gated chloride flux in rat brain synaptoneurosomes.

The effects of the cyclic nucleotide cAMP on gamma-aminobutyric acid-gated chloride channel function were investigated. The membrane-permeant cAMP analog N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate inhibited muscimol-induced 36Cl- uptake into rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (IC50 = 1.3 mM). The inhibition was due to a decrease in the maximal effect of muscimol, with no change in potency. Similar effects were observed with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, 8-bromoadenosine 3',5'-cyclic monophosphate, and the phosphodiesterase inhibitor isobutylmethylxanthine. The effect of endogenous cAMP accumulation on the gamma-aminobutyric acid-gated Cl- channel was studied with forskolin, an activator of adenylate cyclase. Under identical conditions, in the intact synaptoneurosomes, forskolin inhibited muscimol-induced 36Cl- uptake and generated cAMP with similar potencies (IC50 = 14.3 microM; EC50 = 6.2 microM, respectively). Surprisingly, 1,9-dideoxyforskolin, which does not activate adenylate cyclase, also inhibited the muscimol response, suggesting that forskolin and its lipophilic derivatives may interact with the Cl- channel directly. Indeed, forskolin inhibition of muscimol-induced 36Cl- uptake was extremely rapid (within 5 sec), preceding the accumulation of sufficient levels of cAMP. After 5 min, a slower phase of inhibition was seen, similar to the time course for cAMP accumulation. The data suggest that gamma-aminobutyric acid (GABAA) receptor function in brain can be regulated by cAMP-dependent phosphorylation.

1-Methyl-3-isobutylxanthine↗
PubMed1995

A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor.

The reduced progesterone metabolite tetrahydroprogesterone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 3 alpha,5 alpha-THP) is a positive modulator of the gamma-aminobutyric acid type A (GABAA) receptor. Experiments performed in vitro with hypothalamic fragments have previously shown that GABA could modulate the release of gonadotropin-releasing hormone (GnRH). Using GT1-1 immortalized GnRH neurons, we investigated the role of GABAA receptor ligands, including 3 alpha,5 alpha-THP, on the release of GnRH. We first characterized the GABAA receptors expressed by these neurons. [3H]Muscimol, but not [3H]flunitrazepam, bound with high affinity to GT1-1 cell membranes (Kd = 10.9 +/- 0.3 nM; Bmax = 979 +/- 12 fmol/mg of protein), and [3H]muscimol binding was enhanced by 3 alpha,5 alpha-THP. mRNAs encoding the alpha 1 and beta 3 subunits of the GABAA receptor were detected by the reverse transcriptase polymerase chain reaction. In agreement with binding data, the benzodiazepine-binding gamma subunit mRNA was absent. GnRH release studies showed a dose-related stimulating action of muscimol. 3 alpha,5 alpha-THP not only modulated muscimol-induced secretion but also stimulated GnRH release when administered alone. Bicuculline and picrotoxin blocked the effects of 3 alpha,5 alpha-THP and muscimol. Finally, we observed that GT1-1 neurons convert progesterone to 3 alpha,5 alpha-THP. We propose that progesterone may increase the release of GnRH by a membrane mechanism, via its reduced metabolite 3 alpha,5 alpha-THP acting at the GABAA receptor.

Animals↗
PubMed1998

Occurrence of GABA and GABA receptors in human spermatozoa.

Gamma-aminobutyric acid (GABA) concentrations in seminal plasma and washed spermatozoa from normal donors were assessed by a sensitive radioreceptor assay, and were detectable in both fractions. Specific binding of [3H]-muscimol was shown to be dependent on protein concentration, temperature and incubation time. [3H]-muscimol specific binding to human sperm membranes was significantly inhibited by the GABA type A receptor (GABA(A)) antagonist, bicuculline, and by the GABA(A) agonists, muscimol and isoguvacine, but not by the GABA type B receptor (GABA(B)) agonist baclofen. Scatchard analysis of [3H]-muscimol binding yielded a linear plot consistent with a single population of binding sites with a dissociation constant in the low nanomolar range. Incubation with GABA at a high micromolar concentration for 3 h under capacitating conditions resulted in an increase in the percentage of spermatozoa showing hyperactivated motility as assessed by computerized motility analyser. However, low micromolar concentrations of the GABA(A) agonist, muscimol, were sufficient to significantly increase sperm hyperactivity. These results suggest that the effect of GABA on human sperm motility might be mediated through a specific GABA(A) receptor.

