Comparison of the reinforcing efficacy of two dopamine D2-like receptor agonists in rhesus monkeys using a progressive-ratio schedule of reinforcement

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Abstract

High-efficacy D2-like dopamine (DA) receptor agonists can function as positive reinforcers when made available to animals for intravenous self-administration under a fixed-ratio (FR) schedule of reinforcement. In a previous study, however, low-efficacy D2-like agonists failed to maintain self-administration under an FR schedule, suggesting that agonist efficacy is directly related to efficacy as a positive reinforcer. To examine this hypothesis further, the present study compared two D2-like DA receptor agonists that maintained FR responding, but differ in their D2-like receptor efficacy and selectivity, using a procedure designed to rank-order drugs according to their efficacy as reinforcers. Rhesus monkeys (n=5) were prepared with chronic, indwelling intravenous catheters and allowed to self-administer cocaine (0.1 mg/kg/injection) or saline on different days under a progressive-ratio (PR) schedule. When responding was stable, doses of the full D2-like agonist R(−)-propylnorapomorphine (NPA) or the partial D2-like agonist R(−)-apomorphine (APO) were made available for self-administration in the test sessions. Both compounds maintained self-administration with sigmoidal or biphasic dose–response functions. Surprisingly, the lower efficacy agonist APO was the more efficacious positive reinforcer. This result fails to support the hypothesis that D2-like receptor efficacy is directly related to efficacy as a reinforcer. It is possible that other pharmacological effects, e.g., D1 receptor activity, influenced self-administration.

Introduction

The conclusion that increased dopamine (DA) neurotransmission is involved in the reinforcing effects of psychomotor stimulants is well supported experimentally Koob, 1992, Wise, 1996, Woolverton and Johnson, 1992. Further, research has implicated both D1- and D2-like DA receptors in this effect. Both D1- and D2-like agonists function as positive reinforcers in rats Self and Stein, 1982, Yokel and Wise, 1978 and monkeys Grech et al., 1996, Weed and Woolverton, 1995, Woolverton et al., 1984. Moreover, pretreatment with D1- or D2-like antagonists may reduce the reinforcing effect of stimulants in animal subjects Corrigall and Coen, 1991, Koob et al., 1987, Wilson and Schuster, 1972, Woolverton, 1986, Yokel and Wise, 1975.

Research with both D1- and D2-like agonists has suggested that efficacy as a positive reinforcer may be directly related to agonist efficacy at DA receptors. Low-efficacy D1-like agonists failed to maintain self-administration by monkeys when substituted for a baseline drug Grech et al., 1996, Weed and Woolverton, 1995, Woolverton et al., 1984 while high-efficacy D1-like agonists maintained self-administration under these conditions and can be used to establish self-administration in naı̈ve monkeys (Weed and Woolverton, 1995). When a series of D1-like agonists that were reinforcers under a fixed-ratio (FR) schedule were compared under a progressive-ratio (PR) schedule of reinforcement designed to rank-order efficacy as reinforcers, differences between higher efficacy agonists were not obvious (Weed et al., 1997). Thus, although D1-like efficacy appeared to be related to efficacy as a reinforcer, the relationship may be based upon a “threshold” of efficacy necessary to function as a reinforcer, rather than on a continuum (Ruffolo, 1982).

Previous research with D2 agonists supports the conclusion that D2-like agonists are similar to D1-like agonists in this regard Pulvirenti et al., 1998, Ranaldi et al., 2001. That is, higher efficacy D2-like agonists [R(−)-propylnorapomorphine (NPA); R(−)-apomorphine (APO); R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine] maintained self-administration while lower efficacy agonists [R(+)-terguride; S(−)-3-(3-hydroxyphenyl)-N-propylpiperidine] did not. The present study was designed to extend those findings by using a PR schedule to compare two agonists, NPA and APO, that functioned as reinforcers under an FR schedule but that differ in their agonist efficacies at D2-like receptors. NPA has been reported to be a full D2-like agonist Arnt and Hyttel, 1990, Lahti et al., 1992, Nilsson and Eriksson, 1992, while APO has generally been reported to be a moderate efficacy agonist, with efficacy measures reported somewhere between 50% and 80% of DA Lahti et al., 1992, O'Boyle and Lawler, 1996. In addition, NPA appears to be more selective than APO for the D2 receptor Creese et al., 1979, Euvrard et al., 1979, Herrera-Marschitz and Ungerstedt, 1984. Our hypothesis was that the higher efficacy, more selective D2-like agonist, NPA, would be a more effective reinforcer than the lower efficacy D2-like agonist APO.

Section snippets

Methods

All procedures were in compliance with the NIH Guide for the Care and Use of Laboratory Animals.

Results

All monkeys self-administered cocaine (0.05 or 0.1 mg/kg/injection) under baseline conditions. The baseline rates of cocaine self-administration for these monkeys ranged from 12 (L500) to 15 (RIK2) injections per session. The baseline rates of saline self-administration for these monkeys ranged from one to three injections per session for all monkeys. Baseline rates remained stable for an individual monkey over the course of the experiment.

When the PR sequence began at 50, all monkeys

Discussion

Both NPA and APO maintained self-administration under a PR schedule in rhesus monkeys. This finding extends the conditions under which D2-like agonists have been found to function as positive reinforcers. Although NPA was a more potent reinforcer than APO in most monkeys, mean values were not statistically different. In a previous self-administration study with D2-like agonists, we found that both APO and NPA were self-administered under an FR schedule of reinforcement and that NPA was more

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