Alterations in cerebral dopamine function caused by administration of cis- or trans-flupenthixol for up to 18 months.
Rats received either cis-flupenthixol (0.8-1.2 mg/kg per day) or trans-flupenthixol (0.9-1.2 mg/kg per day) continuously in drinking water for periods up to 18 months. cis-Flupenthixol, but not trans-flupenthixol, initially inhibited apomorphine-induced stereotyped behaviour but by 6 months and thereafter the stereotyped response was enhanced compared to age-matched control animals. Striatal and mesolimbic homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations were elevated for up to 3 months after starting cis-, but not trans-flupenthixol intake, but thereafter levels generally fell below those for age-matched control animals. Dopamine concentrations were not altered by cis- or trans-flupenthixol administration. The number of striatal [3H]spiperone binding sites (Bmax) was decreased by 40% after 1 months' administration of cis-flupenthixol but this gradually reversed, such that by 18 months a 40% increase in Bmax was apparent. Administration of trans-flupenthixol decreased Bmax up to 3 months but thereafter values were not different from those found in age-matched control animals. The dissociation constant (KD) for [3H]spiperone binding in striatum was not altered by 6 months cis-flupenthixol intake, but then increased as drug administration continued. trans-Flupenthixol administration did not alter striatal KD values. Bmax for [3H]spiperone binding to mesolimbic preparations was not altered by up to 12 months cis-flupenthixol intake, but was decreased after 18 months drug administration. cis-Flupenthixol administration had no effect on mesolimbic KD values. Administration of trans-flupenthixol for up to 18 months did not alter mesolimbic Bmax or KD values for [3H]spiperone binding.(ABSTRACT TRUNCATED AT 250 WORDS)
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D005475:Flupenthixol / Q000008:administration & dosage* / Q000494:pharmacology; D006719:Homovanillic Acid / Q000032:analysis; D006801:Humans; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013892:Thioxanthenes / Q000008:administration & dosage*; D013997:Time Factors
D013892:Thioxanthenes; D015102:3,4-Dihydroxyphenylacetic Acid; D013134:Spiperone; D000262:Adenylyl Cyclases; D005475:Flupenthixol; D004298:Dopamine; D006719:Homovanillic Acid