ERK2: a logical AND gate critical for drug-induced plasticity?
Introduction
A variety of substances naturally produced by plants (e.g. cocaine, morphine, cannabinoids and nicotine) or made by humans with various degrees of sophistication (e.g. ethanol, heroin and amphetamine) trigger a peculiar behavior of recurrent consumption, both in humans and experimental animals. This response can become compulsive and lead to a pathological state called addiction, with its well-known deleterious consequences for health and society. Addiction is a chronic disease with a high risk of relapse even after a long period of withdrawal, revealing stable brain alterations. A chief aspect of addiction is related to the distortion of reward mechanisms that are dependent upon dopamine (DA) [1, 2, 3]. Thus, drugs of abuse are the source of a major medical problem but, concurrently, the Ariane's thread that could lead neuroscientists through the maze of a major learning mechanism.
Drugs of abuse enhance extracellular DA levels in the forebrain, especially in the nucleus accumbens (NAcc) where they control corticostriatal glutamate transmission [1, 2, 3]. A critical question is the nature of the signaling mechanisms activated by DA in striatal and other target neurons that trigger the long-lasting alterations responsible for the behavioral effects of drugs of abuse. This question is not only theoretical but might also have clinical implications, as deciphering these mechanisms could lead to novel strategies to modify, or even reverse, some of the seemingly irreversible consequences of addiction. Several signaling pathways have been implicated in the actions of DA. Here, we focus on the role of the extracellular signal-regulated kinase (ERK) pathway, one of the highly conserved mitogen-activated protein kinase (MAPK) modules.
Section snippets
The ERK pathway
MAPK modules comprise three classes of enzymes that act in a cascade of activatory phosphorylation: the upstream kinases (MAPK/ERK-kinase-kinases [MEKKs]) phosphorylate and activate the MAPK/ERK-kinases (MEKs). MEKs are dual specificity kinases that trigger the activation of MAPKs by phosphorylating a threonine and a tyrosine in their activation loop. Specificity in the signaling between these modules is achieved by protein–protein interactions and scaffolding molecules [4]. The ERK kinase
Drugs of abuse activate ERK1/2 in a subset of neurons in brain reward circuits
Activation of ERK1/2 in response to addictive drugs was first reported to occur in the ventral tegmental area (VTA) after a five-day exposure of rats to morphine or cocaine [8]. Subsequently, acute treatment of mice with cocaine was shown to induce a rapid and transient increase in ERK phosphorylation in the NAcc [9], an effect reproduced with other drugs of abuse including Δ9-tetrahydrocannabinol (THC), D-amphetamine, 3,4-methylene-dioxy-methamphetamine, morphine and nicotine [10, 11, 12, 13].
Role of ERK in psychomotor sensitization and the rewarding effects of drugs
The major tools used to address the role of ERK1/2 are inhibitors of MEK, either microinjected in specific brain regions (PD98059 and U0126) or, in the case of SL327, which crosses the blood–brain barrier, administered intraperitoneally. The specificity of microinjected inhibitors is difficult to assess, as their concentrations in the vicinity of the injection point is likely to exceed those recommended in vitro. Conversely, the site of action of SL327 injected at the periphery cannot be
Role of ERK1/2 in drug-conditioned responses and their ‘reconsolidation’
Sensory stimuli that by themselves are unable to activate ERK1/2 can do so when they have been associated repeatedly with drugs. After acquisition of cocaine self-administration, the presentation of drug-associated cues increases ERK1/2 phosphorylation in the central amygdala after one month of withdrawal [24••]. In animals trained for CPP with cocaine or methamphetamine, exposure to the test apparatus is sufficient to activate ERK1/2 in the NAcc, caudate-putamen and prefrontal cortex [25, 26••
Molecular targets of ERK
The evidence summarized above strongly supports the role of ERK1/2 in the acquisition of long-lasting behavioral effects of drugs of abuse, and, possibly, in their expression. It is clearly of great interest to identify the substrates of ERK1/2 that are important in either case. Phosphorylated ERK1/2 is detected in both dendrites and perikarya of striatal neurons and rapidly accumulates in the nucleus. The rapid time-scale of the conditioned responses [24••, 25, 26••] suggests that ERK
Opposing roles of ERK1 and ERK2
Although they have 90% sequence identity, ERK 1 and ERK2 appear to have distinct functional effects [44•, 45]. Thus, ERK1 can inhibit ERK2 signaling, possibly by competition for phosphorylation by MEK. Drug-induced phosphorylation of ERK2 appears much stronger than that of ERK1 [14•]. In ERK1 knockout mice, which are viable and fertile, CPP evoked by morphine or cocaine, as well as psychomotor sensitization to cocaine, was enhanced [21•, 45]. Cocaine-induced gene transcription was also
Conclusions: possible role of ERK2 in the effects of drugs of abuse and beyond
The evidence summarized here underlines the key role of the ERK1/2 pathway, and more specifically of ERK2 (see above,) in the long-lasting effects of drugs of abuse. In striatal MSNs, its activation requires both DA and glutamate inputs, suggesting that it functions as a logical AND gate (Figure 3). This gate detects the coincidence of environmental cues (glutamate) and positive reward prediction error signals (dopamine). Evidence suggests that, when activated, the ERK2 pathway places the
Update
As a further indication of the functional importance of the ERK pathway, recent work has shown that in DA transporter-deficient mutant mice the ERK pathway is constitutively activated [56]. In these mice, psychostimulant drugs, serotonin uptake inhibitors and MEK inhibitors attenuate ERK phosphorylation and decrease hyperactivity.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Work in the laboratory of JA Girault related to this review was supported by Inserm, Agence Nationale de la Recherche (ANR), Schlumberger Foundation for Education and Research, Bettencourt-Schueller Foundation, Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie (MILDT) and Université Pierre et Marie Curie (UPMC).
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