CaMKII plays a critical role in the molecular pathway of the reward system in drug addiction, including nicotine dependence, and affects animal responses to drug abuse
[11]. Previous investigations demonstrated that 14 or 28 consecutive days of chronic nicotine administration significantly increased CPP scores in conditioning, nicotine withdrawal, as well as relapse phases and CaMKII autophosphorylation levels in the mouse NAc and hippocampal CA1 region
[12]. The number of CaMKII autophosphorylation-positive cells in the NAc was also elevated following chronic nicotine administration relative to saline-administered mice
[12]. Intracerebroventricular infusion of CaMKII antagonists KN-62 and KN-93 into mice showed impaired nicotine-induced CPP
[13]. CaMKIIα heterozygous (+/−) mice failed to show nicotine-induced CPP behavior, and the increased CaMKII activity in the NAc and VTA in wild-type (WT) mice were blocked by the administration of KN-62
[13]. Nicotine induces significant CPP and elevation of CaMKII activity in a concentration-dependent manner. Some studies identified that intraperitoneal injection of nicotine at doses of 0.25 mg/kg and 1.0 mg/kg could not produce nicotine-induced conditioning, whereas that at a dose of 0.5 mg/kg could
[14][15]. The concentration at 2 mg/kg induced conditioned place aversion but not CPP in mice
[14]. Nicotine concentration lower than 0.1 mg/kg or higher than 1.4 mg/kg could not induce CPP in subcutaneously injected rats
[16]. Although different neurochemical outcomes can be observed with different concentrations of nicotine, our previous data suggest that the daily dose of nicotine at 0.5 mg/kg could execute its functions that induce significant CPP, and elevate CaMKII autophosphorylation level as well as the phosphorylation level of its downstream targets in the NAc and hippocampal CA1 region using an immunoblotting technique
[12]. Consistent with nicotine, other addictive drugs such as morphine and methamphetamine have a similar effect with regard to the interaction with CaMKII. CaMKII modulates memory retention in an N-methyl-D-aspartate receptor (NMDAR)-dependent manner in morphine-sensitized rats
[17]. Reduced activations of CaMKII and cAMP response element-binding protein (CREB) were observed in the morphine self-administered rat NAc following treatment with a TRPV1 antagonist, which is from the transient receptor potential (TRP) cation channel family
[18]. The autophosphorylation level of CaMKII in the limbic forebrain was increased in mice administered with morphine, and this upregulation was blocked by the intracerebroventricular infusion of KN-93
[19]. The CaMKII signal is fully involved in the effect of cocaine- and amphetamine-regulated transcript (CART) peptide, which is a neuropeptide associated with brain reward circuits, in the context of cocaine reward
[20]. In the NAc, CaMKIIα contributes to the psychomotor effects induced by cocaine
[21], reinstatement of cocaine-seeking behaviors
[22], and cocaine-induced CPP behaviors
[23][24]. CaMKIIα expressed in other brain regions such as the prefrontal cortex (PFC) and amygdala is also correlated with cocaine-induced CPP and cue-induced cocaine-seeking behaviors
[23][25]. Furthermore, CaMKIIα autophosphorylation levels were significantly elevated in the PFC, hippocampus, and ventral striatum in rats following ketamine self-administration
[26]. Here, we introduce some evidence suggesting that the activities of CaMKII () are fully involved in certain brain regions located in the brain reward circuitry. Exposure to the stimulant drugs does not cause addiction immediately; it involves various neuronal adaptations that develop over time.
These stimulant drugs have been reported to activate and alter the reward circuitry of the brain, and affect synaptic plasticity, learning acquisition, and glutamatergic inputs into the brain neuronal circuit
[33][34] (). The brain reward circuitry underlying the addiction process is complicated, which mainly includes DA release from DAergic neurons in the VTA of the midbrain and projections to the NAc and PFC region. CaMKIIα autophosphorylation levels were significantly elevated in the PFC of morphine-administered mice
[29]. VTA plays a critical role in the initial stimulant drug exposure and causes long-term adaptation in DAergic neurons in the projection regions
[35]. Stimulant drug exposure increases DA signaling in the NAc and functionally regulates glutamatergic excitatory projections to the NAc medium spiny neurons (MSNs). Addictive drugs trigger and modulate synaptic plasticity in the brain reward circuitry involved in addiction. Some studies have suggested that alterations in synaptic plasticity at glutamatergic inputs from the cortex to the NAc may be the underlying mechanism in stimulant drug addiction
[33][36]. CaMKII is critically associated with the NAc shell DA and glutamatergic inputs involved in synaptic plasticity
[22].