Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice.
The present study investigated the role of the alpha1-containing GABA(A) receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the alpha1 subunit (alpha1 (-/-)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the alpha1 (-/-) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the alpha1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, betaCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (alpha1 (+/+)), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). betaCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the alpha1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the alpha1 subunit of the GABA(A) receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA- and GABA(A) BDZ-dependent mechanisms.
June
Harry L
HL
Division of Alcohol and Drug Abuse, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA. hjune@psych.umaryland.edu
Foster
Katrina L
KL
Eiler
William J A
WJ
Goergen
Joshua
J
Cook
Jason B
JB
Johnson
Nathan
N
Mensah-Zoe
Boikai
B
Simmons
Jothan O
JO
June
Harry L
HL
Yin
Wenyuan
W
Cook
James M
JM
Homanics
Gregg E
GE
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011963:Receptors, GABA-A / Q000172:deficiency; D012054:Reinforcement, Psychology; D012457:Salicylamides / Q000494:pharmacology; D012646:Self Administration
D001552:Benzazepines; D002243:Carbolines; D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D012457:Salicylamides; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; C043232:tert-butyl beta-carboline-3-carboxylate; C045989:eticlopride; D004298:Dopamine