Bicuculline↗
PubMedDate not supplied

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning.

Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily conditioning using local microinfusion of the GABA(A) receptor agonist muscimol or the NMDA receptor antagonist APV into the rat mPFC. Muscimol infusions into the mPFC before daily conditioning significantly retarded CR acquisition and reduced CR expression if applied after sufficient learning. APV infusion also impaired acquisition of CRs, but not expression of well-learned CRs. When infusions were made immediately after daily conditioning, acquisition of the CR was partially impaired in both the muscimol and APV infusion groups. In contrast, rats that received muscimol infusions 3 h after daily conditioning exhibited improvement in their CR performance comparable to that of the control group. Both the pre- and post-conditioning infusion of muscimol had no effect on acquisition in the delay paradigm. These results suggest that the mPFC participates in both acquisition of a CR and the early stage of consolidation of memory in trace, but not delay eyeblink conditioning by NMDA receptor-mediated operations.

Animals↗
PubMed1998

Molecular and functional adaptation of the GABA(A) receptor complex during pregnancy and after delivery in the rat brain.

The abundance of gamma-aminobutyric acid receptor type A (GABAA receptor) subunit mRNAs and polypeptides as well as muscimol-stimulated 36Cl- uptake were measured in rat cerebral cortex or hippocampus at various times during pregnancy and after delivery. RNase protection assays revealed that the amount of the gamma2L subunit mRNA decreased progressively during pregnancy, in the cerebral cortex and hippocampus, and then returned to control values around the time of delivery. A similar pattern was observed for the alpha5 subunit mRNA in the cerebral cortex, whereas no significant changes were apparent for alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3 and gamma2S subunit mRNAs. The amounts of gamma2 and alpha1 proteins in the cerebral cortex were measured by immunoblot analysis; whereas the abundance of gamma2 protein decreased during pregnancy, no change was detected in the amount of alpha1 protein. Evaluation for functional significance of the down-regulated gamma2 and alpha5 subunit was made by determining the GABAA receptor function assessed by measurement of muscimol-stimulated 36Cl- uptake in cerebral cortical membrane vesicles. Muscimol-induced 36Cl- uptake was markedly reduced during of pregnancy compared with rats in oestrus. At this same time, the potentiating effects of diazepam and allopregnanolone on muscimol stimulation of 36Cl- uptake also were reduced. In contrast, the effects of muscimol, allopregnanolone and diazepam were significantly increased, relative to animals in oestrus, after delivery.

Allosteric Regulation↗
PubMed2006

Light and GABA)(A) receptor activation alter period mRNA levels in the SCN of diurnal Nile grass rats.

We examined Period (Per) mRNA rhythms in the suprachiasmatic nucleus (SCN) of a diurnal rodent and assessed how phase-shifting stimuli acutely affect SCN Per mRNA using semiquantitative in situ hybridization. First, Per1 and Per2 varied rhythmically in the SCN over the course of one circadian cycle in constant darkness: Per1 mRNA was highest in the early to mid-subjective day, while Per2 mRNA levels peaked in the late subjective day. Second, acute light exposure in the early subjective night significantly increased both Per1 and Per2 mRNA. Third, Per2 but not Per1 levels decreased 1 and 2 h after injection of the gamma-aminobutyric acid (GABA)(A) receptor agonist muscimol into the SCN during the subjective day. Fourth, muscimol also reduced the light-induced Per2 in the early subjective night, but Per1 induction by light was not significantly affected. Consistent with previous studies, these data demonstrate that diurnal and nocturnal animals show very similar daily patterns of Per mRNA and light-induced Per increases in the SCN. As with light, muscimol alters circadian phase, and daytime phase alterations induced by muscimol are associated with significant decreases in Per2 mRNA. In diurnal animals, muscimol-induced decreases in Per are associated with phase delays rather than advances. The direction of the daytime phase shift may be determined by the relative suppression of Per1 vs. Per2 in SCN cells. As in nocturnal animals, changes in Per1 and Per2 mRNA by photic and non-photic stimuli appear to be associated with circadian phase alteration.

Animals↗
PubMed1983

Modulation of GABA receptor binding by Ca2+.

