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. ? ? Several dopaminergic (DA) agonists were examined for their effects in behavioral activation (locomotor activity) and yawning in rats and mice. Yawning has been proposed as a behavior due primarily (if not exclusively) by agonist actions at DA D3 receptors, and as such is a useful tool for examining the effectiveness of various dopamine agonists at activating this receptor, or the potency of various dopamine antagonists at blocking this receptor. The DA agonists decreased activation in rats at a low dose, with activity returning to control levels at higher doses. 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. 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 species. The DA agonists similarly were ineffective in producing yawning in DA D2-receptor knockout (KO) mice or their normal controls. The DA agonists tested decreased locomotor activity in normal but not KO mice. Decreases in locomotor activity were not antagonized by the putative selective DA D2 antagonist, L-741,626, however, the similarity of the effects of this drug in normal and KO mice suggests that this drug may not be acting as a selective DA D2 antagonist in mice. 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.? ? Pro-erectile (PE) effects produced by dopamine agonists are thought to be due to actions mediated by the dopamine D4 receptor. We characterized effects of several D2, D3, and D4 receptor agonists with respect to their capacity to induce PE and yawning in the rat, as well as D4 receptor KO mice and their normal controls. All agonists that act primarily at dopamine D3 receptors induced dose-dependent increases in PE and yawning over a similar range of doses. In contrast, drugs acting primarily at D4 receptors were not active in producing significant increases in PE or yawning. Dopamine D2, D3, and D4 antagonists were assessed for their capacity to alter apomorphine- and pramipexole-induced PE and yawning. The D3 antagonist, PG01037, inhibited the induction of PE and yawning, while the 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 was further supported as apomorphine was equipotent at inducing PE in D4-receptor KO mice and their normal controls. Together, these studies provide strong support that D2-like agonist-induced PE and yawning by are differentially mediated by D3 (induction) and D2 (inhibition) dopamine receptors. These studies fail to support a role for the D4 receptor in the regulation of PE or yawning by D2-like agonists.? ? Fluoxetine has been shown to enhance several behavioral effects of cocaine, including its discriminative-stimulus effects. An interaction between increased serotonergic and dopaminergic actions produced by the blockade of serotonin and dopamine reuptake, is one possible mechanism for the enhancement. If the interaction of fluoxetine and cocaine is due to this mechanism, then fluoxetine would also be expected to enhance the behavioral effects of direct-acting dopamine agonists. The present study investigated 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. The dopaminergic agonists cocaine-like subjective effects though they were not as effective as cocaine itself in this regard. The 10 mg/kg dose, but not lower doses, of fluoxetine produced a significant increase in the potency of quinpirole to substitute for cocaine. Fluoxetine did not alter the potency or effectiveness of either (-)-NPA or SKF 82958 in substituting for cocaine. The failure of fluoxetine to consistently alter the cocaine-like discriminative effects of the dopaminergic agonists is consistent with the notion that the mechanism underlying fluoxetines enhancement of cocaines discriminative effects is not simply due to an interaction between enhanced serotonergic and D1-like or D2-like dopaminergic activation. The present study indicates that an enhancement of dopaminergic effects by fluoxetine is not generally obtained with direct-acting dopamine receptor agonists and is consistent with a metabolic interaction between fluoxetine and cocaine.
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