Many drugs of abuse exert their addictive effects by increasing extracellular dopamine in the nucleus accumbens, where they likely alter the plasticity of corticostriatal glutamatergic transmission. This mechanism implies key molecular alterations in neurons in which both dopamine and glutamate inputs are activated. Extracellular signal-regulated kinase (ERK), an enzyme important for long-term synaptic plasticity, is a good candidate for playing such a role. Here, we show in mouse that d-amphetamine activates ERK in a subset of medium-size spiny neurons of the dorsal striatum and nucleus accumbens, through the combined action of glutamate NMDA and D1-dopamine receptors. Activation of ERK by d-amphetamine or by widely abused drugs, including cocaine, nicotine, morphine, and ⌬ 9 -tetrahydrocannabinol was absent in mice lacking dopamine-and cAMP-regulated phosphoprotein of M r 32,000 (DARPP-32). The effects of d-amphetamine or cocaine on ERK activation in the striatum, but not in the prefrontal cortex, were prevented by point mutation of Thr-34, a DARPP-32 residue specifically involved in protein phosphatase-1 inhibition. Regulation by DARPP-32 occurred both upstream of ERK and at the level of striatal-enriched tyrosine phosphatase (STEP). Blockade of the ERK pathway or mutation of DARPP-32 altered locomotor sensitization induced by a single injection of psychostimulants, demonstrating the functional relevance of this regulation. Thus, activation of ERK, by a multilevel protein phosphatase-controlled mechanism, functions as a detector of coincidence of dopamine and glutamate signals converging on medium-size striatal neurons and is critical for long-lasting effects of drugs of abuse.dopamine D1 receptor ͉ drug addiction ͉ NMDA receptor ͉ nucleus accumbens ͉ protein kinase M any drugs of abuse share the ability to stimulate dopamine transmission in the nucleus accumbens (1). They are thought to mimic the effects of naturally reinforcing stimuli and divert the normal role of dopamine neurons in coding reward prediction errors (2). Dopamine modulates long-term depression and potentiation at glutamatergic corticostriatal synapses, and current models of striatal circuits suggest that the regulation of the plasticity of corticostriatal transmission is a central mechanism of dopamine-controlled-learning (3, 4). One prediction of these models is that key biochemical events should occur specifically in neurons in which both dopamine and glutamate inputs are activated. Activation of extracellular signal-regulated kinase (ERK) is a candidate for such a role because it depends on both dopamine and glutamate receptors (5). In addition, ERK activity is known to be important for long-term synaptic plasticity (6), and its pharmacological blockade prevents the transcriptional and rewarding effects of cocaine and ⌬ 9 -tetrahydrocannabinol (THC) (5, 7). To determine the role of ERK in the long-term action of dopamine in the striatum, it is critical to identify in which neurons it is activated and the mechanism of this activation. In ...

A central feature of drugs of abuse is to induce gene expression in discrete brain structures that are critically involved in behavioral responses related to addictive processes. Although extracellular signal-regulated kinase (ERK) has been implicated in several neurobiological processes, including neuronal plasticity, its role in drug addiction remains poorly understood. This study was designed to analyze the activation of ERK by cocaine, its involvement in cocaine-induced early and long-term behavioral effects, as well as in gene expression. We show, by immunocytochemistry, that acute cocaine administration activates ERK throughout the striatum, rapidly but transiently. This activation was blocked when SCH 23390 [a specific dopamine (DA)-D1 antagonist] but not raclopride (a DA-D2 antagonist) was injected before cocaine. Glutamate receptors of NMDA subtypes also participated in ERK activation, as shown after injection of the NMDA receptor antagonist MK 801. The systemic injection of SL327, a selective inhibitor of the ERK kinase MEK, before cocaine, abolished the cocaine-induced ERK activation and decreased cocaine-induced hyperlocomotion, indicating a role of this pathway in events underlying early behavioral responses. Moreover, the rewarding effects of cocaine were abolished by SL327 in the place-conditioning paradigm. Because SL327 antagonized cocaine-induced c-fos expression and Elk-1 hyperphosphorylation, we suggest that the ERK intracellular signaling cascade is also involved in the prime burst of gene expression underlying long-term behavioral changes induced by cocaine. Altogether, these results reveal a new mechanism to explain behavioral responses of cocaine related to its addictive properties.