In frozen-thawed repeatedly washed rat cortical synaptic membranes, Ca2+ (1-5 mM) decreased the binding of [3H]muscimol whereas it increased the binding of [3H]gamma-aminobutyric acid (GABA). However, the binding of [3H]GABA was decreased by the same extent as the binding of [3H]muscimol when the membranes were incubated with baclofen (a selective ligand for the GABAB binding site) and Ca2+. Scatchard analysis of [3H]muscimol binding revealed that Ca2+ reduced the density of GABA binding sites without affecting the dissociation constant. Ca2+ was more potent than Ba2+, Mg2+ was ineffective, and the Ca2+ antagonist La3+ stimulated [3H]muscimol binding. The inhibition of [3H]muscimol binding by Ca2+ was not influenced by calmodulin (50 micrograms/ml), trifluoperazine (10(-5) M), verapamil (10(-6) M), quinacrine (10(-4) M), cordycepin (0.1 mM), leupeptin (20 microM), or soybean trypsin inhibitor (0.1 mg/ml). Moreover, the effect of Ca2+ was additive to that of GABA-modulin. These results indicate that Ca2+ decreases the number of GABAA binding sites while unveiling GABAB binding sites.

Animals↗
PubMed1985

Gamma-aminobutyric acid and benzodiazepine receptor changes induced by unilateral 6-hydroxydopamine lesions of the medial forebrain bundle.

Quantitative autoradiography was used to ascertain alterations in [3H]muscimol, [3H]flunitrazepam (FLU), [3H]naloxone, [3H]D-alanine-D-leucine-enkephalin (DADL), and [3H]spiroperidol binding in basal ganglia 1 week, 4 weeks, and 5 months after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) in the rat. At 1 and 4 weeks following lesions, [3H]spiroperidol binding increased 33% in striatum. At 5 months, [3H]spiroperidol was only nonsignificantly increased above control. At 1 week, [3H]muscimol binding decreased 39% in ipsilateral globus pallidus (GP), but increased 41% and 11% in entopeduncular nucleus (EPN) and substantia nigra pars reticulata (SNr), respectively. At 4 weeks, [3H]muscimol binding was reduced 19% in striatum and 44% in GP and remained enhanced by 32% in both EPN and SNr. These changes in [3H]muscimol binding persisted at 5 months. [3H]FLU binding was altered in the same direction as [3H]muscimol binding; however, changes were slower in onset and became significant (and remained so) only at 4 weeks after lesions. Decreases in [3H]naloxone and [3H]DADL binding were seen in striatum, GP, EPN, and SNr. Scatchard analyses revealed that only receptor numbers were altered. This study provides biochemical evidence for differential regulation of striatal GABAergic output to GP and EPN/SNr.

Animals↗
PubMed1988

Benzodiazepine enhancement of gamma-aminobutyric acid-mediated chloride ion flux in rat brain synaptoneurosomes.

Benzodiazepine agonists such as Ro 11-6896 [B10(+)], diazepam, clonazepam, and flurazepam were found to enhance muscimol-stimulated 36Cl- uptake into rat cerebral cortical synaptoneurosomes. The rank order of potentiation was B10(+) greater than diazepam greater than clonazepam greater than flurazepam. These benzodiazepines had no effect on 36Cl-uptake in the absence of muscimol. Further, the inactive enantiomer, Ro 11-6893 [B10(-)], and the peripheral benzodiazepine receptor ligand Ro 5-4864 did not potentiate muscimol-stimulated 36Cl- uptake at concentrations up to 10 microM. In contrast, the benzodiazepine receptor inverse agonists ethyl-beta-carboline-3-carboxylate and 6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylic acid methyl ester inhibited muscimol stimulated 36Cl- uptake. Benzodiazepines and beta-carbolines altered the apparent K0.5 of muscimol-stimulated 36Cl- uptake, without affecting the Vmax. The effects of both benzodiazepine receptor agonists and inverse agonists were reversed by the benzodiazepine antagonists Ro 15-1788 and CGS-8216. These data further confirm that central benzodiazepine receptors modulate the capacity of gamma-aminobutyric acid receptor agonists to enhance chloride transport and provide a biochemical technique for studying benzodiazepine receptor function in vitro.

Animals↗
PubMed1989

Age-related loss of t-[35S]butylbicyclophosphorothionate binding to the gamma-aminobutyric acidA receptor-coupled chloride ionophore in rat cerebral cortex.

