Binding affinity of aripiprazole to the dopamine D2 receptor in different regions of the rat brain
Purpose: The new antipsychotic drug aripiprazole has a high affinity for the dopamine D2 receptor (D2R) and can treat multiple symptoms of schizophrenia with reduced risk of extrapyramidal side-effects (EPS). The question of how aripiprazole achieves its therapeutic benefits through the D2R, without causing EPS is currently unanswered. This study aimed to examine the binding affinity of aripiprazole to D2R in specific nuclei of the mesolimbic and nigrostriatal dopamine pathways, which are implicated in the therapeutic effects and EPS side effects of antipsychotic drugs, respectively. METHODS: Brain tissue obtained from male Sprague Dawley rats (n=7) was sectioned onto polysine slides and D2Rs were visualised by competition autoradiographic techniques using 20nM [3H]raclopride. D2R binding density was quantified in the ventral tegmental area (VTA) and nucleus accumbens (NAc) (mesolimbic pathway), substantia nigra (SN) and caudate putamen (CPU) (nigrostriatal pathway). The mean results of 7 animals were combined for each region of interest. RESULTS: Aripiprazole had a high affinity for the D2R in all regions examined. Aripiprazole had mean inhibition constants (Ki) of: 15nM in the VTA, 71nM in the NAc, 21nM in the SN, 29nM in the CPU. CONCLUSION: Aripiprazole has a high binding affinity for the D2R in specific nuclei of the dopaminergic pathways in the rat brain. Aripiprazole affinity for D2Rs in the NAc was slightly lower than the other regions of interest; however values were similar in range, therefore differences in binding affinity cannot explain its reduced EPS. The mechanisms by which aripiprazole achieves its therapeutic effects, while avoiding EPS, require further investigation.
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