Alterations in different populations of striatal dopamine receptors produced by 18 months continuous administration of cis- or trans-flupenthixol to rats.
Administration of cis-flupenthixol (0.8-1.2 mg/kg per day) for 18 months enhanced stereotyped behaviour induced by apomorphine, bromocriptine and lergotrile, but not that induced by amphetamine or lisuride. Catalepsy induced by acute administration of haloperidol, trifluoperazine or cis-flupenthixol was reduced by continuous chronic intake of cis-flupenthixol. The number (Bmax) and dissociation constant (KD) of specific [3H]spiperone binding sites on striatal membranes was increased by chronic administration of cis-flupenthixol, but not trans-flupenthixol. In contrast, the Bmax and KD for specific binding of [3H]N,n-propylnorapomorphine were decreased by administration of cis-flupenthixol compared to the effect of the trans-isomer. Specific binding of [3H]piflutixol was unaffected by chronic administration of cis- or trans-flupenthixol, but chronic administration of cis-flupenthixol enhanced stimulation by dopamine of the activity of striatal adenylate cyclase. As a result of chronic continuous administration of cis-flupenthixol dopamine receptors in the striatum appeared to be supersensitive to most dopamine agonists but sub-sensitive to dopamine antagonists. This was reflected by increased numbers of D-2 antagonist receptor sites of decreased affinity, but by a decreased number of agonist sites of higher affinity. The D-1 recognition sites appeared to be unaltered, but activity of adenylate cyclase stimulated by dopamine was enhanced, suggesting post-junctional changes. The D-2 receptors appear to be primarily concerned with altered function of dopamine receptors.
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000032:analysis / Q000187:drug effects*; D005475:Flupenthixol / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects*; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013892:Thioxanthenes / Q000494:pharmacology*
D011954:Receptors, Dopamine; D013892:Thioxanthenes; D013134:Spiperone; D000262:Adenylyl Cyclases; D005475:Flupenthixol; D001058:Apomorphine