Aripiprazole differentially affects mesolimbic and nigrostriatal dopaminergic transmission: implications for long-term drug efficacy and low extrapyramidal side-effects.
Aripiprazole has been used effectively to treat schizophrenia in the clinic; however, its mechanisms of action are not clear. This study examined how short- and long-term aripiprazole treatment affects dopaminergic transmission in mesolimbic and nigrostriatal pathways. For comparison, the effects of haloperidol and olanzapine treatment were also examined. Aripiprazole significantly increased D2 receptor mRNA expression and decreased tyrosine hydroxylase (TH) mRNA expression in the ventral tegmental area (VTA) after 1- and 12-wk treatment, but had no effect in substantia nigra (SN) and nucleus accumbens (NAc). Aripiprazole also decreased dopamine transporter (DAT) binding density in NAc (for 1- and 12-wk treatment) and VTA (1-wk treatment). In contrast, haloperidol significantly increased D2 receptor binding density and decreased DAT binding density in NAc and caudate putamen (CPu) after 1- and 12-wk treatment, and it also decreases DAT binding in VTA after 12-wk treatment. Olanzapine had less widespread effects, namely an increase in D2 receptor mRNA in VTA after 12-wk treatment and decreased DAT binding in NAc after 1-wk treatment. These results suggest that aripiprazole has selective effects on the mesolimbic dopaminergic pathway. Selectively reducing dopamine synthesis in VTA is a possible therapeutic mechanism for the long-term efficacy of aripiprazole in controlling schizophrenia symptoms with reduced extrapyramidal side-effects.
Han
Mei
M
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia.
Huang
Xu-Feng
XF
Deng
Chao
C
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000068180:Aripiprazole; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D000077152:Olanzapine; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000009:adverse effects / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D015854:Up-Regulation; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D015363:Quinolones; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D000068180:Aripiprazole; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D000077152:Olanzapine; D004298:Dopamine