Rotational behavior induced by 8-hydroxy-DPAT, a putative 5HT-1A agonist, in 6-hydroxydopamine-lesioned rats.
Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (5HT) agonist drugs. The 5HT-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3-3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative 5HT-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal 5HT levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending 5HT-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems.(ABSTRACT TRUNCATED AT 250 WORDS)
Gerber
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Research Department, CIBA-GEIGY Corporation, Summit, NJ 07901.
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Liebman
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D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012399:Rotation; D012701:Serotonin / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects*; D013563:Sympathectomy, Chemical; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D006892:Hydroxydopamines; D009281:Naphthalenes; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine; D004298:Dopamine