The two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), are involved in the control of gene expression via phosphorylation and activation of the transcription factors cyclic AMP response element binding protein (CREB) and Elk-1. Here, we have examined the effect of haloperidol and clozapine, two antipsychotic drugs, and eticlopride, a selective dopamine D 2 receptor antagonist, on the state of phosphorylation of ERK1/2, CREB and Elk-1, in the mouse dorsal striatum. Administration of the typical anti-psychotic haloperidol stimulated the phosphorylation of ERK1/2, CREB and Elk-1. Virtually identical results were obtained using eticlopride. In contrast, the atypical anti-psychotic clozapine reduced ERK1/2, CREB and Elk-1 phosphorylation. This opposite regulation was specifically exerted by haloperidol and clozapine on ERK, CREB, and Elk-1 phosphorylation, as both anti-psychotic drugs increased the phosphorylation of the dopamine-and cyclic AMPregulated phosphoprotein of 32 kDa (DARPP-32) at the cyclic AMP-dependent protein kinase (PKA) site. The activation of CREB and Elk-1 induced by haloperidol appeared to be achieved via different signalling pathways, as inhibition of ERK1/2 activation abolished the stimulation of Elk-1 phosphorylation without affecting CREB phosphorylation. This study shows that haloperidol and clozapine induce distinct patterns of phosphorylation in the dorsal striatum. The results provide a novel biochemical paradigm elucidating the molecular mechanisms underlying the distinct therapeutic actions of typical and atypical anti-psychotic agents. Treatment with anti-psychotic (or neuroleptic) drugs currently represents the most common therapy for schizophrenia. One major limitation in the use of conventional antipsychotic drugs, such as haloperidol, is that their prolonged administration induces extra-pyramidal side-effects by modifying transmission in the basal ganglia, a group of brain structures involved in the control of voluntary movements. The atypical anti-psychotic, clozapine, has a superior therapeutic efficacy and does not produce extra-pyramidal sideeffects. The use of this drug, however, is complicated by the relatively high incidence of agranulocytosis, a condition that requires the immediate suspension of clozapine administration.A common feature of anti-psychotic drugs is their ability to act as dopamine D 2 receptor antagonists. Blockade of dopamine D 2 receptors profoundly affects gene expression in the striatum, the major receiving area of the basal ganglia.Administration of haloperidol produces a rapid increase in the expression of various genes including the immediate early gene c-fos (Dragunow et al. 1990;Miller 1990) Abbreviations used: CREB, cyclic AMP response element binding protein; DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein of 32 kDa; ERK1/2, extracellular signal-regulated protein kinase 1 and 2; MAPKs, mitogen-activated protein kinases; MEK, MAPK/ERK kinase.