Effects ofd‐Cycloserine on Extinction and Reconditioning of Ethanol‐Seeking Behavior in Mice

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Abstract
Background: d‐Cycloserine (DCS), a partialN‐methyl‐d‐aspartate receptor agonist, has been shown to enhance the extinction of both cocaine and amphetamine‐induced conditioned place preference (CPP). However, there have been no reports of the effects of DCS on the extinction of ethanol‐conditioned behaviors in mice. Thus, the current experiments examined the effects of DCS on the extinction and subsequent reconditioning of ethanol‐induced CPP in mice.Methods: Male DBA/2J mice received either 2 or 4 pairings of ethanol (2 g/kg) with a conditioned stimulus (CS+) floor cue (and an equal number of saline pairings with a CS− floor cue on alternate days) resulting in either a weak or strong ethanol CPP, respectively. Following conditioning of a strong ethanol CPP mice received saline or 30 mg/kg DCS prior to each of the twelve 30‐minute choice extinction trials administered at 48‐hour intervals. Mice that had received conditioning of a weak ethanol CPP received saline, 30 or 60 mg/kg DCS immediately before each of the six 30‐minute choice extinction trials. Following successful ethanol CPP extinction, mice received reconditioning trials similar to the initial conditioning trials. A final experiment examined the effects 12 DCS pre‐exposures (15, 30, and 60 mg/kg) on initial conditioning of ethanol CPP.Results: First, we showed that 2 doses of DCS (30 and 60 mg/kg) did not have aversive properties that could confound the effects on extinction of CPP (Experiment 1). Second, we showed that DCS (30 and 60 mg/kg) had no effect on the rate of extinction of either strong (Experiment 2) or weak (Experiment 3) ethanol‐induced CPP. Interestingly, DCS administered during extinction interfered with reconditioning of ethanol‐induced CPP—an effect specific to reconditioning, as DCS pre‐exposure did not influence initial ethanol CPP conditioning (Experiment 4).Conclusions: These experiments show that although DCS showed no effect on extinction behavior, when given during extinction it interfered with subsequent reconditioning of ethanol CPP. The mechanisms of this effect were not, however, due to nonspecific interference with learning because repeated DCS pre‐exposures did not impair initial conditioning of ethanol CPP.