Igmesine

Abstract: The interaction of neuroactive steroids with the sigma(1)-receptor was investigated in Swiss mice submitted to the forced swimming test. The sigma(1)-agonists igmesine and (+)-SKF-10,047 and the steroid dehydroepiandrosterone sulfate (DHEAS) showed some antidepressant-like activity by shortening the immobility time, these effects being blocked by the sigma(1)-antagonist BD1047 or progesterone. The sigma(1)-agonist PRE-084 or pregnenolone sulfate failed to affect the immobility time. In adrenalectomized/castrated (AdX/CX) mice, the effects of igmesine and DHEAS were significantly potentiated, and PRE-084 or pregnenolone sulfate induced significant decreases of immobility time. The augmented effects in AdX/CX were fully blocked by BD1047. The effects of the classical antidepressants, desipramine or fluoxetine, were unchanged in AdX/CX mice. The effect of stress on the sigma(1)-receptor binding and neurosteroid levels was then examined in different brain structures, in terms of in vivo (+)-[(3)H]SKF-10,047 binding to sigma(1)-sites and neurosteroids levels. In the hippocampus, but not in the cortex or cerebellum, inhibition of in vivo (+)-[(3)H]SKF-10,047 binding was measured in parallel to the extent of progesterone levels according to the endocrine conditions. These data confirmed the antidepressant ability of sigma(1)-receptor agonists and revealed that the endogenous steroidal levels tonically interfere with the efficacy of the sigma(1)-system. It was observed that local modifications in progesterone levels are directly related to the changes of in vivo sigma(1)-binding. Such observations may be of major importance in view of the therapeutic use of selective sigma(1)-agonists in depression.

Abstract: 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). 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.