Calcium-dependent, D2 receptor-independent induction of c-fos by haloperidol in dopamine neurons.

Antipsychotic drugs such as haloperidol act as dopamine D2 receptor antagonists to produce a number of cellular effects including the induction of immediate-early genes such as c-fos. It has been hypothesized that blockade of D2 receptors by antipsychotics is responsible for the induction of c-fos, but the mechanism has not been determined. Using cultured ventral tegmental area (VTA) dopaminergic neurons as a model, we report that nanomolar concentrations of haloperidol cause a time-dependent increase in Fos expression in dopaminergic neurons.Surprisingly, this induction was not mimicked by sulpiride, a selective D2 receptor antagonist, and was not blocked by Rp-cAMPS, an antagonist of protein kinase A (PKA), thus suggesting that D2 receptors and the cAMP cascade are not required. The induction of Fos expression was blocked by tetrodotoxin, BAPTA and KN-93, thus showing that it is activity- and calcium-dependent and requires the activation of a calmodulin-dependent kinase (CaMK). Together, these results suggest that haloperidol induces Fos expression in dopaminergic neurons through a D2 receptor-independent increase in intracellular calcium, leading to CaMK activation.