Sigma1 receptor ligands and related neuroactive steroids interfere with the cocaine-induced state of memory

The present series of experiments examined the involvement of the sigma(1) receptor and related neuroactive steroids in the memory state induced by a very low dose of cocaine. Using a modified passive avoidance procedure in mice, we examined whether cocaine induces state-dependent (StD) learning. Animals trained and tested with saline or the same dose of cocaine (0.1 or 0.3 mg/kg) showed correct retention, measured using two independent parameters: the retention latency and a ratio between the retention latency and the last training latency. Animals trained with cocaine (0.1 mg/kg) and tested with saline or cocaine (0.03, 0.3 mg/kg), or trained with saline and tested with cocaine, showed altered retention parameters, demonstrating that StD occurred. Therefore, cocaine administered before training produced a chemical state used as an endogenous cue to insure optimal retention. Since sigma(1) receptor activation is an important event during the acquisition of cocaine reward, we tested several sigma(1) ligands and related neurosteroids. The sigma(1) agonist igmesine or antagonist BD1047 failed to produce StD, but modified the cocaine state. Among neuroactive steroids, pregnanolone and allopregnanolone, positive modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor, produced StD. However, steroids also acting as sigma(1) agonists, dehydroepiandrosterone (3beta-hydroxy-5alpha-androsten-17-one (DHEA)), pregnenolone, or antagonist, progesterone, failed to induce StD but modified the cocaine state. Furthermore, optimal retention was observed with mice trained with (igmesine or DHEA)+cocaine and tested with a higher dose of cocaine, or with mice trained with (BD1047 or progesterone)+cocaine and tested with vehicle. This study demonstrated that: (i) low doses of cocaine induce a chemical state/memory trace sustaining StD; (ii) modulation of the sigma(1) receptor activation, although insufficient to provoke StD, modulates the cocaine state; (iii) neuroactive steroids exert a unique role in state-dependent vs state-independent learning, via GABA(A) or sigma(1) receptor modulation, and are able to affect the cocaine-induced mnesic trace at low brain concentrations.