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At least 1,099 records · Page 61Linked to original sources
PubMed2001

Discriminative stimulus effects of panadiplon (U-78875), a partial agonist at the benzodiazepine site, in pentobarbital-trained rhesus monkeys.

The pentobarbital-like discriminative stimulus effects of the benzodiazepine receptor partial agonist panadiplon were assessed in rhesus monkeys trained to discriminate pentobarbital (10 mg/kg) from saline. In test sessions, pentobarbital and the benzodiazepine full agonist triazolam engendered near 100% drug-appropriate responding in all monkeys, whereas panadiplon engendered near 100% drug-appropriate responding in two of four monkeys. Panadiplon pretreatment resulted in leftward shifts in the pentobarbital dose-response function but predominantly rightward shifts of the triazolam dose-response function. These results are consistent with findings that benzodiazepine partial agonists have pentobarbital-like discriminative stimulus effects in some subjects only, and further suggest that partial agonists enhance the effects of pentobarbital but antagonize the effects of a benzodiazepine full agonist.

Animals↗
PubMed2001

Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants. We have found a mutation in a gene encoding a GABA(A) receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Age of Onset↗
PubMed2003

Activity of chlormethiazole at human recombinant GABA(A) and NMDA receptors.

1. Investigation into the modulatory effects of chlormethiazole at human recombinant gamma-aminobutyric acid A receptor (GABAA) and N-methyl-d-aspartate (NMDA) receptors was undertaken to gain insight into its mechanism of action and determine if the drug exhibited any subtype-selective activity. 2. Despite a structural similarity to the beta-subunit-selective compound loreclezole, chlormethiazole did not show any difference in maximum efficacy and only a slight difference in EC50 in its potentiating action at alpha1beta1gamma2 and alpha1beta2gamma2 GABAA receptor subtypes with preference for alpha1beta1gamma2. 3. Similar to the previously reported subtype-dependent activity of pentobarbital, chlormethiazole elicited a significantly greater degree of maximum potentiation on receptors lacking a gamma2 subunit, and also those receptors containing an alpha4 or alpha6 subunit. This also demonstrates that chlormethiazole does not act via the benzodiazepine binding site. 4. Unlike pentobarbital and propofol, chlormethiazole elicited only a slight direct GABAA receptor activation at concentrations up to 1 mm. In addition, the drug did not potentiate anaesthetic-mediated currents elicited by pentobarbital or propofol, suggesting that chlormethiazole may be acting via an anaesthetic binding site. 5. Chlormethiazole produced weak nonselective inhibition of human NMDA NR1a+NR2A and NR1a+NR2B receptors. IC50's were approximately 500 microm that likely exceed the therapeutic dose range for chlormethiazole, indicating that the primary mechanism of the compounds in vivo activity is via GABAA receptors.

Animals↗
PubMed2003

Diazepam-induced changes on sleep and the EEG spectrum in mice: role of the alpha3-GABA(A) receptor subtype.

Benzodiazepines reduce EEG slow-wave activity in non-REM sleep by potentiating GABAergic neurotransmission at GABAA receptors via a modulatory binding site. However, the mechanisms of action underlying the effects of benzodiazepines on sleep and the sleep EEG are still unknown. Slow waves during sleep are generated by the corticothalamic system and synchronized by the inhibitory GABAergic neurons of the reticular thalamic nucleus. This region contains exclusively alpha3-containing GABAA receptors. We investigated the role of these receptors in the mediation of diazepam effects on the sleep EEG by studying point-mutated mice in which the alpha3-GABAA receptor is diazepam-insensitive [alpha3(H126R)]. Sleep was recorded for 12 h after i.p. injection of 3 mg/kg diazepam or vehicle at light onset in alpha3(H126R) and wild-type controls (n = 13-17 per genotype). The main effect was a marked reduction of slow-wave activity (EEG power density in 0.75-4.00 Hz) in non-REM sleep and a concomitant increase in frequencies above 15.00 Hz in non-REM sleep and waking in both genotypes. Neither effect of diazepam differed significantly between the genotypes. Despite the exclusive expression of alpha3-containing GABAA receptors in the reticular thalamic nucleus, these receptors do not seem to be critical for the mediation of the effects of diazepam on the sleep EEG.

