Behavioral effects of rimcazole analogues alone and in combination with cocaine

doi:10.1016/S0014-2999(03)01638-8

European Journal of Pharmacology

Volume 468, Issue 2, 9 May 2003, Pages 109-119

https://doi.org/10.1016/S0014-2999(03)01638-8 Get rights and content

Abstract

Several σ 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 σ receptors.

Introduction

Several σ receptor ligands have been reported to decrease the behavioral effects of cocaine. For example, Menkel et al. (1991) showed that rimcazole and BMY 14802 blocked the locomotor-stimulant effects of cocaine, which has also been reported with other σ receptor ligands Karbon et al., 1992, McCracken et al., 1999a, McCracken et al., 1999b. This activity occurred more specifically than for other drugs, such as the dopamine D2 receptor antagonists which only attenuated the effects of cocaine at doses that were by themselves active Chausmer and Katz, 2001, Menkel et al., 1991. More recently, Romieu et al., 2000, Romieu et al., 2002 have shown that σ receptor antagonists attenuate cocaine-induced place preference and that the σ receptor is necessary for both acquisition and expression of this cocaine-induced behavior. Matsumoto et al., 2001a, Matsumoto et al., 2001b have also shown that σ receptor ligands can block some of the acute toxic effects of cocaine. These findings suggested a focus on σ receptor ligands as possible treatments for cocaine abuse.

A previous study from this laboratory indicated that rimcazole not only has affinity for σ receptors but it also has affinity for the dopamine transporter (Izenwasser et al., 1993). In that study, the affinity of rimcazole for the dopamine transporter was comparable to its reported affinity for σ receptors. In a subsequent study, rimcazole was found to have an approximately 4-fold higher affinity for the dopamine transporter (K_i=224 nM) as compared to the σ receptor (K_i=908 nM, Husbands et al., 1999). Notably, despite its comparable dopamine transporter affinity, the behavioral effects of rimcazole are different from those of cocaine. Rimcazole does not stimulate locomotor activity (Menkel et al., 1991), though cocaine and prototypical psychomotor stimulant drugs have this as one of their benchmark actions (Kelleher, 1977). The disparate behavioral effects of rimcazole and cocaine lead to the synthesis of novel rimcazole analogues in order to better investigate relationships between behavioral activity and pharmacological mechanisms (Husbands et al., 1999).

The present study was initiated to better define the behavioral effects of rimcazole and its analogues compared to those of cocaine. Further, because previous studies have reported some attenuation of behavioral effects of cocaine by σ receptor ligands in general (Menkel et al., 1991), and rimcazole and its analogues in particular (Matsumoto et al., 2001c), we examined interactions between rimcazole and several of its analogues with cocaine.

Section snippets

Animals

For studies of locomotor activity, male Swiss Webster mice (Taconic Farms) weighing 24–28 g were used. They were group housed with unrestricted access to food and water under a 12-h light/dark cycle (lights on 07:00 h). Subjects were used only once in these studies.

For studies of the discriminative-stimulus effects of cocaine, male Sprague–Dawley rats (Charles River, Wilmington MA) weighing 320–350 g were individually housed with unrestricted access to water under a 12-h light/dark cycle

Locomotor activity

Cocaine produced dose-related increases in ambulatory activity with a maximum of approximately 580 counts/min at 59 μmol/kg (Fig. 2, filled circles). GBR 12909 (Fig. 2, filled diamonds) also increased locomotor activity, although this effect was greater in the second 30 min after injection (Fig. 2, diamonds) and remained less than that obtained with cocaine in the first 30 min after injection. Rimcazole and its analogues generally produced dose-related decreases in locomotor activity (Fig. 2,

Discussion

The present study investigated the pharmacology of rimcazole and several of its analogues and compared those actions to those of cocaine and GBR 12909, drugs that have behavioral effects mediated primarily by actions at the dopamine transporter (e.g. Heikkila and Manzino, 1984, Heikkila et al., 1979). Previous studies had shown that rimcazole and its analogues had affinities for the dopamine transporter that were comparable to that of cocaine Izenwasser et al., 1993, Husbands et al., 1999.

Acknowledgments

The authors would like to thank Bettye Campbell, Dawn French and Jianjing Cao for technical support, and Patty Ballerstadt for administrative and clerical support. Collection of some of the locomotor activity data were funded through an intra-agency agreement with the NIDA Division of Treatment Research and Development.

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Behavioral effects of rimcazole analogues alone and in combination with cocaine

Abstract

Introduction

Section snippets

Animals

Locomotor activity

Discussion

Acknowledgments

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropsychopharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacotherapies for treatment of cocaine abuse: preclinical aspects

J. Med. Chem.

The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice

Psychopharmacology

Statistical Methods in Biological Assay

Regulation of [3H]dopamine release from rat striatal slices by sigma receptor ligands

J. Pharmacol. Exp. Ther.

The role of D₂-like dopamine receptors in the locomotor stimulant effects of cocaine in mice

Regulation of [³H]dopamine release from rat striatal slices by sigma receptor ligands