Drug-induced alterations in the extracellular signal-regulated kinase (ERK) signalling pathway: implications for reinforcement and reinstatement

Abstract

Drug addiction, characterized by high rates of relapse, is recognized as a kind of neuroadaptive disorder. Since the extracellular signal-regulated kinase (ERK) pathway is critical to neuroplasticity in the adult brain, understanding the role this pathway plays is important for understanding the molecular mechanism underlying drug addiction and relapse. Here, we review previous literatures that focus on the effects of exposure to cocaine, amphetamine, Delta(9)-tetrahydrocannabinol (THC), nicotine, morphine, and alcohol on ERK signaling in the mesocorticolimbic dopamine system; these alterations of ERK signaling have been thought to contribute to the drug's rewarding effects and to the long-term maladaptation induced by drug abuse. We then discuss the possible upstreams of the ERK signaling pathway activated by exposure of drugs of abuse and the environmental cues previously paired with drugs. Finally, we argue that since ERK activation is a key molecular process in reinstatement of conditioned place preference and drug self-administration, the pharmacological manipulation of the ERK pathway is a potential treatment strategy for drug addiction.

Fig. 1

ERK signaling cascade. ERK activation is initially recognized as downstream of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and basic fibroblast growth factor (bFGF). By coupling with the G protein-coupled receptor (GPCR)-AC-PKA pathway, ERK directly responds to extracellular dopamine, glutamate, opioids, and cannabinoids. By coupling with NMDA receptors and acetylcholine receptors (nAChR), ERK can respond to glutamate and nicotine. PD98059, U0126, SL327, and PD184161 are used as pharmacological tools to inhibit MEK, and thus down-regulate ERK phosphorylation

Fig. 2

Cue-induced reinstatement of drug seeking depending on ERK phosphorylation and NMDA glutamate receptor activation. Rats were first trained for cocaine self-administration. When returned to their training environments for the extinction test, the rats showed higher lever-press responses at withdrawal day 30 (A, left, *P < 0.05 versus withdrawal day 1, accompanied by enhanced ERK phosphorylation in the central amygdala (A, right, *P < 0.05 versus non-extinction test). This higher lever-press response could be inhibited by the MEK inhibitor U0126 (B, left, *P < 0.05 versus active lever in vehicle group) and NMDA receptor antagonist AP-5 (C, left, *P < 0.05 versus active lever in vehicle group). Decreased lever-press response was associated with specific down-regulated ERK phosphorylation in the central amygdala (B and C, right, *P < 0.05 versus vehicle), but not the basolateral amygdala. Adapted from Lu et al. (2005b) with permission from Nature Publishing Group