Animals↗
PubMed2007

Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats.

Food-deprived Wistar rats were exposed to a fixed-time 60-s food delivery schedule until they developed schedule-induced polydipsia. Every fifth lick was then followed by an electric shock during two, signalled, 5-min periods, which ran concurrently with the food delivery schedule. Shock intensities were adjusted to reduce licking to 60-70% of the unpunished licking rates. The benzodiazepine full agonists, diazepam (0.3-3.0 mg/kg), chlordiazepoxide (0.3-10.0 mg/kg), oxazepam (0.3-3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0-17.0 mg/kg), led to increases in punished responding at intermediate doses and decreases at the highest doses tested. All benzodiazepine agonists brought about dose-dependent decreases in unpunished schedule-induced polydipsia, with doses required to reduce drinking proving higher than doses required to increase punished schedule-induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by flumazenil and the benzodiazepine inverse agonist, RU-34000. Flumazenil effects, however, could reflect actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the rate-increasing effect of 0.3 mg/kg of diazepam, but at 17.0 mg/kg partially blocked such antipunishment effect. Overall, the present results extend the similarities of the effects of benzodiazepine compounds on adjunctive and operant patterns of behaviour by showing similar interactions within the benzodiazepine receptor complex.

Animals↗
PubMed2004

Activation of GABA(A) receptors containing the alpha4 subunit by GABA and pentobarbital.

The activation properties of GABA(A) receptors containing alpha4beta2gamma2 and alpha4beta2delta subunits were examined in the presence of GABA or pentobarbital. The receptors were expressed transiently in HEK 293 cells, and the electrophysiological experiments were carried out using cell-attached single-channel patch clamp or whole-cell macroscopic recordings. The data show that GABA is a stronger activator of alpha4beta2gamma2 receptors than alpha4beta2delta receptors. Single-channel clusters were recorded from alpha4beta2gamma2 receptors in the presence of 10-5000 microm GABA. The maximal intracluster open probability was 0.35, with a half-maximal response elicited by 32 microm GABA. Simultaneous kinetic analysis of single-channel currents obtained at various GABA concentrations yields a channel opening rate constant of 250 s(-1), and a K(D) of 20 microm. In contrast, only isolated openings were observed in the presence of GABA for the alpha4beta2delta receptor. Pentobarbital was a strong activator of both alpha4beta2gamma2 and alpha4beta2delta receptors. The maximal cluster open probability, recorded in the presence of 100 microm pentobarbital, was 0.7. At higher pentobarbital concentrations, the cluster open probability was reduced, probably due to channel block. The results from single-channel experiments were confirmed by macroscopic recordings from HEK cells in the presence of GABA or pentobarbital.

Cell Line↗
PubMed2001

Synaptically released neurotransmitter fails to desensitize postsynaptic GABA(A) receptors in cerebellar cultures.

GABA concentration jump experiments performed on membrane patches predict that postsynaptic GABA(A) receptors will become desensitized following the release of the contents of a single GABA-containing synaptic vesicle. To examine this we used a single synaptic bouton stimulation technique to directly examine whether postsynaptic GABA(A) receptors in cultured cerebellar granule cells exhibit transmitter-induced desensitization. In a large number of recordings, no evidence was found for desensitization of postsynaptic GABA(A) receptors by vesicularly released transmitter. This was the case even when as many as 40 vesicles were released from a single bouton within 1.5 s. In addition, postsynaptic depolarization and application of the benzodiazepine flunitrazepam, manipulations previously shown to enhance desensitization of GABA(A) receptors, failed to unmask transmitter-induced desensitization. In contrast, a single 2- to 3-s application of a high concentration of exogenous GABA was able to depress synaptic responsiveness for up to 70 s. Furthermore, pharmacological depletion of GABA eliminated inhibitory synaptic communication, suggesting that GABA is the transmitter and the desensitization-resistant inhibitory postsynaptic currents are not mediated by a "nondesensitizing" ligand such as beta-alanine. Overall our data indicate that a specific desensitization-resistant population of GABA(A) receptors are present at postsynaptic sites on cultured cerebellar granule cells.

