Enhanced cortical dopamine output and antipsychotic-like effect of raclopride with adjunctive low-dose L-dopa.
BACKGROUND
Clozapine shows superior efficacy in schizophrenia and enhances prefrontal dopamine (DA) output like other atypical, but not typical, antipsychotic drugs (APDs). Clinical data also suggest an improved effect of typical APDs in schizophrenia by adjunctive treatment with low doses of 3,4-dihydroxyphenylalanine (L-dopa), but experimental support is scarce, and the underlying mechanisms are poorly understood.


METHODS
Antipsychotic efficacy of the D2 antagonist raclopride with or without adjunctive treatment with a low dose of L-dopa was assessed with the conditioned avoidance response paradigm. Extrapyramidal side effects were scored by the catalepsy test. Finally, in vivo microdialysis was used to measure DA efflux in the prefrontal cortex and the nucleus accumbens.


RESULTS
A low dose of L-dopa (3 mg/kg) combined with benserazide, an inhibitor of peripheral DOPA decarboxylase, significantly enhanced the antipsychotic-like effect of raclopride without any associated catalepsy. L-dopa/benserazide alone had no effect. In contrast to raclopride alone, combined L-dopa/raclopride also produced a much larger increase in DA output in the prefrontal cortex than in the nucleus accumbens.


CONCLUSIONS
These data support the clinical observation that low-dose L-dopa might improve the effect of typical APDs in schizophrenia and indicate that increased prefrontal DA output per se enhances the antipsychotic effect of typical APDs.
Eltayb
Amani
A
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
Wadenberg
Marie-Louise G
ML
Svensson
Torgny H
TH
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001545:Benserazide / Q000494:pharmacology; D002375:Catalepsy / Q000188:drug therapy / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009714:Nucleus Accumbens / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D020891:Raclopride / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D020891:Raclopride; D007980:Levodopa; D001545:Benserazide; D004298:Dopamine