The roles of specific dopamine (DA) receptors in the behavioral effects of cocaine, including its psychomotor stimulant and subjective interoceptive, and reinforcing effects have been investigated. Using DA receptor knockout mice along with relatively selective DA antagonists we assessed the roles of dopamine receptors in various behavioral effects of cocaine.? The effects on learned operant behavior of agonist actions at dopamine D1-like receptors have not been fully characterized. We compared three D1-like receptor agonists (SKF 38393, SKF 77434 and SKF 82958), both alone and in combination with the D1-like receptor antagonist, SCH 23390. Lever pressing was maintained by food reinforcement under a fixed-ratio 30-response schedule (each thirtieth response produced reinforcement), and the effects of the three agonists were assessed by cumulative dosing. Each drug produced dose-related reductions in response rates, in order of potency: SKF 82958 > SKF 77434 > SKF 38393. Antagonism of these behavioral effects by SCH 23390 was only significant for SKF 82958; surprisingly, SCH 23390 enhanced the effects of SKF 38393. For SKF 82958, the antagonism was receptor subtype-specific, since the D2-like receptor antagonist spiperone was ineffective. The non-selective serotonergic antagonist metergoline produced a significant rightward shift of the SKF 38393 dose-response function, indicating effective antagonism, although the degree of antagonism was not dose-related. These results support the view that the behavioral effects of D1-like receptor agonists differ in their susceptibility to antagonism by D1-like receptor antagonists, and that some effects of SKF 38393 are mediated by serotonergic activity rather than by activity at D1-like receptors.
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