Action Potentials↗
PubMed1998

Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke.

BACKGROUND AND PURPOSE: Therapy of acute ischemic stroke can only be effective as long as neurons are viable and tissue is not infarcted. Since gamma-aminobutyric acid receptors are abundant in the cortex and sensitive to ischemic damage, specific radioligands to their subunits, the central benzodiazepine receptors (BZR), may be useful as indicators of neuronal integrity and as markers of irreversible damage. To test this hypothesis we studied the binding of the BZR ligand [11C]flumazenil (FMZ) early after ischemic stroke in comparison to the extent of final infarcts and hypometabolic cortical areas. METHODS: In 10 patients cerebral blood flow, cerebral metabolic rate for oxygen (CMRO2), oxygen extraction fraction (OEF), and FMZ binding were studied by positron emission tomography 3.5 to 16 hours after onset of their first hemispheric stroke. Early changes in flow, oxygen metabolism, and FMZ binding were compared with permanent disturbances in glucose metabolism, and the size of the final infarcts was determined on MRI or CT 12 to 22 days after the stroke. RESULTS: In all patients except one cerebral blood flow was disturbed, with marked decreases in eight and a hyperperfusion in one patient corresponding to the location of neurological deficits. In these areas CMRO2 was also reduced but to a variable degree, inducing highly variable OEF. Areas with markedly decreased CMRO2 (<60 micromol/100 g per minute) corresponded to regions with decreased FMZ binding (<4.0 times the mean value in the white matter). In all patients the final cortical infarcts were visible on the early FMZ images. Infarcts could be discriminated from noninfarcted cortex by decreased FMZ binding despite a wide range of OEF. In finally hypometabolic cortex FMZ binding was initially decreased or normal, with OEF covering a wide range; this suggested neuronal loss and/or deactivation as the cause of metabolic disturbance. Additionally, a highly significant correlation was found between FMZ distribution within the first 2 minutes after injection and regional cerebral blood flow. CONCLUSIONS: These results demonstrate that permanently and irreversibly damaged cortex can be detected by reduced FMZ binding early after stroke. Since FMZ distribution additionally images regional cerebral perfusion, BZR radioligands have a potential as clinically useful tracers in patients with acute ischemic stroke. The evidence of tissue damage furnished by these tracers might be of relevance for the selection of individual therapeutic strategies.

Aged↗
PubMed2000

Evidence that long-lasting potentiation in limbic circuits mediating defensive behaviour in the right hemisphere underlies pharmacological stressor (FG-7142) induced lasting increases in anxiety-like behaviour: role of benzodiazepine receptors.

The hypothesis that benzodiazepine receptors mediate initiation of lasting behavioural changes induced by FG-7142 was supported in this study. Behavioural changes normally induced by FG-7142 were blocked by prior administration of the competitive benzodiazepine receptor blocker, Flumazenil. When cats were subsequently given FG-7142 alone, the drug produced lasting behavioural changes in species characteristic defensive responses to rodent and cat vocal threat. FG-7142 also induced long-lasting potentiation (LLP) of evoked potentials in a number of efferent pathways from the amygdala in both hemispheres. Flumazenil given prior to FG-7142 blocked LLP in all but one of the amygdala efferent pathways, suggesting benzodiazepine receptor dependence of initiation of LLP. Three physiological changes were most closely correlated with behavioural changes. LLP in the right amygdalo-ventromedial hypothalamic (VMH) and amygdalo-periacqueductal gray (PAG) pathways coincided closely with behavioural changes, as did a reduced threshold for the right amygdalo-VMH evoked potential. Administration of Flumazenil after FG-7142 returned defensive behaviour to pre FG-7142 baseline levels in a drug-dependent manner. At the same time LLP only in the right amygdalo-PAG pathway was reduced by Flumazenil. LLP in other pathways and amygdalo-VMH threshold were unaltered by Flumazenil. Moreover, covariance analyses indicated that increased defensiveness depended solely on LLP in the right amygdalo-PAG. These findings support the view that maintenance of lasting increases in defensive behaviour depend upon LLP of excitatory neural transmission between amygdala and lateral column of the PAG in the right hemisphere. Moreover, FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety, especially in view of the recent data in humans implicating right hemispheric function in persisting negative affective states in post-traumatic stress disorder.

