Abstract
Objective: Nicotine is an active compound in tobacco and has a rewarding effect in the central nervous system (CNS), which may lead to dependence. Although nicotine dependence is elucidated by brain mechanisms, synaptic molecular substrates underlying the dependence remain unclear. We hypothesized that reward signaling is mediated by dopamine and glutamate receptors, in where calcium/calmodulin-dependent kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) may mediate the synaptic signaling of dependence.
 Methods: To investigate the roles of both CaMKII and ERK on nicotine dependence were assessed by conditioned place preference (CPP) methods followed by dissection. One day after conditioning, preference scores were measured to evaluate nicotine dependence. Mice were sacrificed and their striatum were dissected out for immunoblotting analyses of CaMKII and ERK phosphorylation.
 Results: Nicotine-induced conditioned place preference as a symptom of nicotine dependence. CaMKII and ERK phosphorylation in striatum significantly increased along with the development of nicotine dependence.
 Conclusion: We should next apply pharmacological strategies to manipulate CaMKII and ERK signaling. In particular, disruption of reconsolidation by disrupting CaMKII and ERK signaling may propose an attractive therapeutic approach to inhibit nicotine dependence.
Highlights
Nicotine is an active compound and the main addictive material in tobacco products; nicotine dependence symptoms are characterized by compulsive use, craving, tolerance from continued use and withdrawal upon cessation [1]
Nicotine binds by main receptor nicotinic acetylcholine receptors, which are pentamers consisted of α2, α4 α7, α10, and β2β4 subunits [3]. nAChRs are widely distributed in the central nervous system (CNS), including cortical and limbic regions
These receptors are critical for drug addiction through stimulation of synaptic activity in the hippocampus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc) and striatum region [4]
Summary
Nicotine is an active compound and the main addictive material in tobacco products; nicotine dependence symptoms are characterized by compulsive use, craving, tolerance from continued use and withdrawal upon cessation [1]. NAChRs are widely distributed in the central nervous system (CNS), including cortical and limbic regions. These receptors are critical for drug addiction through stimulation of synaptic activity in the hippocampus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc) and striatum region [4]. NAChRs are ligand-gated ion channels that were activated by the endogenous neurotransmitter acetylcholine (ACh) and the exogenous tertiary alkaloid nicotine [5]. Activation of nAChRs by nicotine stimulates calcium influx Calcium through nAChRs, especially via the alpha-bungarotoxin-sensitive alpha7-containing nAChRs, which is a very effective subtype of nAChRs on enhancing cytoplasmic calcium level [6]. Calcium entry through voltage-gated Ca2+channels is critical in develop the Calcium/Calmodulin Protein Dependent Kinase (CaMKII) level [7]. Influx Ca2+intracellular to result in activation and phosphorylation of PYK2, turn on the RAS through tyrosine kinase receptor and upstream the activity of extracellular regulated kinase 1/2 (ERK1/2) [8]
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