Behavioral effects of rimcazole analogues alone and in combination with cocaine.
Several sigma receptor ligands have been reported to also have affinity for the dopamine transporter, among them rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride). However, rimcazole lacks behavioral effects like those of other dopamine uptake inhibitors, such as cocaine and GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride). Because of this profile, the interactions with cocaine of rimcazole and several of its novel analogues were assessed. The compounds studied were rimcazole, its N-methyl analogue, SH 1-73 (9-[3-(cis-3,5-dimethyl-4-methyl-1-piperazinyl)-propyl]carbazole hydrobromide), the dibrominated analogue, SH 1-76 (3,6-dibromo-9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl]carbazole hydrochloride), and the N-propylphenyl analogues, SH 3-24 ([3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride) and SH 3-28 (9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide). The former has a diphenyl-amine group in place of the carbazole moiety of rimcazole, giving the compound additional structural similarity to GBR 12909. The rimcazole analogues produced dose-related decreases in locomotor activity, and also decreased cocaine-stimulated activity in mice. In rats trained to discriminate 10 mg/kg cocaine (i.p.) from saline injections, cocaine and GBR 12909 each produced a dose-related increase in cocaine-appropriate responding. Cocaine also increased rates of responding. SH 3-28 decreased cocaine-appropriate responding at the cocaine training dose to about 58% (SH 3-28) with two of five subjects selecting the cocaine response key. Neither rimcazole nor SH 3-24 produced a significant attenuation of the discriminative effects of cocaine. Rimcazole and its analogs all attenuated the increases in rates of responding produced by cocaine. In contrast to effects obtained with rimcazole analogs, GBR 12909 potentiated the cocaine-induced increases in locomotor activity and operant behavior, as well as the discriminative-stimulus effects of cocaine. The present results indicate that analogues of rimcazole can attenuate the behavioral effects of cocaine, and though the mechanism for these effects is not presently clear, it is possible that this attenuation maybe mediated by actions of the rimcazole analogues at the dopamine transporter and/or sigma receptors.
Katz
Jonathan L
JL
Department of Health and Human Services, Medications Discovery Research Branch, NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA. jkatz@intra.nida.nih.gov
Libby
Therissa A
TA
Kopajtic
Theresa
T
Husbands
Stephen M
SM
Newman
Amy Hauck
AH
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002227:Carbazoles / Q000008:administration & dosage / Q000819:agonists / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D002227:Carbazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D017480:Receptors, sigma; C034931:rimcazole; D003042:Cocaine