Glycogen synthase kinase 3β in the nucleus accumbens core mediates cocaine‐induced behavioral sensitization

Abstract

Glycogen synthase kinase 3β (GSK‐3β) is a ubiquitous serine/threonine protein kinase involved in a number of signaling pathways. Previous studies have demonstrated a role for GSK‐3β in the synaptic plasticity underlying dopamine‐associated behaviors and diseases. Drug sensitization is produced by repeated exposure to the drug and is thought to reflect neuroadaptations that contribute to addiction. However, the role of GSK‐3β in cocaine‐induced behavior sensitization has not been examined. The present study investigated the effects of chronic cocaine exposure on GSK‐3β activity in the nucleus accumbens (NAc) and determined whether changes in GSK‐3β activity in the NAc are associated with cocaine‐induced locomotor sensitization. We also explored whether blockade of GSK‐3β activity in the NAc inhibits the initiation and expression of cocaine‐induced locomotor sensitization in rats using systemic or brain region‐specific administration of the GSK‐3β inhibitors lithium chloride (LiCl) and SB216763. GSK‐3β activity in the NAc core, but not NAc shell, increased after chronic cocaine (10 mg/kg, i.p.) administration. The initiation and expression of cocaine‐induced locomotor sensitization was attenuated by systemic administration of LiCl (100 mg/kg, i.p.) or direct infusion of SB216763 (1 ng/side) into the NAc core, but not NAc shell. Collectively, these results indicate that GSK‐3β activity in the NAc core, but not NAc shell, mediates the initiation and expression of cocaine‐induced locomotor sensitization, suggesting that GSK‐3β may be a potential target for the treatment of cocaine addiction.

Nucleus Accumbens Core Mammalian Target of Rapamycin Signaling Pathway Is Critical for Cue-Induced Reinstatement of Cocaine Seeking in Rats

“…The following NAc core coordinates were used: anteroposterior, ϩ1.5 mm; lateral, Ϯ 3.8 mm; dorsoventral, Ϫ6.2 mm. The following NAc shell coordinates were used: anteroposterior, ϩ1.8 mm; lateral, Ϯ 3.2 mm; dorsoventral, Ϫ6.6 mm (Zangen et al, 2006;Bossert et al, 2007;Xu et al, 2009). The cannulae were anchored to the skull with stainless steel screws and dental cement.…”

Role of calcineurin in the VTA in rats behaviorally sensitized to methamphetamine

“…Cyclosporin A was obtained from NCPC (St. Louis, MO) and dissolved in dimethyl sulfoxide at a concentration of 100% according to our previous report (Xu et al 2009). The drugs were freshly prepared before use, and the doses used in the present study were based on a previous report (Addy et al 2007).…”

Dopamine D₁-D₂ Receptor Heteromer Regulates Signaling Cascades Involved in Addiction: Potential Relevance to Adolescent Drug Susceptibility

“…For example, whereas meth-AMPH increased GSK-3β activity in the VTA [40], the inhibition of GSK-3β specifically in the rat NAc core, but not NAc shell, suppressed both meth-AMPH and cocaine-induced locomotor sensitization in rats [42,43]. Similarly, GSK-3β inhibition in the CP of mice resulted in a significant attenuation of the development of cocaine sensitization [81].…”

“…A direct role for GSK-3β in addiction has yet to be evaluated; however, some studies have examined its involvement in psychostimulant-induced locomotor sensitization [40,42,43,81]. For example, whereas meth-AMPH increased GSK-3β activity in the VTA [40], the inhibition of GSK-3β specifically in the rat NAc core, but not NAc shell, suppressed both meth-AMPH and cocaine-induced locomotor sensitization in rats [42,43].…”

“…CaMKII has been shown to play an integral role in addictive processes [33,34,35,36] and has been linked to both brain-derived neurotrophic factor (BDNF) expression [37] and glycogen synthase kinase 3 (GSK-3) activity [38], two proteins that also play an important role in processes that contribute to drug addiction [39,40,41,42,43]. In addition, phosphorylation by CaMKII is also involved in the functional regulation of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) [44], thus contributing to AMPAR-induced changes in synaptic plasticity that mediate the development of addiction [44,45,46].…”