Blockade of GABA(A) receptors within the extended amygdala attenuates D(2) regulation of alcohol-motivated behaviors in the ventral tegmental area of alcohol-preferring (P) rats.
The dopamine (DA) mesolimbic pathway, which originates from DA cell bodies within the ventral tegmental area (VTA), has been shown by various studies to play a role in the mediation of various drugs of abuse including alcohol (EtOH). It has been suggested that the VTA's control of EtOH reward is mediated in part by the D2 receptors within the VTA. These receptors may be under the regulation of reciprocal GABAergic inputs from forebrain components of the mesolimbic path such as the nucleus accumbens (NAcc), a classic EtOH reward substrate, and the bed nucleus of the stria terminalis, a substrate recently implicated in EtOH reinforcement, forming a self-regulating feedback loop. To test this hypothesis, D2 regulation of EtOH self-administration (SA) was evaluated by the microinfusion of the D2 antagonist eticlopride into the VTA of P rats, which produced profound reductions in EtOH SA in the highest (20.0 and 40.0microg) doses tested in both BST/VTA and NAcc/VTA implanted P rats. To determine the role of GABA in the mediation of EtOH SA, a 32.0ng dose the non-selective GABA antagonist SR 95531 was microinfused into the BST producing no effect on responding for EtOH and into the NAcc which lead to a reduction in EtOH responding. Finally, the hypothesis that GABA innervation of the VTA from the mesolimbic forebrain may influence EtOH SA was examined by the simultaneous infusion of eticlopride (40.0microg) into the VTA and SR 95531 (32.0ng) into either the BST or NAcc. This combination infusion completely attenuated the reduction in EtOH SA observed with the 40.0microg dose of eticlopride alone in both groups of animals. These results suggest that while the D2 receptors within the VTA regulate EtOH-motivated behaviors, this is modulated by GABAergic input from the mesolimbic forebrain, specifically from the BST and NAcc.
Eiler
William J A
WJ
Psychobiology of Addictions Program, Department of Psychology, Indiana University-Purdue University, Indianapolis, IN 46202, USA.
June
Harry L
HL
D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D001522:Behavior, Animal; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D012457:Salicylamides / Q000008:administration & dosage; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D004338:Drug Combinations; D018756:GABA Antagonists; D011724:Pyridazines; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D012457:Salicylamides; D000431:Ethanol; C049853:gabazine; C045989:eticlopride