Baclofen Blocks Expression and Sensitization of Anxiety‐Like Behavior in an Animal Model of Repeated Stress and Ethanol Withdrawal

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Abstract
Background:Repeated exposures to forced ethanol diets (EDs) or restraint stress sensitize anxiety‐like behavior during a future ethanol withdrawal. The present investigation assessed whether pretreatment of rats with agents targeting receptor systems thought to be important in treating relapse in alcoholic patients would prevent sensitization of anxiety‐like behavior.Methods:Groups of rats were exposed to either (1) three 5‐day cycles of ED with 2 days of withdrawal between cycles, (2) continuous ED, or (3) 5 days of ED in a single cycle preceded by 2 episodes of restraint stress 6 days apart. Drugs [baclofen, acamprosate, naloxone, lamotrigine, ifenprodil, dizocilpine (MK‐801), CGS19755, diazepam, flumazenil, or 6‐methyl‐2‐(phenylethynyl)pyridine] were given prophylactically during the first and second withdrawal periods only or, in separate baclofen experiments, acutely during the third withdrawal or during withdrawal from continuous ED. Baclofen administration preceded each stress session in the stress‐withdrawal protocols. Anxiety‐like behavior was assessed in the social interaction (SI) test 5 hours after the ethanol was removed or after 3 days of abstinence.Results:Baclofen (1.25, 2.5, and 5 mg/kg), flumazenil (5 mg/kg), and diazepam (1 mg/kg) blocked the reduction in SI induced by ethanol withdrawal. Among the drugs that alter glutamate function, only acamprosate (300 mg/kg) was effective. In the stress protocols, baclofen (5 mg/kg) given before each of the 2 restraint stress sessions before ethanol exposure or before stress during abstinence also attenuated SI deficits.Conclusions:These findings suggest that GABABand GABAA, but not glutamate or opioid mechanisms, are involved in adaptive changes associated with anxiety‐like behavior induced by these repeated ethanol‐withdrawal and stress‐withdrawal paradigms. The lack of action of agents attenuating different aspects of glutamate function suggests that acamprosate's action is related to some other, as yet undetermined, mechanism.