RELATIVE SELECTIVITY OF 6,7-DIHYDROXY-2-DIMETHYLAMINOTETRALIN, N-NORMAL-PROPYL-3-(3-HYDROXYPHENYL)PIPERIDINE, N-NORMAL-PROPYLNORAPOMORPHINE AND PERGOLIDE AS AGONISTS AT STRIATAL DOPAMINE AUTORECEPTORS AND POSTSYNAPTIC DOPAMINE-RECEPTORS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (2) , 519-525
Abstract
6,7-Dihydroxy-2-dimethylaminotetralin (TL-99), N-N-propyl-3(3-hydroxyphenyl)piperidine [(.+-.)-3PPP], N-n-propylnorapomorphine and pergolide were evaluated for activity on a number of biochemical parameters that are presumed to indicate an agonist effect at dopamine (DA) autoreceptors (antagonism of the .gamma.-hydroxybutyrate-induced increase in dopa formation), at postsynaptic DA receptors (elevatin of acetylcholine levels) or at both types of DA receptors (diminution of DA synthesis and homovanillic acid levels) in rat striatum. All 4 agents decreased striatal dopa accumulation (in the presence and in the absence of .gamma.-hydroxybutyrate). N-propylnorapomorphine, pergolide and TL-99 also reduced homovanillic acid levels and increased acetylcholine concentrations in striatum whereas (.+-.)-3-PPP was inactive. The compounds were all more potent in diminishing dopa accumulation caused by .gamma.-hydroxybutyrate treatment than in increaisng acetylcholine levels [.+-.)-3-PPP showing the highest dissociation] indicating a preferential agonist acitivity at DA autoreceptors. The relative selectivity of the compounds for DA autoreceptors and postsynaptic DA receptors was evaluated further by studying the antagonism by these drug of the activation of striatal dopa formation (index of both DA autocreceptor and postsynaptic DA receptor stimulation) and tyrosine hydroxylase (index of postsynaptic DA receptor stimulation only) induced by haloperidol or reserpine. The DA agonists were all more potent in antagonizing the neuroleptic-induced increase in DA synthesis than in counteracting the drug-induced activation of tyrosine hydroxylase, with (.+-.)-3-PPP exhibiting the highest dissociation. The DA agonists studied posses some selectivity for striatal DA autoreceptors, (.+-.)3-PPP being the most selective in this respect.