The sigma1 (σ1) receptor activation is a key step for the reactivation of cocaine conditioned place preference by drug priming
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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 sigma1 (σ1) 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 σ1 receptor in reinstatement of Cocaine-seeking, Swiss mice acquired CPP with cocaine (30 mg/kg, ip) and then CPP was extinguished.
A challenge cocaine priming (15 mg/kg) reactivated CPP up to 140% of the post-conditioning response. Pre-administration of the σ1 receptor antagonist BD1047 (330 mg/kg, ip) or repeated treatment with an antisense probe targeting the σ1 receptor prevented CPP reactivation. The σ1 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 [3H](+)-SKF-10,047 binding levels to the σ1 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.
Since activation of the σ1 receptor is not sufficient to sustain CPP in naive animals [Neuropsychopharmacology 26 (2002) 444], it is concluded that σ1 receptor activation is a key event for relapse to drug seeking. Activation may occur via sensitization due to enhanced in vivo available of receptors.
KeywordsCocaine relapse Conditioned place preference Sigma1 (σ1) receptor Sensitization Dehydroepiandrosterone Mouse
We thank M. Michaud, and Drs J.-M. Kamenka and F.J. Roman for their gifts of drugs. This work was supported by CNRS.
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