2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and pregnenolone-sulfate

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Binding Sites; Blotting, Western; Brain; Cerebral Cortex; Dehydroepiandrosterone; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Memory; Mice; Morpholines; Oligonucleotides, Antisense; Phenazocine; Pregnenolone; Receptors, sigma; Sigma-1 Receptor

Recent reports suggest an interaction between neuro-(active)steroids and sigma1 (sigma 1) receptors, affecting biochemical parameters as well as physiological responses mediated by sigma 1 ligands in the rodent brain. In this study, we examined the modulation by neurosteroids of the haloperidol-sensitive in vivo (+)-[3H]SKF-10,047 binding to sigma 1 sites in the mouse hippocampus and cortex. Progesterone (PROG; 2-40 mg/kg), pregnenolone sulfate (PREGS; 10-40 mg/kg), and dehydroepiandrosterone sulfate (DHEAS; 10-40 mg/kg) were administered systemically 10 min before the radioactive tracer. The total amount of (+)-[3H]SKF-10,047 bound in each structure was significantly affected by PROG and PREGS only at the highest dose tested and was unaffected by DHEAS. However, bound to free (B/F) radioactivity ratios were highly significantly decreased by 30-40% in each structure by PROG and PREGS. DHEAS, at 40 mg/kg, induced a significant 20% decrease in the hippocampus. Furthermore, the in vivo (+)-[3H]SKF-10,047 binding parameters were diminished in pregnant female mice compared to non-pregnant or male mice. These results confirm the in vitro binding results, bring a direct in vivo demonstration of the interaction between neurosteroids and sigma 1 receptors, and show that physiologic modulations of the steroidal concentrations affect the sigma 1 systems.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Cerebral Cortex; Dehydroepiandrosterone Sulfate; Dose-Response Relationship, Drug; Female; Gonadal Steroid Hormones; Hippocampus; Male; Mice; Phenazocine; Pregnancy; Pregnenolone; Progesterone; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, sigma; Tritium