Sensitization to the Rewarding Effects of the Specific Dopamine Uptake Inhibitor GBR12783 GWENAELLE LE PEN, DOMINIQUE DUTERTE-BOUCHER and JEAN COSTENTIN

The conditioned place preference (CPP) induced by increasing doses (1.25–40 mg/kg) of cocaine or the specific dopamine uptake inhibitor GBR12783 was investigated in rats previously treated with cocaine (10 or 20 mg/kg), GBR12783 (10 mg/kg) or morphine (10 mg/kg) for 15 days. In solvent-pretreated rats, cocaineand GBR12783-induced CPPs were biphasic, with the highest scores observed at 20 mg/kg. Prior exposure to GBR12783 sensitized the rats to the rewarding effects of low doses of either GBR12783 or cocaine. Pretreatment with cocaine 20 mg/kg, but not 10 mg/kg, sensitized the rats to its own rewarding effects. Furthermore, it was less efficient than GBR12783 in sensitizing the animals to the rewarding effects of both drugs. These data confirm the major role of dopamine uptake inhibition in the sensitization process. On the other hand, the magnitude of CPP induced by a high dose of both drugs (20 mg/kg) was decreased after pretreatment with either GBR12783 or cocaine, reaching the lower scores observed at 40 mg/kg. This decrease was unrelated to altered anxiety level but was associated with sensitization to stereotypies. Morphine pretreatment modified neither the CPP induced by high doses of cocaine or GBR12783 nor cocaineor GBR12783-induced stereotypies. However, prior exposure to morphine sensitized the rats to the rewarding effects of cocaine (2.5 mg/kg) but not to those of GBR12783, suggesting that other mechanisms working in concert with dopamine may facilitate the rewarding effect of cocaine without affecting that of GBR12783. Drugs of abuse such as cocaine, morphine and amphetamine share several behavioral and rewarding properties (Kalivas and Stewart, 1991; Koob, 1992; Robinson and Berridge, 1993). Repeated exposures to these drugs produce a locomotor sensitization that results in a potentiated response to a challenge dose of the drug (Post and Rose, 1976; Robinson and Becker, 1986; Kalivas and Duffy, 1987; Kalivas and Stewart, 1991). Cross-sensitization between the locomotoractivating effects of cocaine, morphine or amphetamine has also been reported (Vezina and Stewart, 1990; Kalivas and Stewart, 1991; Cunningham et al., 1997). Until recently, sensitization and cross-sensitization to the rewarding effects of these drugs have received less attention. This issue deserves further investigation in view of the postulated role of the sensitization process in the development of addiction (Robinson and Berridge, 1993). Few results have yet been reported. The acquisition of cocaine or amphetamine self-administration is facilitated after pre-exposure to these drugs (Horger et al., 1990; Piazza et al., 1990). Furthermore, amphetamine has been reported to sensitize rats to the rewarding effects of cocaine (Horger et al., 1992). Morphine potentiates the action of amphetamine on brain stimulation reward (Bespalov and Zvartau, 1995) or on the conditioned reinforcement paradigm (Cunningham and Kelley, 1992). Repeated exposure to amphetamine, morphine or cocaine was found to enhance the drug-induced rewarding effects as measured by CPP. Cross-sensitization between morphine and amphetamine was obtained, and an increased sensitivity to cocaine was also observed after chronic treatment with morphine or amphetamine (Lett, 1989; Shippenberg and Heidbreder, 1995; Shippenberg et al., 1996). In this last procedure, the drug is paired with distinctive environmental stimuli, and a preference for this drug-paired environment in a drug-free state is considered to be a measure of reward