The sigma1 (σ1) receptor activation is a key step for the reactivation of cocaine conditioned place preference by drug priming

Rationale: Cocaine-seeking behavior can be investigated in rodents using the conditioned place preference (CPP) paradigm, in which the drug-paired environment serves as a conditioned stimulus. Such approach allowed to previously demonstrate the importance of the neuromodulatory sigma(1) (sigma(1)) receptor in acquisition of cocaine-induced CPP. CPP can be extinguished and then reactivated, notably using a cocaine challenge (i.e., priming). Objectives and methods: In order to examine the role of the a, receptor in reinstatement of Cocaine-seeking, Swiss mice acquired CPP with cocaine (30 mg/kg, ip) and then CPP was extinguished. Results: A challenge cocaine priming (15 mg/kg) reactivated CPP up to 140% of the post-conditioning response. Pre-administration of the sigma(1) receptor antagonist BD1047 (330 mg/kg, ip) or repeated treatment with an antisense probe targeting the a, receptor prevented CPP reactivation. The a, agonist igmesine (1-10 mg/kg, ip) or the steroid dehydroepiandrosterone (DHEA, 10-40 mg/kg, sc) reactivated CPP, in a BD1047-sensitive manner. Moreover, the in vivo [H-3](+)-SKF-10,047 binding levels to the a, receptor were increased after cocaine conditioning in numerous brain structures and these increases subsisted after extinction. Finally, cross-reactivation of cocaine-induced CPP was observed after phencyclidine (PCP), morphine, nicotine and ethanol administration. However, BD1047 blocked reactivation of CPP induced by PCP, morphine and nicotine but not ethanol. Conclusions: Since activation of the a, receptor is not sufficient to sustain CPP in naive animals [Neuropsychopharmacology 26 (2002) 444], it is concluded that or, receptor activation is a key event for relapse to drug seeking. Activation may occur via sensitization due to enhanced in vivo available of receptors.