Muscimol and t-butylbicyclophosphorothionate (TBPS) are known to label two distinct sites within the gamma-aminobutyric acidA (GABAA) receptor complex, i.e., the GABA recognition site and the chloride ionophore, respectively. Age-dependent changes in the specific binding of [3H]muscimol and [35S]TBPS were compared in membranes prepared from the cerebral cortex of rats, 2-800 days old. Perinatal (day 2) binding of muscimol and TBPS represented 8 and 20% of the respective values for adults (day 180). After the first week, muscimol binding increased more rapidly than TBPS binding. Levels near those of adults were reached at day 20 and remained practically unchanged in adulthood (day 180). In aged (780-day-old) rats, the binding of TBPS was significantly reduced, whereas muscimol binding did not change compared with adult values. This decrease of TBPS binding derived from a reduced density of binding sites, rather than from affinity changes. The allosteric responsiveness of TBPS binding to exogenous GABA was also reduced in aged animals. These findings indicate an age-related change in the molecular (structural) organization of the GABAA receptor-chloride ionophore complex in rat cerebral cortex.

Aging↗
PubMed1987

Adaptation of the GABAA-receptor complex in rat brain during chronic elevation of GABA by ethanolamine O-sulphate.

Slice preparations of rat cuneate nucleus were used for studies on the gamma-aminobutyric acid GABAA-receptor complex following chronic and acute pretreatment with GABA-alpha-ketoglutarate aminotransferase (GABA-T) inhibitors. The whole brain GABA concentration was significantly increased 2.9 fold and 2.6 fold following treatment with ethanolamine O-sulphate (EOS, orally) for 15-30 days and 56-64 days, respectively. One hour after a single injection of gamma-acetylenic GABA (GAG) i.p., there was a significant 2.1 fold increase in whole brain GABA. Superfusion of a slice with muscimol or the GABA uptake inhibitor nipecotic acid depolarized the afferent nerve fibres. These effects were potentiated by flurazepam (1 microM) and pentobarbitone (10 microM) and antagonized by picrotoxin (3 microM, 30 microM). Following 15-30 days of EOS-treatment, the depolarization response to muscimol was decreased and that to nipecotic acid increased. These changes were no longer significant by 56-64 days of pretreatment. The acute dose of GAG did not affect the depolarization response to muscimol but increased that to nipecotic acid. The potentiations of muscimol by flurazepam (1 microM) and pentobarbitone (10 microM) were enhanced following chronic EOS treatment (15-64 days). The enhancement of flurazepam was less after 56-64 days than after 15-30 days pretreatment whereas the enhancement of pentobarbitone was similar at both times. Acute GAG treatment had no effect. The potency of picrotoxin as an antagonist of muscimol was reduced following chronic EOS treatment; the enhancement was less after 56-64 days than after 15-30 days pretreatment. Acute GAG treatment caused only a very small reduction in picrotoxin potency. Possible adaptations in the GABAA-receptor complex and its modulation during chronic elevation of brain GABA are discussed.

4-Aminobutyrate Transaminase↗
PubMed1989

Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus.

1. Several derivatives of pregnane and androstane that have hypnotic properties have been investigated for their ability to potentiate responses to the GABAA receptor agonist muscimol and to reduce the effect of the non-competitive GABAA antagonist picrotoxin. 2. Depolarizing responses to muscimol in slices of rat cuneate nucleus were potentiated most potently by 3 alpha-hydroxy,5 alpha-pregnane-11,20-dione (alphaxalone), which gave half-maximal potentiation at 0.15 microM. The 5 beta isomer of alphaxalone had little effect up to 3 microM but in analogues lacking an 11-keto substituent (pregnanolones), both the 5 alpha- and 5 beta-isomers potentiated with potencies 20 and 10 times lower, respectively, than that of alphaxalone. The alpha configuration of the 3-hydroxy was essential in alphaxalone, the 3 beta-hydroxy isomer being inactive. However, there was little difference between the potencies of the 3 alpha- and 3 beta-hydroxy configurations in the pregnanolones, although the maximal effects of the 3 beta-hydroxy isomers were rather lower than those of the 3 alpha-hydroxy isomers. 3. Reductions in the effect of picrotoxin as an antagonist of muscimol were caused most potently by the 3 alpha-hydroxy pregnanolones, with a ten fold reduction in picrotoxin potency at 1 microM concentrations of these steroids. Alphaxalone and its 5 beta-isomer were about half as potent. Androsterone was about 10 times less potent and the 3 beta-hydroxy pregnanolones were ineffective. 4. This difference in the structure-activity relationships for steroidal potentiation of muscimol and reduction in picrotoxin antagonism of muscimol is reminiscent of an analogous distinction found with the barbiturates.

