Effects of Dopamine D1-like and D2-like Agonists in Rats that Self-Administer Cocaine

The reinforcing effects of D1-like and D2-like agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01–1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D1-like agonists SKF 82958 (0.001– 0.032 mg i.v.) and SKF 77434 (0.001–0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D2-like agonists quinelorane (0.001–0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01–0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped doseeffect functions. Pretreatment with the D1-like agonists SKF 82958 and SKF 77434 (0.1–1.0 mg/kg i.p.) shifted the doseeffect function for cocaine self-administration downward, whereas pretreatment with the D2-like agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32–1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D1-like and D2-like agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D1-like agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D2-like agonists increased the intervals between self-administered cocaine injections. The results suggest that D2-like agonists, but not D1-like agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D2 receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine. Drug self-administration procedures have been useful for investigating the neurobiological and pharmacological mechanisms underlying the reinforcing effects of cocaine, and such information may lead to the development of new and effective medications for cocaine abuse and dependence (Mello and Negus, 1996; Mendelson and Mello, 1996). Cocaine nonselectively blocks the reuptake of the monoamine neurotransmitters dopamine, norepinephrine, and serotonin (Taylor and Ho, 1978); however, the reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist (Wise and Bozarth 1987; Koob, 1992). In this regard, the potency with which many monoamine reuptake inhibitors serve as i.v. reinforcers is highly correlated with their binding to the dopamine transporter (Ritz et al., 1987; Bergman et al., 1989). Moreover, in contrast to selective dopamine reuptake inhibitors, selective norepinephrine and serotonin reuptake inhibitors have not been shown to produce reinforcing effects in drug self-administration procedures. Studies with direct dopamine receptor agonists offer another pharmacological method for elucidating the neurobiological mechanisms underlying the abuse-related effects of cocaine. In contrast to cocaine or other dopamine reuptake inhibitors, which increase the activation of dopamine receptors nonselectively, direct dopamine agonists can be used to selectively activate D1-like (D1, D5) or D2-like (D2, D3, D4) receptors which, in turn, have different anatomical and functional characteristics. For example, D1-like agonists modulate the expression of dynorphin and Substance P within striatonigral neurons, whereas D2-like agonists regulate enkephalin expression within striatopallidal neurons (Gerfen et al., 1990). In addition, D1 receptors are positively coupled with adenylyl cyclase through stimulatory G-proteins, whereas D2 receptors are negatively coupled to adenylyl cyclase through inhibitory G-proteins (Schwartz et al., 1992). Moreover, adaptations in these different systems occur in response to chronic cocaine administration (Terwilliger et al., 1991; Nestler and Aghajanian, 1997). Thus, studies with selective Received for publication January 29, 1999. 1 This research was supported in part by Grants T32-DA07252, P50DA04059, and K05-DA00101 from the National Institute on Drug Abuse, National Institutes of Health. Preliminary data were presented to the College on Problems of Drug Dependence in 1998 and to the Society for Neuroscience in 1997. ABBREVIATIONS: 7-OH-DPAT, 7-hydroxy-dipropylaminotetralin; FR, fixed ratio; A50, dose calculated to produce 50% of the measured effect; TO, timeout. 0022-3565/99/2911-0353$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 291, No. 1 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 291:353–360, 1999 353 at A PE T Jornals on July 0, 2017 jpet.asjournals.org D ow nladed from D1-ike and D2-like agonists may provide one way to clarify the roles of distinct neural pathways and molecular mechanisms involved in cocaine addiction. Although it is generally believed that both D1-like and D2-like receptor mechanisms may be involved in the reinforcing and other behavioral effects of cocaine, recent studies suggest that D1-like and D2-like agonists have differing profiles of cocaine-related actions. On the one hand, both D1-like and D2-like agonists have been reported to maintain i.v. self-administration in animals previously trained to self-administer cocaine (Woolverton et al., 1984; Self and Stein, 1992; Caine and Koob, 1993, 1995; Weed and Woolverton, 1995; Nader and Mach, 1996), and this is consistent with findings that both D1-like and D2-like receptor blockers seem to antagonize cocaine self-administration behavior (Bergman et al., 1990; Caine and Koob, 1994). On the other hand, D1-like agonists may not maintain responding as robustly or under as wide a range of conditions as was reported for cocaine and D2-like agonists (Grech et al., 1996). In addition, in both rats and monkeys, D1-like agonists may attenuate the ability of cocaine to reinstate responding after extinction of cocaine self-administration whereas D2-like agonists appear to enhance this effect of cocaine (Self et al., 1996; Barrett-Larimore and Spealman, 1997). These latter results agree with previous findings that D2-like agonists produced leftward shifts in the dose-effect function for cocaine self-administration (Caine and Koob, 1995; Caine et al., 1997). The effects of D1-like agonists on cocaine self-administration are unknown, but, based on results from the studies described above, D1-like agonists may differ qualitatively from D2-like agonists in the manner by which they modify the abuse-related effects of cocaine. The present study was designed to further evaluate differing roles of D1-like and D2-like receptors in mediating the abuse-related effects of cocaine by systematically comparing the effects of D1-like and D2-like agonists in rats trained to self-administer cocaine. First, D1-like or D2-like agonists were substituted for cocaine in rats with extensive cocaine selfadministration experience to rigorously evaluate and compare the reinforcing effects of these agents. Second, modification of the reinforcing effects of cocaine by D1-like and D2-like agonists was studied by assessing the effects of pretreatments on full dose-effect functions for cocaine self-administration. In general, the results of this study suggest that D2-like agonists, but not D1-like agonists, maintain selfadministration and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration training. These results are consistent with those from parallel studies in which the cocaine-discriminative stimulus generalized to D2-like agonists, but not D1-like agonists, in rats with extensive cocaine discrimination training (Caine et al., unpublished observations). Materials and Methods