Aggression↗
PubMed2000

Slow death of postnatal hippocampal neurons by GABA(A) receptor overactivation.

Neurotransmitters can have both toxic and trophic functions in addition to their role in neural signaling. Surprisingly, chronic blockade of GABA(A) receptor activity for 5-8 d in vitro enhanced survival of hippocampal neurons, suggesting that GABA(A) receptor overactivation may be neurotoxic. Potentiating GABA(A) receptor activity by chronic treatment with the endogenous neurosteroid (3alpha,5alpha)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in culture. Other potentiators of GABA(A) receptors, including benzodiazepines, mimicked the cell loss, suggesting that potentiating endogenous GABA activity is sufficient to produce neuronal death. Neurosteroid-treated neurons had lower resting intracellular calcium levels than control cells and produced smaller calcium rises in response to depolarizing challenges. Manipulating intracellular calcium levels with chronic elevated extracellular potassium or with the calcium channel agonist Bay K 8644 protected neurons. The results may have implications for the mechanisms of programmed cell death in the developing CNS as well as implications for the long-term consequences of chronic GABAmimetic drug use during development.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Benzodiazepine receptor binding in Huntington's disease: [11C]flumazenil uptake measured using positron emission tomography.

We used positron emission tomography and [11C]flumazenil to analyze the benzodiazepine receptor binding in symptomatic and asymptomatic carriers of the Huntington's disease gene. We found an inverse relationship between [11C]flumazenil and [11C]raclopride binding in the putamen of symptomatic patients, and interpret this result as GABA receptor upregulation.

Adult↗
PubMed2002

Augmentation of analgesic effect of ibuprofen by alprazolam in experimental model of pain.

The reports of analgesic effects of benzodiazepines are inconsistent. There is evidence of a hyperalgesic effect induced by activation of supraspinal GABAA receptors and an antinociceptive effect induced by activation of receptors located in the spinal cord (dorsal horns). The aim of the study was to discover whether the systemic administration of a benzodiazepine agent alprazolam increases the systemic analgesic efficacy of non-opioid analgesic ibuprofen. Experimental studies combining these agents have not yet been published. We used three experimental methods - writhing test (with acetic acid), tail-flick test and plantar test to assess analgesic action. The drugs were administered orally. Augmentation of the analgesic effect of ibuprofen by alprazolam was proved for the writhing test at a dose of 30 mg/kg of ibuprofen and alprazolam 1 mg/kg. The reaction time of the combination was significantly prolonged in comparison with ibuprofen alone. The results of the tail-flick test and plantar test were negative. The effect of ibuprofen was not enhanced by alprazolam in tests of acute thermal pain. Our results have demonstrated that the analgesic action of ibuprofen is only weakly enhanced by alprazolam.

Acetic Acid↗
PubMed1997

Evoked potentials and the effect of flumazenil in patients with liver cirrhosis.

The presence of increased amount of ligands for benzodiazepine receptors has been demonstrated in cirrhotic patients. Evoked potentials (EP) recordings are a simple, suitable, and objective method for comprehensive evaluation of hepatic encephalopathy (HE). We evaluated the visual EP, brain stem auditory EP, and somatosensory EP (SSEP) and the effect of benzodiazepine receptor antagonist flumazenil in patients with liver cirrhosis. EP of 38 patients with liver cirrhosis were recorded on the electrodiagnostic system Neuropack 8 (JB-441 B, Nihon Kohden). Eleven patients (nine males and two females; mean age 60 years; six with stage 0,4 with stage one, and one with stage 2 HE) showed impairment in SSEP N13-N19 interval. After baseline period, boluses of 1 mg, 2 mg, and 3 mg flumazenil were injected every thirty minutes and SSEP recordings were repeated after every dosage. We did not find any difference before and after flumazenil in SSEP N13-N19 interval (7.3 +/- 0.4, 7.1 +/- 0.5, 7.1 +/- 0.4, and 7.1 +/- 0.6 minutes, respectively) (p < 0.05). But four patients (36%) showed a clear SSEP improvement with flumazenil. Our results suggest that in a subset of cirrhotic patients, flumazenil may have a role.

