Chronic treatment with SCH 23390 and haloperidol: effects on dopaminergic and serotonergic mechanisms in rat brain.
Effects of chronic administration (18 days) with SCH 23390 (0.1 or 0.5 mg/kg/day s.c.) and haloperidol (1 mg/kg/day s.c.) on dopamine and serotonin synthesis and metabolism in discrete dopaminergic and serotonergic nuclei of rat brain were studied. Additionally, the effects of these treatments on dopamine D-1 and D-2 receptor characteristics in rat caudate-putamen were investigated. Chronic administration with both dose regimens of SCH 23390 decreased DA metabolism significantly (basal homovanillic acid concentrations) in nucleus caudatus. In another set of experiments dopamine synthesis (rate of accumulation of 3,4-dihydroxyphenylalanine after 3,4-dihydroxyphenylalanine-decarboxylase inhibition) was reduced significantly only in nucleus accumbens after the higher SCH 23390 dose regimen. In turn, chronic administration with haloperidol decreased basal dopamine metabolism and synthesis in nucleus caudatus and nucleus accumbens. Chronic haloperidol, but not SCH 23390, treatment induced a clear-cut increase in [3H]spiperone binding in caudate-putamen. Interestingly, neither SCH 23390 nor haloperidol treatments affected [3H]SCH 23390 binding in caudate-putamen. SCH 23390 and haloperidol had no significant effects on serotonin synthesis and metabolism in serotonergic and dopaminergic areas. In conclusion, the classical antipsychotic drug, haloperidol, clearly decreases dopamine turnover in nigrostriatal and mesolimbic dopaminergic systems. The D-1 antagonist, SCH 23390, also decreases dopaminergic activity in nigrostriatal and mesolimbic systems although DA synthesis and metabolism are affected to different degrees in nucleus caudatus and nucleus accumbens. Therefore, we suggest that if D-1 antagonists such as SCH 23390 show antipsychotic activity in clinical studies, they may not be free of extrapyramidal side-effects.
Lappalainen
J
J
Department of Pharmacology, University of Turku, Finland.
Hietala
J
J
Koulu
M
M
Seppälä
T
T
Sjöholm
B
B
Syvälahti
E
E
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000032:analysis; D006220:Haloperidol / Q000494:pharmacology*; D006834:Hydrazines / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism
D001552:Benzazepines; D006834:Hydrazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; C004297:3-hydroxybenzylhydrazine; D006220:Haloperidol; D004298:Dopamine