EFFECTS OF THE SELECTIVE SIGMA-RECEPTOR LIGAND, [6-(4-HYDROXYPIPERIDINYL)HEXYLOXY]-3-METHYLFLAVONE (NPC-16377), ON BEHAVIORAL AND TOXIC EFFECTS OF COCAINE

Certain sigma receptor ligands have been shown to block locomotor stim ulation produced by cocaine at doses that do not have significant beha vioral activity when given alone. Using a potent and selective ligand of sigma binding sites, [6-(4-hydroxypiperidinyl)hexyloxy]-3-methylfla vone (NPC 16377), we further investigated the influence of sigma ligan ds on additional behavioral and toxic effects of cocaine in mice. A be haviorally inactive dose of NPC 16377 shifted the dose-effect function for the locomotor stimulant effects of cocaine to the right by a fact or of 2.5. A higher dose of NPC 16377 produced an insurmountable block ade of this stimulant effect of cocaine. Prior exposure to cocaine enh ances the locomotor stimulant effects of cocaine (sensitization). NPC 16377 prevented the development of cocaine sensitization without produ cing behavioral effects of its own. However, NPC 16377 was unable to b lock the expression of sensitization in mice previously exposed to coc aine. NPC 16377 also did not consistently alter the discriminative sti mulus effects of cocaine or methamphetamine in rats discriminating eit her 3 or 10 mg/kg of cocaine, or 1 mg/kg of methamphetamine from salin e. The potential phencyclidine-like behavioral effects of NPC 16377 we re also evaluated. Unlike the NMDA channel ligand, dizocilpine, NPC 16 377 did not increase responding under a fixed-interval schedule of foo d presentation in rats nor did it substitute for the discriminative st imulus effects of either 1.5 mg/kg of phencyclidine or 0.2 mg/kg of di zocilpine in rats discriminating these drugs from saline. NPC 16377 di splayed limited but significant anticonvulsant activity against diazep am-sensitive cocaine convulsions. The lethal effects of higher doses o f cocaine were neither significantly blocked nor enhanced in rats or m ice with NPC 16377. These findings extend earlier observations on the cocaine-blocking effects of sigma ligands to a novel structure with ex ceptional selectivity for sigma sites. These data indicate that some s igma ligands may be capable of altering certain behavioral and toxic a ctions of cocaine without notable behavioral side effects as evidenced in preclinical tests. As such, these compounds may ultimately be usef ul in the treatment of cocaine abuse.