Antagonism of the discriminative stimulus effects of (+)-7-OH-DPAT by remoxipride but not PNU-99194A

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Abstract

The dopamine (DA) agonist 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin (7-OH-DPAT) has been used extensively as a tool to investigate the role of DA D3 receptors in the reinforcing and discriminative stimulus properties of psychostimulant drugs. The present study examined the relative importance of D3 vs. D2 receptor actions in the discriminative stimulus effects of (+)-7-OH-DPAT (0.03 mg/kg, sc) in 16 male Sprague–Dawley rats trained to discriminate this compound from saline in a two-lever, water-reinforced operant procedure under a FR 20 schedule. Stimulus generalization and antagonism tests were conducted with cocaine and with various selective D2 and D3 receptor ligands. In contrast to previous findings that (+)-7-OH-DPAT substitutes for cocaine, the present results demonstrated that cocaine does not produce stimulus generalization in animals trained to discriminate (+)-7-OH-DPAT. Although two D3-preferring agonists, PD-128907 and pramipexole, produced complete stimulus generalization to the training drug, two highly selective D3 antagonists (PNU-99194A, PD 152255) failed to block the discriminative stimulus effects of (+)-7-OH-DPAT. However, the D2 antagonist remoxipride (3.0 mg/kg) produced a rightward shift in the (+)-7-OH-DPAT dose–response curve. These findings suggest that D2 receptors are critically involved in mediating the cue properties of (+)-7-OH-DPAT. However, alternative interpretations that PNU-99194A is not entirely D3 receptor selective should also be considered.

Introduction

Recent investigations of the behavioral pharmacology of addictive psychostimulant drugs have focused on the dopamine (DA) D3 receptor Bevins et al., 1997, Caine and Koob, 1995, Lamas et al., 1996, Spealman, 1996, a subtype of the D2 family of DA receptors Civelli et al., 1991, Sibley and Monsma, 1992. This receptor subtype is localized in limbic brain regions (Levesque et al., 1992), areas well known to be involved in the reinforcing and discriminative stimulus properties of psychostimulants. Increased understanding of the role of D3 receptors in mediating the behavioral effects of psychostimulant drugs may benefit the development of pharmacological treatment interventions for stimulant abuse, as well as the treatment of central nervous system (CNS) diseases involving the DA system.

Because of their reported selectivity for the DA D3 receptor, compounds such as 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin (7-OH-DPAT) and PD-128907 have been used to characterize the function of this receptor subtype Damsma et al., 1993, Levesque et al., 1992, Pugsley et al., 1995. These compounds have been reported to have as much as a 100-fold greater affinity for D3 over D2 receptors based on in vitro binding assays Burris et al., 1995, Levesque et al., 1992, Pugsley et al., 1995. However, many of these assays utilized a D2 receptor antagonist rather than a D2 agonist as the competitive ligand. Moreover, functional assays such as mitogenesis in Chinese hamster ovary cells indicate that the D3 selectivity of these compounds is approximately five- to sevenfold (Sautel et al., 1995). The D3 selectivity regarding the behavioral effects of these compounds remains speculative.

Several investigations have reported either complete or partial generalization to 7-OH-DPAT and (+)-PD-128907 in animals trained to discriminate cocaine Acri et al., 1995, Lamas et al., 1996, Spealman, 1996 or d-amphetamine Baker et al., 1998, Bevins et al., 1997. Based on these findings, some investigators have concluded that D3 receptors may play an important role in the discriminative stimulus effects of cocaine and d-amphetamine. However, recent studies have demonstrated that the D3-preferring antagonist, PNU-99194A fails to block the discriminative stimulus effects of these psychostimulants (Baker et al., 1997) or the stimulus generalization produced by 7-OH-DPAT in rats trained to discriminate d-amphetamine or cocaine Baker et al., 1998, Garner and Baker, 1999. Preliminary investigations demonstrated that PNU-99194A only partially blocked the training dose of (+)-7-OH-DPAT, while greater antagonism was observed with the D2 antagonist remoxipride (Baker et al., 1999). These results question the importance of D3 receptors in the discriminative stimulus effects of (+)-7-OH-DPAT.

The present study further examined the antagonism of (+)-7-OH-DPAT with remoxipride, PNU-99194A and another D3 antagonist, PD 152255, by testing their effects on the full dose–response function of (+)-7-OH-DPAT. Additionally, stimulus generalization was assessed with other putative D3 agonists, (+)-PD-128907 and pramipexole, as well as with cocaine. Finally, PNU-99194A was also tested for stimulus generalization to (+)-7-OH-DPAT.

Section snippets

Subjects

Sixteen male Sprague–Dawley rats (Harlan Breeding Laboratories, Indianapolis, IN) aged 50–60 days and weighing 250–300 g at the beginning of the study served as subjects. The animals had no previous operant training and were drug naive at the beginning of the present study. Animals were individually housed in plastic cages, in a colony maintained on a 12 h light/12 h dark cycle (lights on 07:00–19:00 hours) and at a relatively constant temperature (19–23°C) and humidity (50–60%). Commercial rat

Results

(+)-7-OH-DPAT readily produced discriminative stimulus control in all 16 subjects. The mean number of sessions to criterion was 34±11.75 (Range=22–63; Median=28). Results of stimulus generalization tests with (+)-7-OH-DPAT, (+)-PD-128907, pramipexole and cocaine are displayed in Fig. 1. (+)-7-OH-DPAT produced a dose-dependent increase in drug-appropriate responding with complete stimulus generalization at 0.03 and 0.10 mg/kg (ED50=0.01 mg/kg; 95% confidence intervals: 0.008–0.012 mg/kg). The

Discussion

The results of the present study support previous findings that discriminative stimulus control is readily established in rats by 7-OH-DPAT Depoortere et al., 2000, McElroy, 1994, Sanger and Depoortere, 1997, Varty and Higgins, 1997 or its (+)-isomer (Baker et al., 1999). Previous studies have indicated a potential modulatory role of the D3 receptor subtype in the stimulus effects of 7-OH-DPAT Bevins et al., 1997, Sanger and Depoortere, 1997, Varty and Higgins, 1997. Specifically, the potencies

Acknowledgements

The authors wish to acknowledge Dr. Kjell Svensson and Dr. Susan Haadsma-Svensson of Pharmacia for providing many of the compounds for this study and Dr. Kjell Svensson for his editorial comments on the manuscript. The authors also acknowledge Kristen Beuving for technical assistance with the experiments. This research was supported by the National Institute on Drug Abuse (1RO3DA11291-1).

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