The effects on learned operant behavior of dopamine (DA) agonists acting primarily at DA D1 receptors have not been fully characterized. We compared the effects of DA D1 receptor agonists, SKF 38393, SKF 77434 and SKF 82958. Binding affinities for the agonists at dopamine D1 receptors from rat striatum membranes were determined and compared with effects on behavior. Learned behavior maintained by food reinforcement under conditions in which each 30th response produced food reinforcement was decreased in a dose-related manner by each drug. The order of potency (SKF 82958> SKF 77434> SKF 38393) agreed with rank order of binding affinities suggesting that the behavioral effects were due to actions at the DA D1 receptor. However, antagonism of these behavioral effects by the selective DA D1 receptor antagonist, SCH 23390, was only significant for SKF 82958. SCH 23390 enhanced the effects of the partial D1 agonist, SKF 38393. The DA D2 receptor antagonist, spiperone, was ineffective as an antagonist. The nonselective serotonergic antagonist metergoline produced a significant rightward shift of the SKF 38393 doseresponse function, though not in a dose-related manner. The results support the view that the behavioral effects of D1-like receptor agonists differ in the degree to which they are mediated by DA D1 receptors, and that some effects of SKF 38393 may be mediated by serotonergic mechanisms. ? ? Another study examined the role of DA D3 receptors in the behavioral effects of cocaine. Dopamine 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 activity of the D3 receptor is not necessary for a discriminative effect of cocaine, as the effects were obtained in both lines of mice, though there is an involvement of this receptor in WT mice.
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