MOUSE LOCOMOTOR-ACTIVITY - AN INVIVO TEST FOR DOPAMINE AUTORECEPTOR ACTIVATION

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 229  (3) , 706-711
Abstract
A pharmacologic test is described for assessing selective dopamine (DA) autoreceptor activation using locomotor activity (LMA) of the mouse as the dependent variable. In this test, 3 criteria must be satisfied to indicate selectivity for the DA autoreceptor. A dose-related fall in LMA, taken as a measure of DA autoreceptor activation, should be produced by the putative autoreceptor agonist. To demonstrate that a DA system is involved, the reduction in LMA should be blocked by a DA receptor antagonist. The test compound should produce no LMA-stimulating (i.e., postsynaptic DA receptor agonist) effects over prolonged periods of observation. Using these criteria, 15 DA agonists were evaluated for DA autoreceptor selectivity. Four agents satisfied all criteria as selective DA autoreceptor agonists: CF 25-397 [9,10-didehydro-6-methyl-8.beta.-(2-pyridylthiomethyl)ergoline]. N-n-3-propyl-3-hydroxyphenylpiperidine, 6,7-dihydroxy-2-dimethylaminotetralin (TL-99) and 2-amino-6,7-dibenzoyloxy-1,2,3,4-tetrahydronaphthalene. Seven DA agonists produced U-shaped dose-responses curves indicative of activity at both the autoreceptor and postsynaptic DA receptor. These agents were: apomorphine, n-propylnorapomorphine, pergolide RU24213 [N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine], RU24926 [N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamide hydrochloride], (-)-6-ethyl-9-oxaergoline and lisuride. SKF 38393 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine] failed to exert any significant effect on the LMA of the mouse. Both lergotrile and bromocriptine produced dose-related falls in LMA, but both caused a rebound increase in LMA before their durations of action were terminated. Although 3,4-dihydroxyphenylamino-2-imidazoline did produce a dose-related fall in LMA, the inhibition produced by 3,4-dihydroxyphenylamino-2-imidazoline was not reduced by sulpiride, suggesting a nondopaminergic action for 3,4-dihydroxyphenylamino-2-imidazoline. Potency relative to apomorphine for producing a 30% fall in LMA was computed for each compound. The overall significance of these results in studying the pharmacology of DA receptor agonists is discussed.