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.
The mitogen-activated protein kinase/extracellular signalregulated kinase (MAPK/ERK) signaling cascade contributes to synaptic plasticity and to long-term memory formation, yet whether MAPK/ERK controls activity-dependent gene expression critical for long-lasting changes at the synapse and what the events underlying transduction of the signal are remain uncertain. Here we show that induction of long-term potentiation (LTP) in the dentate gyrus in vivo leads to rapid phosphorylation and nuclear translocation of MAPK/ERK. Following a similar time course, the two downstream transcriptional targets of MAPK/ERK, cAMP response element-binding protein (CREB) and the ternary complex factor Elk-1, a key transcriptionalregulator of serum response element (SRE)-driven gene expression, were hyperphosphorylated and the immediate early gene zif268 was upregulated. The mRNA encoding MAP kinase phosphatase MKP-1 was upregulated at the time point when MAPK/ERK phosphorylation had returned to basal levels, suggesting a negative feedback loop to regulate deactivation of MAPK/ERK. We also show that inhibition of the MAPK/ERK cascade by the MAPK kinase MEK inhibitor SL327 prevented CREB and Elk-1 phosphorylation, and LTP-dependent gene induction, resulting in rapidly decaying LTP. In conclusion, we suggest that Elk-1 forms an important link in the MAP kinase pathway to transduce signals from the cell surface to the nucleus to activate the genetic machinery necessary for the maintenance of synaptic plasticity in the dentate gyrus. Thus, MAPK/ERK activation is required for LTP-dependent transcriptional regulation and we suggest this is regulated by two parallel signaling pathways, the MAPK/ERK-Elk-1 pathway targeting SRE and the MAPK/ERK-CREB pathway targeting CRE.
A major goal of research on addiction is to identify the molecular mechanisms of long-lasting behavioural alterations induced by drugs of abuse. Cocaine and delta-9-tetrahydrocannabinol (THC) activate extracellular signal-regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho-ERK immunoreactive neurons in CD-1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor-dependent mechanism. Although some non-addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long-term effects of drugs of abuse, and suggest mapping ERK activation in brain as a way to identify potential sites of action of psychoactive drugs.
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