The roles of specific dopamine (DA) receptors in the expression of various behavioral effects, including those induced by cocaine, are the subject of these investigations. Particular attention is focused on psychomotor stimulant and subjective interoceptive, and reinforcing effects. We use genetically engineered subjects, along with relatively selective DA receptor agonists and antagonists to assess the roles of specific dopamine receptors in behavior. One study examined the role of DA D3 receptors in the behavioral effects of cocaine. DA D3 receptor knockout (KO) and wild-type (WT) mice were trained to discriminate 10 mg/kg cocaine from saline injections under a fixed-ratio 10 schedule of food reinforcement. After testing with various doses of cocaine, the putative D3 partial agonist, BP897, and antagonists, NGB 2904 and nafadotride, were tested alone and with cocaine. None of the drugs produced cocaine-like responding in either line of mice. BP897 significantly shifted the cocaine curve 3.51 and 1.47-fold to the right in WT and KO mice, respectively. NGB 2904 significantly shifted the cocaine curve 2-fold to the left in WT mice, and had no significant effect on cocaine in KO mice. Nafadotride, and the DA D2 receptor selective antagonist, L741,626, each shifted the cocaine curve to the right comparably in both lines of mice. The data indicate that the role of DA D3 receptors in the subjective effects of cocaine is relatively minor. DA D2-like agonists induce penile erection (PE) and yawning in a variety of species, effects that recently were suggested to be specifically mediated by DA D4 and D3 receptors, respectively. We conducted studies aimed at characterizing the contributions of these receptors to the effects of several DA D2, D3, and D4 agonists. All of the agonists having effects at DA D3R induced dose-dependent increases in PE and yawning over a similar range of doses, while significant increases in PE or yawning were not observed with any of the selective D4 agonists. Likewise, D2, D3, and D4 antagonists were assessed for their capacity to alter apomorphine- and pramipexole-induced PE and yawning. The selective D3 antagonist, PG01037, inhibited the induction of PE and yawning, while the selective D2 antagonist, L-741,626, reversed the inhibition of PE and yawning observed at higher doses. The D4 antagonist, L-745,870, did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D3 receptor in PE was further supported as apomorphine was equipotent at inducing PE in D4R WT and KO mice, effects that were inhibited by the D3 antagonist, PG01037, in both D4R wild-type and knock-out mice. Together, these studies indicate that D2-like agonist-induced PE and yawning are induced by D3 DA receptors, and fail to support a role for the D4 receptor in the regulation of either effect. Several dopaminergic (DA) agonists were examined for their effects in behavioral activation (locomotor activity) and yawning in rats and mice. Previous studies (see above) indicate that yawning is induced by agonist actions at DA D3 receptors. As such, yawning is a useful tool for examining the effectiveness of various DA agonists at activating this receptor, or the potency of various DA antagonists at blocking this receptor. In mice, the DA agonists decreased locomotor activity across a 1,000- to 10,000-fold range of doses, with the decreases normally followed by increases in activity at the highest doses. However, and in contrast to effects obtained with rats, none of the agonists produced yawning in mice. Though yawning was not produced in the mice by the dopaminergic agonists, it was reliably elicited by administration of the cholinergic agonist, physostigmine, in both rats and mice. The DA agonists similarly were ineffective in producing yawning in DA D2R KO mice or their WT controls. The DA agonists tested decreased locomotor activity in normal but not KO mice. Decreases in locomotor activity were not antagonized by the selective DA D2R antagonist, L-741,626. Together the findings suggest profound differences in the pharmacology DA agonists in mice and rats. Yawning provides a reasonably selective in vivo indicator of DA D3-receptor agonist activity in rats, but not in mice. Although adenylyl cyclase (AC) formation and phosphoinositide (PI) hydrolysis have been identified as second-messenger effects associated with DA D1-like receptor stimulation, the behavioral effects of agonist drugs at DA D1-like receptors are not easily related to the drugs effects on AC or PI. We compared the behavioral effects of a number of D1-like receptor agonists that have different efficacies in terms of second messenger effects, and have different affinities for the D1-like receptor. In the first experiment, the rank order for stimulation of locomotor activity was: SKF 82958>SKF 77434>A-77636>dihydrexidine>SKF 83959>SKF 75670>SKF 81297>(+)SKF 38393>A-68930>(-)SKF 38393>SKF 80723>fenoldopam. The efficacies of the drugs did not significantly correlate with their efficacies in stimulation of AC or PI. For example, the AC partial agonists SKF 77434 and SKF 75670 were behaviorally more effective than the full agonists SKF 81297 and A-68930. In rats trained to discriminate the full agonist SKF 82958 (0.03 mg/kg) from saline, complete substitution was produced by the full agonist SKF 81297, and the partial agonists (+)SKF 38393 and SKF 77434. The full agonists, A-68930, and A-77636, only partially substituted for SKF 82958. Hence the partial agonists (+)SKF 38393 and SKF 77434 substituted more completely for SKF 82958 than did the full efficacy agonists A-68930 and A-77636. SKF 83959, a potent in vitro antagonist of AC-coupled D1-like receptors, increased locomotor activity dose-dependently and substituted for SKF 82958 to a greater extent than did many of the other agonists, whether full or partial. Together, these findings support the view that factors other than AC or PI intrinsic efficacies contribute substantially to the behavioral effects of putative D1-like agonists. Fluoxetine has been shown to enhance several behavioral effects of cocaine, including its subjective, discriminative-stimulus, effects. A pharmacodynamic interaction between increased serotonergic and dopaminergic actions produced by the blockade of serotonin and DA reuptake, is one possible mechanism for the enhancement. Alternatively, fluoxetine may interact with cocaine metabolically, attenuating its metabolism. If the interaction is pharmacodynamic, fluoxetine would also be expected to enhance the cocaine-like behavioral effects of direct-acting DA agonists. The effects of fluoxetine on the cocaine-like subjective effects of the D2-like agonists quinpirole and (-)-NPA, and the D1-like agonist SKF 82958 were investigated. Fluoxetine produced a modest increase in the potency of quinpirole, but did not alter the potency orr efficacy of (-)-NPA or SKF 82958. The failure of fluoxetine to consistently alter the cocaine-like discriminative effects of the dopaminergic agonists is consistent with the notion that the interaction is pharmacokinetic rather than pharmacodynamic.
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