Background-Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice.

We examined the interaction of ethanol with the ␥-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CeA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11-66 mM ethanol significantly increased GABA type A (GABA A) receptormediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent EC50 of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABAA IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GABA B) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased pairedpulse facilitation of evoked GABAA IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GABA A IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GABAB antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre-and postsynaptic sites. These findings add further support to the contention that the ethanol-GABA interaction in CeA plays an important role in the reinforcing effects of ethanol.alcohol ͉ GABA IPSP͞Cs ͉ paired-pulse facilitation ͉ miniature synaptic current ͉ electrophysiology T he amygdala formation is a complex of interconnected nuclei that has been implicated in various physiological functions such as attention (1), memory (1-4), emotion (5-7), and autonomic control (3). This complex has been linked to the motivational effects of drugs of abuse and alcoholism in particular (8).The ␥-aminobutyric acid (GABA)ergic system, particularly in the central amygdala nucleus (CeA), has been implicated in the expression of emotionality, including behavioral states of fear and anxiety, as well as states associated with consummatory responses (9). The CeA is considered to be crucial in mediating the behavioral effects of acute and chronic ethanol consumption (10, 11). Because stress reduction has long been considered to contribute to ethanol-seeking behavior in humans, researchers hypothesized that the CeA and its connections might be sites for a GABA-like action of ethanol to mediate ethanol reinforcement. Behavioral studies indicate that injection of GABAergic antagonists directly into the CeA decreases motivated responding for oral self-administration of ethanol in rats, whereas infusion of GABA agonists and benzodiazepines decreased anxiety (11,12). Thus, these studies suggest that GABAergic systems in the CeA play a major role in the acute reinforcing effects of ethanol (13) and in the anxiogenic response to ethanol withdrawal (14).There has been a continuing controversy over the ability of ethanol to enhance GABAergic neurotransmission [inhib...

The central nucleus of amygdala (CeA) is important in regulating alcohol consumption and plays a major role in the anxiogenic response to ethanol withdrawal. We showed previously that acute ethanol augments GABA A receptor-mediated IPSPs and IPSCs, possibly by a presynaptic mechanism. Here, we have examined the interaction of acute ethanol with the GABAergic system in chronic ethanol-treated (CET) rats using an in vitro CeA slice preparation and in vivo brain microdialysis. We found that in CeA slices from CET rats, the baseline evoked IPSP and IPSC amplitudes were increased, and paired-pulse facilitation ratios were lower than in naive rats, suggesting an increased GABAergic transmission after chronic ethanol treatment. Interestingly, acute ethanol (5-66 mM) significantly enhanced IPSPs and IPSCs equally in CET and naive rats, indicating a lack of tolerance for this effect of acute ethanol. Analysis of miniature IPSC frequency suggests that the increased GABAergic transmission by both acute and chronic ethanol arises from a presynaptic mechanism involving enhanced vesicular release of GABA. These data are supported by microdialysis studies showing that CET rats presented a fourfold increase in baseline GABA dialysate content compared with naive rats. In vivo administration of ethanol (0.1, 0.3, and 1.0 M) produced a dose-dependent increase in GABA release in the CeA dialysate in both CET and naive rats. These combined findings suggest that acute and chronic ethanol increases GABA release in CeA and support previous reports that the behavioral actions of ethanol are mediated, in part, by increased GABAergic transmission in the CeA.

No abstract

The central amygdala (CeA) plays a role in the relationship among stress, corticotropin-releasing factor (CRF), and alcohol abuse. In whole-cell recordings, both CRF and ethanol enhanced gamma-aminobutyric acid-mediated (GABAergic) neurotransmission in CeA neurons from wild-type and CRF2 receptor knockout mice, but not CRF1 receptor knockout mice. CRF1 (but not CRF2) receptor antagonists blocked both CRF and ethanol effects in wild-type mice. These data indicate that CRF1 receptors mediate ethanol enhancement of GABAergic synaptic transmission in the CeA, and they suggest a cellular mechanism underlying involvement of CRF in ethanol's behavioral and motivational effects.

No abstract

Immunocytochemical and electrophysiological evidence suggests that somatostatin may be a transmitter in the hippocampus. To characterize the ionic mechanisms underlying somatostatin effects, voltage-clamp and current-clamp studies on single CA1 pyramidal neurons in the hippocampal slice preparation were performed. Both somatostatin-28 and somatostatin-14 elicited a steady outward current and selectively augmented the noninactivating, voltage-dependent outward potassium current known as the M-current. Since the muscarinic cholinergic agonists carbachol and muscarine antagonized this current, these results suggest a reciprocal regulation of the M-current by somatostatin and acetylcholine.

We recently reported that chronic ethanol treatment (CET) and early withdrawal (2-8 h) altered glutamatergic transmission at both preand postsynaptic sites in central nucleus of the amygdala (CeA). Acute ethanol (44 mM) inhibited the NMDA receptor (NMDAR)-mediated EPSCs (NMDA-EPSCs) more in CeA neurons from CET rats than from naïve rats and also decreased paired-pulse facilitation (PPF) of NMDA-EPSCs only in CET rats. To determine whether these CET effects persisted after prolonged withdrawal, we recorded intracellularly in rat CeA slices and measured mRNA and protein expression of CeA NMDAR subunits from CET rats and those withdrawn from ethanol for 1 or 2 weeks. At 1 week withdrawal, acute ethanol decreased evoked NMDA-EPSC amplitudes and NMDA currents induced by exogenous NMDA (B20%) equally to that in naïve rats, indicating that CET effects on postsynaptic mechanisms reversed 1 week after CET cessation. However, acute ethanol still decreased PPF of NMDA-EPSCs, indicating that the acute ethanolinduced increase in glutamate release in CeA seen in CET rats was still present at this time. CET also significantly increased mRNA levels of NR1 and NR2B NMDAR subunits compared to control rats. At 1 week withdrawal, mRNA levels for NR1 and NR2B subunits were significantly decreased. These changes reversed at 2 weeks withdrawal. In Western blots, a significant increase in protein for all three subunits occurred in CeA from CET rats, but not after 1 and 2 weeks of withdrawal. These data indicate that CET induces reversible neuroadaptations in synaptic function, gene expression, and protein composition of NMDAR at CeA synapses. Neuropsychopharmacology (2006) 31, 988-996.