cgp-55845a and Body-Weight

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.. Using naive and ethanol-dependent rats, we compared electrophysiologic effects and interactions of CRF and ethanol on CeA GABAergic transmission, and we measured GABA dialyzate in CeA after injection of CRF(1) antagonists and ethanol. We also compared mRNA expression in CeA for CRF and CRF(1) using real-time polymerase chain reaction. We assessed effects of chronic treatment with a CRF(1) antagonist on withdrawal-induced increases in alcohol consumption in dependent rats.. CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF(1)) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF(1) antagonists on CeA GABA release. Intra-CeA CRF(1) antagonist administration reversed dependence-related elevations in GABA dialysate and blocked ethanol-induced increases in GABA dialyzate in both dependent and naive rats. Polymerase chain reaction studies indicate increased expression of CRF and CRF(1) in CeA of dependent rats. Chronic CRF(1) antagonist treatment blocked withdrawal-induced increases in alcohol drinking by dependent rats and tempered moderate increases in alcohol consumption by nondependent rats in intermittent testing.. These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Alcoholism; Amygdala; Animals; Body Weight; Central Nervous System Depressants; Corticotropin-Releasing Hormone; Cyclophilins; Ethanol; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Hormone Antagonists; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Microdialysis; Neurons; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger; Time Factors; Valine

In previous studies, we found that chronic intermittent ethanol (CIE) treatment-a model of ethanol consumption in which animals are exposed to and withdrawn from intoxicating levels of ethanol on a daily basis-produces neuroadaptive changes in hippocampal area CA1 excitatory synaptic transmission and plasticity. Synaptic responses mediated by N-methyl-D-aspartate (NMDA) receptors are known to be sensitive to ethanol and could play an important role in the neuroadaptive changes induced by CIE treatment. To address this issue, we compared electrophysiological recordings of pharmacologically isolated NMDA-receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 region of hippocampal slices prepared from control rats and rats exposed to 2 weeks of CIE treatment administered by vapor inhalation. We found that fEPSPs induced by NMDA receptor activation were unaltered in slices prepared shortly after cessation of CIE treatment (i.e., < or = 1 day of withdrawal from CIE). However, following 7 days of withdrawal from CIE treatment, NMDA-receptor-mediated fEPSPs were augmented relative to age-matched controls. Western blot analysis of NMDA receptor subunit expression showed that, at 7 days of withdrawal, the level of protein for NR2A and NR2B subunits was elevated in the CA1 region of hippocampal slices from CIE-treated animals compared with slices from age-matched controls. These results are consistent with an involvement of NMDA-receptor-mediated synaptic responses in the neuroadaptive effects of CIE on hippocampal physiology and suggest that such changes may contribute to ethanol-induced changes in processes dependent on NMDA-receptor-mediated synaptic responses such as learning and memory, neural development, hyperexcitability and seizures, and neurotoxicity.

Topics: Animals; Blotting, Western; Body Weight; Brain; Central Nervous System Depressants; Dose-Response Relationship, Radiation; Drug Administration Schedule; Drug Interactions; Electric Stimulation; Ethanol; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Hippocampus; In Vitro Techniques; Male; Organ Size; Phosphinic Acids; Picrotoxin; Propanolamines; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Time Factors; Valine