Inhibition of dopamine synthesis in rat striatal minces: evidence of dopamine autoreceptor supersensitivity to S(+)- but not R(-)-N-n-propylnorapomorphine after pretreatment with fluphenazine.
This study provides in vitro evidence that rats pretreated with fluphenazine for 10 days, but not acutely, developed moderate but significant striatal autoreceptor supersensitivity as measured by the ability of S(+)-NPA, a selective DA autoreceptor agonist and very weak postsynaptic agonist, to inhibit tyrosine hydroxylase activity. In contrast, autoreceptor supersensitivity was not found with the nonselective auto- and postsynaptic receptor agonist R(-)-NPA. Presumably, this effect represents some modification of a presynaptic regulatory mechanism controlling DA synthesis which can occur despite a reportedly high striatal DA autoreceptor reserve in rat striatum [2, 7]. Such a mechanism, by tending to reduce synaptic availability of DA, may contribute to tolerance to the transient, early DA-synthesis stimulating actions of acutely administered neuroleptics [4], and help to counterbalance increases in postsynaptic DA receptor abundance and sensitivity associated with long-term neuroleptic treatment.
Department of Psychiatry, Harvard Medical School, Boston, MA.
R G
RG
Booth
R J
RJ
Baldessarini
A
A
Campbell
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005476:Fluphenazine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism / Q000502:physiology; D013237:Stereoisomerism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors
D015259:Dopamine Agents; D011954:Receptors, Dopamine; C009074:N-n-propylnorapomorphine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D005476:Fluphenazine; D004298:Dopamine