Androsterone↗
PubMed1990

GABA(B)-related activity involved in synaptic processing of somatosensory information in S1 cortex of the anaesthetized cat.

1. The possible role of GABA(B) receptor mechanisms in information processing in primary somatosensory (S1) cortex was assessed by use of extracellular recording combined with microiontophoretic methods from 161 neurones in anaesthetized, paralysed cats. 2. Baclofen-induced suppressions of cell responses were reversible and stereoselective, the (+)-isomer being inactive and the (-)-isomer having two to three times the apparent potency of gamma-aminobutyric acid (GABA). The responses measured were threshold to natural stimulation of receptive fields (RFs), responsiveness to thalamic electrical stimulation, change in RF size and magnitude of firing elicited by iontophoretic glutamate. 3. The action of GABA always was mimicked by muscimol or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) but not always by (-)-baclofen; in certain cases (-)-baclofen enhanced neuronal responses while the opposite occurred with GABA or with the other GABA(A) agonists. The elevation of response thresholds by (-)-baclofen was relatively stronger in peripheral than in central subregions of cutaneous RFs, by contrast with the action of muscimol which was relatively non-selective as to the area in which it was effective. 4. Glutamate-induced and thalamically-evoked cortical responses as well as spontaneous activity were differentially sensitive to the suppressant effects of muscimol and (-)-baclofen. 5. Bicuculline methiodide reversibly blocked THIP- and muscimol-induced suppressions of tactile- (air puffer)-induced S1 responses but spared those produced by (-)-baclofen. Phaclofen and delta-amino-n-valeric acid were essentially inactive as blockers of (-)-baclofen-induced effects and in fact often acted as (-)-baclofen-like agonists, phaclofen being considerably weaker than delta-amino-n-valeric acid in this respect. 6. The range of suppressant effects produced by GABA as well as by muscimol and THIP, considered in conjunction with the actions of bicuculline methiodide, suggest that the effects observed by ejected GABA are likely to be due principally to GABA(A) processes, those mediated by GABA(B) receptors largely being masked. However, GABA(B) mechanisms are extant and do appear to be active, probably presynaptically and probably at sites distal to the soma.

Anesthesia↗
PubMed1995

Pharmacological modulation of adrenal medullary GABAA receptor: consistent with its subunit composition.

1. Muscimol, the specific GABAA receptor agonist, increased the secretion of catecholamines by chromaffin cells with an EC50 of 2.9 +/- 0.4 microM. 2. GABAA receptors of these cells were modulated by the same drugs which modulate GABAA receptors in brain tissue. 3. Benzodiazepines enhanced muscimol-evoked catecholamine secretion by between 20 and 80%. This effect seems to be mediated by binding to a central type of benzodiazepine receptor because it was completely blocked by the specific antagonist, Ro 15 1788. This antagonist was able to displace [3H]-flunitrazepam binding with an EC50 of 0.26 +/- 0.05 nM. 4. beta-Carbolines weakly inhibited muscimol-induced catecholamine secretion and were able to displace [3H]-flunitrazepam binding with an EC50 between 0.2 and 0.9 nM, depending on the beta-carboline used. 5. Pregnanolone and related neuroactive steroids enhanced muscimol-evoked catecholamine secretion by up to 87%, in a dose-dependent fashion. In contrast pregnenolone weakly inhibited muscimol-evoked catecholamine secretion. 6. Zn2+ did not affect GABAA receptor-induced catecholamine secretion. 7. These pharmacological results are absolutely concordant with the theoretical properties given by the GABAA receptor subunit composition of bovine adrenal medulla -alpha 1, alpha 4, beta 1-3, gamma 2-previously characterized by Western blot analysis.

Adrenal Glands↗
PubMedDate not supplied

The ontogeny of GABAergic enhancement of the gamma-hydroxybutyrate model of generalized absence seizures.

