Expression of noradrenergic α1, serotoninergic 5HT2a and dopaminergic D2 receptors on neurons activated by typical and atypical antipsychotic drugs

Antipsychotic agents produce activation of a subset of largely dynorphinergic/GABAergic neurons in the shell of nucleus accumbens (AcbShB), central amygdaloid nucleus (CeA) and midline thalamic central medial nucleus (CM) in rats. It is not known why these particular neurons respond to antipsychotic drugs. The present study tested the hypothesis that activated neurons bear subtypes of monoamine receptors to which antipsychotic drug are known to bind, including dopaminergic D2, serotoninergic 5HT2a and noradrenergic α1 receptors. Rats were treated with the typical antipsychotic haloperidol or the atypical antipsychotic clozapine. Double immunofluorescence labeling was performed with antibodies directed against (1) the expression of Fos proteins, indicating drug-induced cell activation, and (2) each of the monoamine receptor proteins noted. All three receptors examined were expressed in haloperidol- and clozapine-activated neurons in AcbSh. Furthermore, noradrenergic α1 receptors were extensively expressed in activated neurons in CeA and CM, as well. The results suggest that bearing monoamine receptors with high binding affinity for typical and/or atypical antipsychotic drugs might be a key feature of neurons which respond to these drugs. In AcbSh, activated neurons appeared to bear each receptor and, therefore, it is possible that not only the individual but also the combined effect of antipsychotic drugs at multiple receptors may explain why they directly activate certain cells and not others. Also, bearing noradrenergic α1 receptor neurons was a shared feature of all activated cells in each location tested, suggesting inhibition of noradrenergic α1 receptors may contribute to antipsychotic drug action at these sites.