Reversal of ethanol-seeking behavior by D1 and D2 antagonists in an animal model of relapse: differences in antagonist potency in previously ethanol-dependent versus nondependent rats.
Mesocorticolimbic dopamine (DA) transmission has been implicated in the consummatory and, more recently, the incentive-motivational aspect of ethanol's actions. The purpose of this study was to test whether ethanol-seeking behavior induced by an ethanol-associated contextual stimulus is sensitive to antagonism of DA transmission. Male Wistar rats were trained to orally self-administer 10% ethanol and to associate olfactory discriminative stimuli with the availability of ethanol (S(+)) versus nonreward (S(-)). Ethanol-reinforced operant responding then was extinguished by withholding ethanol and the associated S(+). After reaching a predetermined extinction criterion, reinstatement tests were conducted in which the animals were presented noncontingently with only the S(+) or S(-). Exposure to the S(+) but not the S(-) reinstated responding at the previously active lever. The D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 5, 10, 50 microg/kg s.c.) and the D2 antagonist eticlopride (5, 10, 50 microg/kg s.c.) dose dependently decreased the number of S(+)-induced responses and increased response latency. During a second test, conducted in the same rats, 3 weeks after withdrawal from a 12-day ethanol vapor inhalation procedure, the response-reinstating efficacy of the S(+) remained unaltered. However, the potency of both DA antagonists to inhibit the S(+)-induced drug-seeking response was significantly increased. The results confirm that ethanol-related contextual stimuli reliably elicit drug-seeking behavior and suggest that this effect requires activation of DA neurotransmission. The results also indicate that chronic ethanol exposure produces changes in D1 and D2 receptor function that lead to enhanced sensitivity to the behavioral effects of antagonists for these receptors.
Liu
Xiu
X
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA. xliu@scripps.edu
Weiss
Friedbert
F
D000280:Administration, Inhalation; D000437:Alcoholism / Q000188:drug therapy* / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D012008:Recurrence; D012457:Salicylamides / Q000494:pharmacology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000523:psychology
D001552:Benzazepines; D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D012457:Salicylamides; D000431:Ethanol; C045989:eticlopride