Acamprosate and alcohol: III. Effects on alcohol discrimination in the rat

It has been shown that acamprosate (calcium-acetyl homotaurinate) decreases voluntary ethanol drinking in laboratory animals as well as relapse behaviour in human alcoholics. Although glutamatergic mechanisms have been implicated in several recent studies in the action of acamprosate, the basic mechanism remains unknown. In order to gain more insight into possible mechanisms underlying the ethanol intake-suppressing effects of acamprosate, we investigated this compound in an ethanol discrimination test. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses for food following ethanol (1 g/kg i.p.; 12% v/v ethanol solution) or saline vehicle injections with a fixed ratio schedule of food reinforcement (FR 10) and a post-administration interval of 10 min. Once rats had acquired the discrimination, the criterion for stimulus control was set as at least 90% ethanol- or vehicle appropriate responding during ten consecutive sessions, an ethanol dose-response test (0.25-1.5 g/kg i.p.) was conducted. The effects of acamprosate on the discrimination were assessed in two ways: (i) Generalization test: acamprosate (25-250 mg/kg i.p.) was given either 30 or 120 min before the animals were put in the operant chambers. (ii) Antagonism test: acamprosate (25-250 mg/kg i.p.) was given 120 min before the animals were injected with ethanol, 10 min later the animals were tested. Data obtained in the dose-response test showed a dose-dependent effect with an ED50 of 0.53 g/kg ethanol. The results of generalization testing revealed that acamprosate failed to substitute for the ethanol cue, whereas, in comparison, dizocilpine (0.01-0.2 mg/kg i.p.) completely generalized for the ethanol cue (ED50 = 0.05 mg/kg). Acamprosate also had no effect when tested as an antagonist. Thus, neither the ethanol nor the saline discrimination was altered by acamprosate pretreatment. Furthermore, acamprosate had no effect on response latencies at all doses tested. In conclusion, acamprosate does not generalize for the ethanol cue, suggesting that it is not a substitution drug. Further, acamprosate does not seem to act via the dizocilpine binding site of the N-methyl-D-aspartic acid (NMDA) channel.