Adult↗
PubMedDate not supplied

[Interaction of GABA-ergic component of NAD with benzodiazepine receptors during epileptogenesis].

Nitrozepam has been shown to decrease specific binding of [14C]NAD by the synaptic mem-branes approximately by 40%. Alongside with the latter GABA in the concentration of 10(-5) M potentiates the effect observed. Blocking in vitro of GABA receptors by bicuculin removes both the tranquilizer and GABA effect. While simulating epileptogenesis in animals the nitrazepam effect on [14C]NAD specific binding sites was somewhat more expressed in comparison with the norm. The interaction of NAD reception systems with benzodiazepine under the pathology is capable to be mediated not only by increasing GABA-ergic transfer, but it can occur place without GABA-ergic component of GABA-benzodiazepine receptor complex.

Animals↗
PubMed2006

Differential behavioral effects of low efficacy positive GABAA modulators in combination with benzodiazepines and a neuroactive steroid in rhesus monkeys.

In the clinic, low efficacy positive GABAA modulators might be preferred to high efficacy positive modulators insofar as low efficacy modulators might have comparatively less abuse and dependence liability. Drug discrimination was used to examine the behavioral effects of L-838,417 and bretazenil, two low efficacy positive GABAA modulators that act at benzodiazepine sites, alone and in combination with benzodiazepines and a neuroactive steroid (alfaxolone). In rhesus monkeys (n = 5) discriminating midazolam, alfaxolone substituted for midazolam. In four monkeys, L-838,417 and bretazenil did not substitute for, but rather dose-dependently antagonized, midazolam; L-838-417 and bretazenil, as well as flumazenil, enhanced the midazolam-like effects of alfaxolone. L-838,417 and bretazenil substituted for midazolam in a fifth monkey. In a separate group of rhesus monkeys (n = 3) that received 5.6 mg kg(-1) per day of diazepam and that discriminated flumazenil, L-838,417 and bretazenil substituted for flumazenil. These results demonstrate that L-838,417, bretazenil, and flumazenil can have agonist or antagonist actions in the same animal depending upon whether they are studied in combination with a higher efficacy positive GABAA modulator acting at the same (benzodiazepine) or a different (neuroactive steroid) site. Thus, combinations of low efficacy positive modulators acting at different sites on the GABAA receptor complex could yield drug mixtures with significant therapeutic effects and with reduced abuse and dependence liability, as compared to higher efficacy positive modulators such as currently available benzodiazepines.

Animals↗
PubMed1996

Interaction of positive allosteric modulators with human and Drosophila recombinant GABA receptors expressed in Xenopus laevis oocytes.

