σ1 Receptor Ligands and Related Neuroactive Steroids Interfere with the Cocaine-Induced State of Memory

Abstract

The present series of experiments examined the involvement of the s 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 s 1 receptor activation is an important event during the acquisition of cocaine reward, we tested several s 1 ligands and related neurosteroids. The s 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 g-aminobutyric acid type A (GABA A ) receptor, produced StD. However, steroids also acting as s 1 agonists, dehydroepiandrosterone (3b-hydroxy-5a-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 s 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 s 1 receptor modulation, and are able to affect the cocaine-induced mnesic trace at low brain concentrations.

Differential Effects of σ1 Receptor Blockade on Self-Administration and Conditioned Reinstatement Motivated by Cocaine vs Natural Reward

“…The reason for the failure of BD1047 to alter SCM S + -induced behavior at low doses, paired with the full suppression of this behavior only at the highest dose is presently unclear. This effect cannot be attributed to motor impairment or sedation, because BD1047 did not interfere, even at the highest dose, with the high rate of responding in rats self-administering SCM (Figure 2b), confirming previous reports that s 1 receptor antagonists are devoid of general suppressant effects on behavior (McCracken et al, 1999a;Romieu et al, 2006). In particular, while BD1047 reduces the acute locomotor stimulant effects of cocaine as well as cocaine-induced convulsions and lethality, the s 1 receptor antagonist does not interfere with spontaneous locomotor activity (McCracken et al, 1999a).…”

Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse

“…Administration of 3α,5α-THP to mice produces CPP (Finn et al, 1997) and state dependent reward (Romieu et al, 2005).Among rats, 3α,5α-THP administration can dose-dependently increase the release of dopamine in the nucleus accumbens (Rouge-Pont et al, 2002). However, a conditioned place aversion has been demonstrated among rats administered 3α,5α-THP (Beauchamp et al, 2000).…”

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

“…A modified passive avoidance procedure was used in mice to examine whether cocaine induces state-dependent learning (StD) (203). Cocaine administration, at the low dose of 0.1 mg / kg before training, produced a chemical state in the brain that served as an endogenous cue.…”