SUBCHRONIC ADMINISTRATION OF PHENYL)ETHYL]-N-METHYL-2-(DIMETHYLAMINO)ETHYLAMINE (BD1047) ALTERS SIGMA(1) RECEPTOR-BINDING

BD1047 phenyl)ethyl]-N-methy-2-(dimethylamino)ethylamine) is known to bind with high affinity and selectivity to a sites in vitro. In prior in vivo studies, it has been shown to attenuate the dystonic postures and orofacial dyskinesias that are produced by sigma receptor ligands, including the neuroleptic haloperidol. Since abnormal movements, such as dystonic postures and orofacial dyskinesias, are side effects that are associated with many sigma-active neuroleptics, compounds such as BD1047 may have therapeutic potential for preventing and treating the se unwanted movements. A possible limitation to the therapeutic potent ial of BD1047, however, is that at least in cell culture and albeit we ak, it can be cytotoxic. Therefore, the present study analyzed the pos sible neurotoxic effects of in vivo subchronic intracerebroventricular infusion of BD1047 (10 nmol/h) or artificial cerebrospinal fluid (CSF ) into rat brains using osmotic minipumps for 7 or 14 days. Following a 24 h wash-out period, the animals were killed, the brains removed, a nd P-2 membranes prepared. Membranes from rats treated for 7 or 14 day s with BD1047 showed a marked decrease in [H-3](+)-pentazocine binding as compared to membranes from CSF-treated animals, suggesting a loss of sigma(1) receptor binding. Histological examination of brain sectio ns processed for Nissl stains and glial fibrillary acidic protein (GFA P) immunohistochemistry excluded the possibility of a cytotoxically in duced down-regulation, suggesting possible receptor internalization or desensitization mediated via sigma(1) sites. Under the conditions use d in our study, BD1047 does not appear to be neurotoxic, and the data, when taken together with other studies, suggest that BD1047 acts as a partial agonist at sigma sites. (C) 1997 Elsevier Science B.V.