1. A comparative study of the actions of structurally diverse allosteric modulators on mammalian (human alpha 3 beta 2 gamma 2L) or invertebrate (Drosophila melanogaster Rdl or a splice variant of Rdl) recombinant GABA receptors has been made using the Xenopus laevis oocyte expression system and the two electrode voltage-clamp technique. 2. Oocytes preinjected with the appropriate cRNAs responded to bath applied GABA with a concentration-dependent inward current. EC50 values of 102 +/- 18 microM; 152 +/- 10 microM and 9.8 +/- 1.7 microM were determined for human alpha 3, beta 1 gamma 2L, Rdl splice variant and the Rdl receptors respectively. 3. Pentobarbitone enhanced GABA-evoked currents mediated by either the mammalian or invertebrate receptors. Utilizing the appropriate GABA EC10, the EC50 for potentiation was estimated to be 45 +/- 1 microM, 312 +/- 8 microM and 837 +/- 25 microM for human alpha 3, beta 1 gamma 2L, Rdl splice variant and Rdl receptors respectively. Maximal enhancement (expressed relative to the current induced by the EC10 concentration of GABA where this latter response = 1) at the mammalian receptor (10.2 +/- 1 fold) was greater that at either the Rdl splice variant (5.5 +/- 1.3 fold) or Rdl (7.9 +/- 0.8 fold) receptors. 4. Pentobarbitone directly activated the human alpha 3 beta 1 gamma 2L receptor with an EC50 of 1.2 +/- 0.03 mM and had a maximal effect amounting to 3.3 +/- 0.4 fold of the response evoked by the EC10 concentration of GABA. Currents evoked by pentobarbitone were blocked by 10-30 microM picrotoxin and potentiated by 0.3 microM flunitrazepam. Pentobarbitone did not directly activate the invertebrate GABA receptors. 5. 5 alpha-Pregnan-3 alpha-ol-20-one potentiated GABA-evoked currents mediated by the human alpha 3 beta 1 gamma 2L receptor with an EC50 of 87 +/- 3 nM and a maximal enhancement of 6.7 +/- 0.8 fold of that produced by the GABA EC10 concentration. By contrast, relatively high concentrations (3-10 microM) of this steroid had only a modest effect on the Rdl receptor and its splice variant. 6. A small direct effect of 5 alpha-pregnan-3 alpha-ol-20-one (0.3-10 microM) was detected for the human alpha 3 beta 1 gamma 2L receptor (maximal effect only 0.08 +/- 0.01 times that of the GABA EC10). This response was antagonized by 30 microM picrotoxin and enhanced by flunitrazepam (0.3 microM). 5 alpha-Pregnan-3 alpha-ol-20-one did not directly activate the invertebrate GABA receptors. 7. Propofol enhanced GABA-evoked currents mediated by human alpha 3 beta 1 gamma 2L and Rdl splice variant receptors with EC50 values of 3.5 +/- 0.1 microM and 8 +/- 0.3 microM respectively. The maximal enhancement was similar at the two receptor types (human 11 +/- 1.8 fold; invertebrate 8.8 +/- 1.4 fold that of the GABA EC10). 8. Propofol directly activated the human alpha 3 beta 1 gamma 2L receptor with an EC50 of 129 +/- 10 microM, and at a maximally effective concentration, evoked a current amounting to 3.5 +/- 0.5 times that elicited by a concentration of GABA producing 10% of the maximal response. The response to propofol was blocked by 10-30 microM picrotoxin and enhanced by flunitrazepam (0.3 microM). Propofol did not directly activate the invertebrate Rdl splice variant receptor. 9. GABA-evoked currents mediated by the human alpha 3 beta 1 gamma 2L receptor were potentiated by etomidate (EC50 = 7.7 +/- 0.2 microM) and maximally enhanced to 8 +/- 0.8 fold of the response to an EC10 concentration of GABA. By contrast, the Rdl, or Rdl splice variant forms of the invertebrate GABA receptor were insensitive to the positive allosteric modulating actions of etomidate. Neither the mammalian nor the invertebrate receptors, were directly activated by etomidate. 10. delta-Hexachlorocyclohexane enhanced GABA-evoked currents with EC50 values of 3.4 +/- 0.1 microM and 3.0 +/- 0.1 microM for the human alpha 3 beta 1 gamma 2L receptor and the Rdl splice variant receptor respectively. The maximal enhancement was 4.5

Allosteric Regulation↗
PubMed2006

Ethanol modulation of GABAergic transmission: the view from the slice.

For almost three decades now, the GABAergic synapse has been the focus of intense study for its putative role in mediating many of the behavioral consequences associated with acute and chronic ethanol exposure. Although it was initially thought that ethanol interacted solely with the postsynaptic GABAA receptors that mediate the majority of fast synaptic inhibition in the mammalian central nervous system (CNS), a number of recent studies have identified novel pre- and postsynaptic mechanisms that may contribute to the acute and long-term effects of ethanol on GABAergic synaptic inhibition. These mechanisms appear to differ in a brain region specific manner and may also be influenced by a variety of endogenous neuromodulatory factors. This article provides a focused review of recent evidence, primarily from in vitro brain slice electrophysiological studies, that offers new insight into the mechanisms through which acute and chronic ethanol exposures modulate the activity of GABAergic synapses. The implications of these new mechanistic insights to our understanding of the behavioral and cognitive effects of ethanol are also discussed.

Amygdala↗