The Role of CaMKII and ERK Signaling in Addiction

Abstract

Nicotine is the predominant addictive compound of tobacco and causes the acquisition of dependence through its interactions with nicotinic acetylcholine receptors and various neurotransmitter releases in the central nervous system. The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) play a pivotal role in synaptic plasticity in the hippocampus. CaMKII is involved in long-term potentiation induction, which underlies the consolidation of learning and memory; however, the roles of CaMKII in nicotine and other psychostimulant-induced addiction still require further investigation. This article reviews the molecular mechanisms and crucial roles of CaMKII and ERK in nicotine and other stimulant drug-induced addiction. We also discuss dopamine (DA) receptor signaling involved in nicotine-induced addiction in the brain reward circuitry. In the last section, we introduce the association of polyunsaturated fatty acids and cellular chaperones of fatty acid-binding protein 3 in the context of nicotine-induced addiction in the mouse nucleus accumbens and provide a novel target for the treatment of drug abuse affecting dopaminergic systems.

Keywords: Ca2+/calmodulin-dependent protein kinase II; dopamine D1 receptor; dopamine D2 receptor; extracellular signal-regulated kinase; fatty acid-binding protein 3; nicotine-induced addiction.

Figure 1

Simplified schematic representation of the mouse brain reward circuitry. The scheme of the mesolimbic DAergic projections (purple) of the mouse brain sagittal section emphasizes the predominant afferents that originate in the VTA and input into the NAc as well as the PFC, which are modulated by stimulant drug exposure through CaMKII functions. Glutamatergic inputs (red) that regulate neuronal circuits in response to drug abuse from the PFC to the NAc and from the HP to the VTA through the subiculum are highlighted [81]. Since CaMKIIβ regulates synaptic activity in the Hb in the context of depressive behaviors, it increases glutamatergic inputs onto VTA GABAergic interneurons to inhibit VTA DAergic neurons, thereby decreasing the DA release in the NAc [82,83]. VTA, ventral tegmental area; NAc, nucleus accumbens; PFC, prefrontal cortex; HP, hippocampus; Hb, habenula.

Figure 2

Simplified schematic diagram of ERK signal cascade in the mouse brain involved in psychostimulant-induced addiction. Nicotine and other stimulant drugs activate D1R and facilitate DA release in the DA terminals, leading to PKA and Raf activation. D1R activation causes L-type Ca²⁺ channels activation [92], contributing to Ca²⁺ influx and elevation of Ca²⁺ level, which leads to the activation of Raf. Raf is also activated by Ca²⁺ influx through NMDAR, which is mediated by the stimuli of Ras-GRF1 [93], and by BDNF through the binding and activation of TrkB. In turn, Raf activation leads to the phosphorylation and activation of MEK and ERK. The phosphorylation of ERK evokes the activation of downstream targets such as Elk1 and MSK1. The latter could activate and phosphorylate CREB. These transcriptional factors cause the transcription of IGEs such as c-Fos and zif268, which become the underlying mechanism of psychostimulant-induced addiction. D1R, dopamine D1 receptor; DA, dopamine; PKA, protein kinase A; NMDAR, N-methyl-D-aspartate receptor; Ras-GRF1, Ras protein-specific guanine-nucleotide releasing factor; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; MEK, MAPK-ERK kinase; MSK1, mitogen- and stress-stimulated kinase 1; CREB, cAMP response element-binding protein; IGEs, immediate early genes.

Figure 3

Schematic model of dopamine signaling pathways underlying nicotine-induced addiction in the FABP3^−/− mice NAc. In FABP3^−/− mice, the lowered cAMP/Ca²⁺ levels regulated by D2R/FABP3 signaling derepresses due to the impaired D2R function through the lacking FABP3, which provokes elevated cAMP/Ca²⁺ levels and increases CREB/c-Fos signaling. These constitutive elevated cAMP/Ca²⁺ levels and signals underlie the mechanism of failed acquisition of nicotine-induced addiction in FABP3^−/− mice.