Differential effects of σ1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs natural reward

Growing evidence suggests a role for sigma(1) (sigma(1)) receptors in cognitive function, anxiety, depression, regulation of stress responses, and, recently, the appetitive effects of cocaine as measured by conditioned place preference. This study was designed to extend understanding of the role of sigma(1) receptors in addiction-relevant conditioned effects of cocaine by testing the effects of a potent and selective sigma(1) receptor antagonist, BD1047, on conditioned reinstatement of cocaine-seeking. To determine whether modification of conditioned reinstatement by BD1047 is selective for drug-directed behavior or reflects general suppressant effects on motivated behavior, BD1047 was tested also on reinstatement induced by stimuli conditioned to a natural reward, sweetened condensed milk (SCM). Additionally, because sigma(1) receptors have been implicated also in processes linked to the acute reinforcing actions of cocaine, tests of the effects of BD1047 on cocaine self-administration - including a comparison with the sigma(1) antagonist effects on SCM self-administration - were conducted as well. Cocaine self-administering male Wistar rats were trained to associate a discriminative stimulus (S-D) with the availability of cocaine or SCM, and then subjected to reinstatement tests following extinction of cocaine or SCM-reinforced behavior. BD1047 (1 - 30mg/kg) reversed response reinstatement induced by the cocaine S-D at 20 and 30 mg/kg but did not modify SCM S-D-induced responding at all but the highest 30mg dose, at which responding was reversed to extinction levels. BD1047 did not modify responding reinforced directly by SCM or cocaine. The findings support a role for sigma(1) receptors in regulating conditioned responses to cocaine-related contextual stimuli and identify this receptor as a potential treatment target for the prevention of craving and relapse.