Synergistic behavioural effects of dopamine D1 and D2 receptor agonists are determined by circadian rhythms

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The effects of continuous subcutaneous infusions of rats for 336 h with vehicle, SKF 38393 (a dopamine D1 receptor agonist), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a dopamine D2 receptor agonist) or both D1 and D2 receptor agonists, on locomotor activity were investigated. Rats were maintained under constant lighting conditions, either continuous dark (dark:dark) or continuous light (light:light), before and during drug treatments in order to determine the influence of free-running circadian rhythms on drug responses. The D2 receptor agonist initially increased locomotion in rats kept under dark:dark during both subjective night (period of maximum locomotion) and day (period of minimum locomotion), but had no effect in rats maintained in light:light throughout the 336 h of treatment. The motor stimulant effects of the D2 receptor agonist on rats kept in dark:dark increased during the course of treatment during subjective night (sensitization), but decreased during the rats' subjective day (tolerance). The D1 receptor agonist, SKF 38393, had no effect on its own regardless of the lighting conditions and the duration of treatment. However, the D1 receptor agonist interacted synergistically with the D2 receptor agonist in rats maintained under light:light, depending on the duration of treatment. Synergistic effects were also observed on initiation of treatment in rats dark:dark but only during subjective day. Tolerance to the synergistic effects of the receptor agonists occured as a function of treatment duration, but only during subjective day. The D1 receptor agonist blocked the effects of the D2 receptor agonist during the rats' subjective night after 100h of traatment, but not after 25 or 325 h. It is concluded that the motor stimulant effects of a D2 receptor agonist, behavioural D1/D2 dopamine receptor interactions, and the development of sensitization and tolerance to the locomotor effects of a D2 receptor agonist are determined by endogenous free-running circadian rhythms, lighting conditions and duration of treatment.

Original languageEnglish
Pages (from-to)119-125
Number of pages7
JournalEuropean Journal of Pharmacology
Issue number1
Publication statusPublished - 29 Apr 1992
Externally publishedYes


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