The ontogeny of GABAergic enhancement of generalized absence seizures was examined in the gamma-hydroxybutyrate (GHB) model of generalized absence seizures. The GHB seizure was quantitated in developing and adult rats in the presence of varying doses of the GABAa agonist muscimol or intracerebroventricularly (i.c.v.) administered GABA. Both GABA and muscimol potentiated GHB-induced seizures in an age-dependent fashion. The adult dose of 1 mg/kg muscimol was extremely potent in rats less than 28 days of age and resulted in the death of all younger animals tested secondary to profound hypothermia. A dose of 0.1 mg/kg muscimol was associated with a significant prolongation of GHB seizure in rats less than 35 days of age, but had no effect on older animals. The response to GHB was also age dependent, with the greatest sensitivity occurring during the fourth and fifth week of life. The developmental sensitivity of the rat to GHB seizure correlated with enhancement of the seizure by muscimol and GABA, and both phenomena parallel the maturation of thalamocortical recruiting mechanisms thought to play a role in the pathogenesis of the bilaterally synchronous spike wave discharges that characterize generalized absence seizures.

4-Butyrolactone↗
PubMed1995

GABAergic transmission in the nucleus accumbens is involved in the termination of ethanol self-administration in rats.

Long-Evans rats (n = 12) were trained to lever-press on a fixed-ratio 4 schedule of reinforcement with ethanol (10% v/v) presented as the reinforcer. After implantation of bilateral stainless-steel guide cannulae aimed at the nucleus accumbens, site-specific microinjections of muscimol (1-30 ng) and bicuculline (1-10 ng) were tested for effects on ethanol-reinforced responding. Baseline response patterns were characterized by initial high rates that terminated abruptly after approximately 20 min. Muscimol administration in the nucleus accumbens decreased the total number of ethanol-reinforced responses and obtained reinforcers. Bicuculline also decreased ethanol-reinforced responses and reinforcers at the highest dose tested. When a dose of bicuculline (1 ng) that was ineffective by itself was coadministered with an effective dose of muscimol (10 ng), the muscimol-induced decreases in responding were blocked. Analysis of response patterns showed that muscimol decreased ethanol self-administration by terminating responding, normally lasting 20 min, after approximately 10 min with no changes in local response rate. Bicuculline decreased total responding by producing parallel, but nonsignificant, changes in time course and response rate. These data suggest that GABAergic transmission in the nucleus accumbens is involved in the termination, but not the onset or maintenance of ethanol self-administration. The specificity of this effect gives emphasis to the importance of measuring behavioral parameters, as well as products of behavior (such as intake volume) in the study of ethanol self-administration.

Alcohol Drinking↗
PubMed1996

Discriminative stimulus function of ethanol: role of GABAA receptors in the nucleus accumbens.

Because the subjective effects of drugs may be related to abuse potential, this study was conducted to assess the involvement of GABAA receptor systems in the nucleus accumbens (N Acc) in the discriminative stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (IP) injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 schedule of sucrose (10% w/v) reinforcement. When performance during training sessions met the accuracy criteria (> 80% correct responding for five consecutive days), an ethanol generalization curve was determined. The rats were then surgically implanted with bilateral stainless-steel guide cannulae aimed at the N Acc. Intra-accumbens (IA) substitution test sessions were conducted during which the direct GABAA agonist muscimol (0.01, 0.04, 0.10, and 0.40 micrograms/microliter; IA) was administered in combination with saline (IP). The direct GABAA antagonist bicuculline (0.03, 0.10, and 0.30 micrograms/microliter; IA) was administered in combination with the training dose of ethanol (1 g/kg, ip). At 10-min postinjection, IA muscimol partially substituted for IP ethanol. However, at 15-min postinjection, muscimol (0.10 microgram/microliter; IA) fully substituted for IP ethanol. Bicuculline attenuated the discriminative stimulus properties of IP ethanol, but only at doses that significantly decreased response rate. At 10-min postinjection, muscimol (0.01 and 0.04 micrograms/microliter) potentiated (> 80% ethanol lever responding) the discriminative stimulus properties of a dose of ethanol (0.5 g/kg) that alone produced only partial generalization. These data suggest that ethanol discrimination is mediated centrally and demonstrate that infusions of the GABAA agonist muscimol in the N Acc are sufficient to produce the stimulus effects corresponding to a 1.0 g/kg training dose of ethanol. When taken together with data showing that GABAA receptor activation in the N Acc potentiates the termination of ethanol self-administration, these data suggest that ethanol's discriminative stimulus function may influence its reinforcement function.

Alcohol Drinking↗