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.
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.
Authors: George Bartzokis; Po H Lu; Keith H Nuechterlein; Michael Gitlin; Clarissa Doi; Nancy Edwards; Christopher Lieu; Lori L Altshuler; Jim Mintz Journal: Schizophr Res Date: 2007-04-03 Impact factor: 4.939
Authors: Monica M Marcus; Kent Jardemark; Anna Malmerfelt; Carl Björkholm; Torgny H Svensson Journal: Neuropsychopharmacology Date: 2010-05-12 Impact factor: 7.853
Authors: George Bartzokis; Po H Lu; Stephanie B Stewart; Bolanle Oluwadara; Andrew J Lucas; Joanna Pantages; Erika Pratt; Jonathan E Sherin; Lori L Altshuler; Jim Mintz; Michael J Gitlin; Kenneth L Subotnik; Keith H Nuechterlein Journal: Schizophr Res Date: 2009-07-17 Impact factor: 4.939
Authors: Olivia Frånberg; Charlotte Wiker; Monica M Marcus; Asa Konradsson; Kent Jardemark; Björn Schilström; Mohammed Shahid; Erik H F Wong; Torgny H Svensson Journal: Psychopharmacology (Berl) Date: 2007-10-17 Impact factor: 4.530
Authors: Jonathan Chetrit; Bérangère Ballion; Steeve Laquitaine; Pauline Belujon; Stéphanie Morin; Anne Taupignon; Bernard Bioulac; Christian E Gross; Abdelhamid Benazzouz Journal: PLoS One Date: 2009-07-09 Impact factor: 3.240