Effect of σ₁ receptor antagonism on ethanol and natural reward seeking.

σ₁ Receptors have been implicated in cognitive function, anxiety, depression, and the regulation of stress responses. In addition, σ₁ receptors have been shown to participate in the behavioral and motivational effects of psychostimulants. Recent studies have shown that σ₁ receptor antagonism prevents ethanol-induced conditioned place preference in mice and excessive drinking in alcohol-dependent or alcohol-preferring rats. Therefore, this study was designed to determine whether this role for σ₁ receptors extends to ethanol-seeking behavior using an animal model of relapse and tested whether the suppressant effect of a potent σ₁ receptor antagonist, BD1047, generalizes to natural reward-seeking behavior. Two separate groups of rats were trained to orally self-administer 10% (w/v) ethanol or a highly palatable reinforcer, 3%/0.125% (w/v) glucose/saccharin (SuperSac), in the presence of a discriminative stimulus (S). Following extinction, during which the reinforcers and S were withheld, the presentation of the ethanol or SuperSac S produced comparable recovery of responding. BD1047 (1-20 mg/kg) exerted similar behavioral effects on both ethanol S-induced and SuperSac S-induced reinstatement, with the prevention of conditioned reinstatement only at the highest BD1047 dose. The present results show that σ₁ receptor blockade under the present conditions exerts similar effects on conditioned reinstatement induced by ethanol-related and SuperSac-related stimuli, suggestive of overlapping neural mechanisms that control ethanol and natural reward seeking.