Biochemical effects in brain of low doses of haloperidol are qualitatively similar to those of high doses.
Typical and atypical antipsychotic drugs (APD) show differential effects in brain on both dopamine output and activation of Fos-like immunoreactivity (FLI) in dopamine nerve terminal regions. Typical APD increase dopamine output preferentially in the core and atypical APD increase dopamine output preferentially in the shell of the nucleus accumbens (NAC). Whereas both typical and atypical APD increase FLI in NAC, typicals cause FLI activation in the striatum and atypicals cause FLI activation in the prefrontal cortex. Clinically, low doses of haloperidol cause less side-effects than higher doses, and low-dose haloperidol has been suggested as a cost-effective alternative to atypical APD. Here, in vivo voltammetry in anaesthetised, pargyline-pretreated rats was used to measure dopamine output in the two subdivisions of the NAC and, in addition, immunohistochemistry was used to assess FLI activation in dopamine target areas, following acute haloperidol administration. Haloperidol, 0.001 and 0.01 mg/kg i.v., caused a significantly higher dopamine output in the core than in the shell of the NAC. Moreover, haloperidol 0.05 and 0.5, but not 0.005, mg/kg s.c. increased FLI in the NAC and the striatum, but not in the medial prefrontal cortex. Thus, even extremely low doses of haloperidol generate, in principle, the same biochemical effects in brain as higher doses, and these effects remain different from those of atypical APD. These biological data indicate that clinical differences between haloperidol and atypicals are qualitative rather than dose-dependent. Consequently, our results do not support the use of low-dose haloperidol as replacement for atypical APD in the treatment of schizophrenia.
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77, Stockholm, Sweden.
M M
MM
Marcus
A
A
Malmerfelt
S
S
Nyberg
T H
TH
Svensson
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D006220:Haloperidol; D004298:Dopamine