It is now well established that central effects of Delta 9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana, are mediated by CB1 cannabinoid receptors. However, intraneuronal signalling pathways activated in vivo by THC remain poorly understood. We show that acute administration of THC induces a progressive and transient activation (i.e. phosphorylation) of the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) in the dorsal striatum and the nucleus accumbens (NA). This activation, corresponding to both neuronal cell bodies and the surrounding neuropil, is totally inhibited by the selective antagonist of CB1 cannabinoid receptors, SR 141716A. However, blockade of dopaminergic (DA) D1 receptors by administration of SCH 23390, prior to THC, totally prevents ERK activation in the striatum, thus demonstrating a critical involvement of DA systems in THC-induced ERK activation. DA-D2 and glutamate receptors of NMDA subtypes also participate, albeit to a lesser extent, to THC-induced ERK activation in the striatum, as shown after injection of selective antagonists (raclopride and MK801, respectively). Furthermore, THC-induced phosphorylation of the transcription factor Elk-1, and up-regulation of zif268 mRNA expression are blocked by SL327, a specific inhibitor of MAPK/ERK kinase (MEK), the upstream kinase of ERK, as well as SCH 23390. Finally, using the place-preference paradigm, we show that ERK inhibition blocks THC-induced rewarding properties. Altogether, our data strongly support that ERK activation in the striatum is critically involved in long-term neuronal adaptive responses underlying THC-induced long-term behaviours.