Blocking GABA(A) receptors in the anterior ventral tegmental area attenuates ethanol intake of the alcohol-preferring P rat.
The effect of blocking the A subtype of gamma-aminobutyric acid (GABA(A)) receptors in the anterior ventral tegmental area (VTA) on ethanol (EtOH; 10% v/v) and saccharin (SACC; 0.0125%) consumption was investigated in alcohol-preferring P rats. Picrotoxin (0.005, 0.01, 0.05 and 0.10 microg/0.5 microl) was injected into the VTA, and consumption of EtOH and SACC was assessed in two 2-h limited-access drinking paradigms (concurrent EtOH/SACC access, and alternate-day-access to EtOH and SACC). Under concurrent-access conditions, the picrotoxin microinjections resulted in a 55 and 84% decrease in EtOH consumption at the 0.05 and 0.10 microg doses, respectively, compared with consumption following microinjections of vehicle solution (P<0.05). Saccharin intake was not significantly altered by picrotoxin. Under alternate-day-access drinking conditions, the picrotoxin microinjections resulted in dose-dependent decreases in EtOH consumption of 37-68%, with significant decreases following the 0.005, 0.05 and 0.10 microg doses (P<0.04). Saccharin intake was significantly reduced only at the 0.05 microg dose. The decrease in EtOH consumption after 0.10 microg picrotoxin was attenuated by co-administration of 0.01 microg muscimol. This dose of muscimol had no effect on EtOH consumption when injected alone. Intra-VTA injections of bicuculline (0.04 microg), another GABA(A) antagonist, reduced EtOH intake, comparable to the reduction following 0.10 microg picrotoxin. Microinjections of 0.10 microg picrotoxin in regions outside the VTA failed to decrease EtOH intake. These results suggest that anterior VTA mechanisms regulating alcohol drinking behavior are under tonic GABA inhibition, mediated by GABA(A) receptors. The results also suggest that different neural mechanisms are regulating voluntary EtOH and SACC drinking behaviors.
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis 46202-4887, USA.
K L
KL
Nowak
W J
WJ
McBride
L
L
Lumeng
T K
TK
Li
J M
JM
Murphy
D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D009118:Muscimol / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D018755:GABA Agonists; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D009118:Muscimol; D010852:Picrotoxin; D011963:Receptors, GABA-A