Selective antidopaminergic effects of S(+)N-n-propylnoraporphines in limbic versus extrapyramidal sites in rat brain: comparisons with typical and atypical antipsychotic agents.
Dopamine (DA), injected unilaterally into rat forebrain after pretreatment with a monoamine oxidase inhibitor, equipotently induced locomotor arousal when placed in the nucleus accumbens septi (a limbic site) and contralateral deviation of the head when placed in the corpus striatum (an extrapyramidal target); testing was done with an ED50 dose of DA (16 micrograms). Systemic injections (IP) of the representative typical neuroleptic haloperidol showed high potency and minor striatal selectivity against the behavioral effects of intracerebral DA [accumbens ID50 = 0.090, striatum = 0.027 mg/kg (0.24 and 0.072 mumol/kg); ID50 ratio = 3.3, favoring striatum]. The atypical antipsychotic agent clozapine was less potent against DA in both brain regions but, paradoxically, showed ever greater striatal selectivity [ID50 = 12 and 1.4 mg/kg (37 and 4.2 mumol/kg); ratio = 8.8, favoring striatum], while its analog, the piperazinyl-dibenzothiazepine ICI-204,636 showed intermediate potency and the lowest striatal selectivity of these three neuroleptic agents [ID50 = 1.8 and 0.88 mg/kg (4.1 and 2.0 mumol/kg); ratio = 2.1]. In striking contrast, the S(+) isomers of N-n-propylnorapomorphine, its orally active 10,11-methylenedioxy prodrug derivative, and its 11-monohydroxy analog all induced potent antagonism of limbic DA but had little effect on extrapyramidal injections of DA except at high systemic doses [ID50, accumbens = 0.18-0.52, striatal = 10-15 mg/kg (0.50-1.6 and 29-42 mumol/kg); regional ID50 ratios = 18-69, favoring accumbens]. The S(+)aporphines showed limbic potency similar to that of haloperidol and 25-73 times greater than that of clozapine.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Psychiatry, Harvard Medical School, Boston, MA.
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A
Campbell
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Yeghiayan
R J
RJ
Baldessarini
J L
JL
Neumeyer
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011712:Pyramidal Tracts / Q000187:drug effects*; D000069348:Quetiapine Fumarate; D051381:Rats; D011919:Rats, Inbred Strains
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018492:Dopamine Antagonists; D000069348:Quetiapine Fumarate; C009074:N-n-propylnorapomorphine; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine