Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434
Introduction
A great deal of work implicates mesolimbic dopamine transmission in reward-related learning (for review, see Willner and Scheel-Krüger, 1991), but less is known about how different dopamine receptor subtypes mediate this learning. Prior to identification of the five currently recognized dopamine receptor subtypes (D1–5), dopamine receptors were divided into two groups based on their effect on the enzyme adenylate cyclase. Activation of dopamine D1 receptors was shown to result in stimulation of adenylate cyclase, whereas dopamine D2 receptor activation either inhibited or failed to affect this enzyme (Kebabian and Calne, 1979). Dopamine D1 and D5 receptors have been found to be D1-like but at present pharmacological agents acting selectively at either subtype are not available. Dopamine D2, D3 and D4 receptors are D2-like (Seeman and Van Tol, 1994).
The place conditioning paradigm has been used extensively to ascertain the role of dopamine D1- and D2-like receptors in reward-related learning (see Beninger, 1993; Beninger and Miller, 1997for reviews). Generally, results have supported a role for dopamine D2-like receptors in reward, but corresponding data for dopamine D1-like receptor involvement have been equivocal. Antagonism of either dopamine D1- or D2-like receptors abolished the rewarding properties of dopaminergic drugs in rats, suggesting that both families of dopamine receptors may be involved in reward-related learning (Spyraki et al., 1982; Mackey and van der Kooy, 1985; Mithani et al., 1986; Hoffman and Beninger, 1989; Hiroi and White, 1991). In agreement with these results, dopamine D2-like receptor agonists produced a place preference (Morency and Beninger, 1986; Hoffman et al., 1988; Hoffman and Beninger, 1988, Hoffman and Beninger, 1989; White et al., 1991). However, results with the dopamine D1-like receptor agonist SKF 38393 were not straightforward. When injected into the nucleus accumbens, SKF 38393 produced a place preference (White et al., 1991), yet systemic administration produced an aversion (Hoffman and Beninger, 1988, Hoffman and Beninger, 1989; White et al., 1991). Perhaps the aversion was the result of pharmacological properties specific to SKF 38393.
The possibility that pharmacological characteristics unique to SKF 38393 may be responsible for behavioral findings in place conditioning is supported by results from self-administration studies. In agreement with place conditioning results, pretreatment with either dopamine D1- or D2-like receptor antagonists disrupted self-administration of cocaine or amphetamine in rodents and primates, supporting the idea that both dopamine receptor families may be involved in reward (Yokel and Wise, 1975, Yokel and Wise, 1976; Risner and Jones, 1976; De Wit and Wise, 1977; Roberts and Vickers, 1984, Roberts and Vickers, 1987; Koob et al., 1987; Bergman et al., 1990; Corrigall and Coen, 1991; Caine and Koob, 1994). Also similar to place preference studies, dopamine D2-like receptor agonists were self-administered (Woolverton et al., 1984; Wise et al., 1990) and the dopamine D1-like receptor agonist SKF 38393 was not (Woolverton et al., 1984; Weed and Woolverton, 1995). However, other dopamine D1-like receptor agonists from the same chemical family (benzazepines) recently have been shown to support self-administration: SKF 82958 in rats and squirrel monkeys, SKF 81297 in rhesus and squirrel monkeys, and SKF 77434 in rats but not squirrel monkeys (Self and Stein, 1992; Self et al., 1993, Self et al., 1996; Weed et al., 1993; Grech et al., 1996). When all four benzazepine-based compounds were compared in a single study of rhesus monkeys, only SKF 82958 and SKF 81297 were self-administered; responding for SKF 38393 and SKF 77434 was not different from responding for vehicle (Weed and Woolverton, 1995).
Differences in pharmacological properties of the dopamine D1-like receptor agonists may help to make sense of these results. Thus, SKF 82958 has been shown to be a full dopamine receptor agonist in both the rat and squirrel monkey, with observations of adenylate cyclase activation ranging from 78–148% of dopamine (O'Boyle et al., 1989; Izenwasser and Katz, 1993). SKF 81297 has also been reported to be a high efficacy dopamine receptor agonist in the rat, with corresponding values of 68–88% (Anderson and Jansen, 1990; Arnt et al., 1992; Izenwasser and Katz, 1993). In contrast, SKF 77434 and SKF 38393 are generally considered to be low efficacy agents, with adenylate cyclase responses of about 48–55% and 44–59% of dopamine, respectively (Anderson et al., 1985; O'Boyle et al., 1989; Izenwasser and Katz, 1993). It has been suggested elsewhere that our understanding of the functional role of dopamine D1-like receptors has been obscured by the use of SKF 38393 (Self and Stein, 1992).
Thus, despite negative results with SKF 38393, recent results from self-administration studies suggest that activation of the dopamine D1-like receptor indeed may be important to reward. It is hypothesized here that administration of high efficacy dopamine D1-like receptor agonists, previously shown to be self-administered, will result in a place preference. Three dopamine D1-like receptor agonists (SKF 82958, SKF 81297, and SKF 77434) were administered systemically at a range of doses to test this hypothesis; amphetamine (2.0 mg/kg, i.p.) and distilled water (i.p.) were also tested as paradigm controls.
Section snippets
Subjects
Two-hundred and nine male Wistar rats (Charles River, Canada), weighing between 200 and 250 g upon arrival at the colony had free access to both food and water in their home cages, and were group housed (four per cage) in a temperature controlled (21°C) facility with a 12 h light/dark cycle (lights on at 08.00 h). Care and treatment of the animals was in full compliance with guidelines set forth by the Canadian Council on Animal Care, the Animals for Research Act, and relevant Queen's
Results
Dependent variables included time spent on the drug-paired side and time spent in the tunnel on three pre-conditioning and one test days, and activity during eight conditioning sessions. Time and activity data will be treated separately.
Discussion
This study is the first to report that a place preference is produced by systemic administration of a dopamine D1-like receptor agonist. The reliability of this result was confirmed in two separate experiments using two different routes of administrations (s.c. and i.p.). In contrast, the dopamine D1-like receptor agonists SKF 81297 and SKF 77434 failed to produce place conditioning over a wide range of doses. Note also that all agents tested (excluding distilled water alone) stimulated locomotor
Acknowledgements
Amphetamine was the generous gift of SmithKline Beecham Pharma Inc. of Canada. Funded by a grant to R.J.B. from the Natural Sciences and Engineering Research Council of Canada.
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