Behavioral effects of rimcazole analogues alone and in combination with cocaine
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 (Ki=224 nM) as compared to the σ receptor (Ki=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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