5-HT2 receptor blockade by ICI 169,369 and other 5-HT2 antagonists modulates the effects of D-2 dopamine receptor blockade.
The effects of D-2 dopamine (DA) receptor blockade were modulated by ICI 169,369, a selective 5-hydroxytryptamine (5-HT)2 receptor antagonist, and by other 5-HT2 antagonists. Specifically, it appears that blockade of 5-HT2 receptors can attenuate the effects of D-2 receptor blockade on rat striatal dopaminergic transmission. Thus, the blockade of D-2 receptors by haloperidol results in a compensatory increase in rat striatal DA metabolism, which is enhanced by ICI 169,369. By itself, ICI 169,369 did not significantly alter DA metabolism. Conversely, several compounds which possess appreciable activity at 5-HT2 sites in ex vivo binding assays, but possess little activity at D-2 sites (i.e., pirenperone, setoperone, fluperlapine and clozapine), all produced large increases in striatal DA metabolism. Therefore, these data suggest that the 5-HT2 component of these compounds, by enhancing DA metabolism, may act to attenuate the blockade of striatal D-2 receptors by these compounds. Consistent with this hypothesis, the chronic blockade of D-2 receptors by haloperidol increases the number of striatal D-2 DA receptors, and these increases are attenuated by the coadministration of ICI 169,369. Likewise, pirenperone and clozapine, at doses which acutely produced elevations in DA metabolism which were similar to those produced by haloperidol, failed to increase the number of D-2 receptors in striatum. Interestingly, 5-HT2 receptor blockade did not appear to potently modulate the effects of D-2 receptor blockade in the olfactory tubercle, a brain region which is innervated by mesolimbic DA-containing neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Saller
C F
CF
Biomedical Research, ICI Pharma, a Business Unit of ICI Americas, Inc., Wilmington, Delaware.
Czupryna
M J
MJ
Salama
A I
AI
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D011388:Prolactin / Q000097:blood; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D011804:Quinolines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C054363:2-((2-(dimethylamino)ethyl)thio)-3-phenylquinoline; D011388:Prolactin; D006220:Haloperidol; D004298:Dopamine