Glycogen synthase kinase 3β in the basolateral amygdala is critical for the reconsolidation of cocaine reward memory

Abstract

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07277.x Abstract Exposure to cocaine‐associated conditioned stimuli elicits craving and increases the probability of cocaine relapse in cocaine users even after extended periods of abstinence. Recent evidence indicates that cocaine seeking can be inhibited by disrupting the reconsolidation of the cocaine cue memories and that basolateral amygdala (BLA) neuronal activity plays a role in this effect. Previous studies demonstrated that glycogen synthase kinase 3β (GSK‐3β) plays a role in the reconsolidation of fear memory. Here, we used a conditioned place preference procedure to examine the role of GSK‐3β in the BLA in the reconsolidation of cocaine cue memories. GSK‐3β activity in the BLA, but not central amygdala (CeA), in rats that acquired cocaine (10 mg/kg)‐induced conditioned place preference increased after re‐exposure to a previously cocaine‐paired chamber (i.e., a memory reactivation procedure). Systemic injections of the GSK‐3β inhibitor lithium chloride after memory reactivation impaired the reconsolidation of cocaine cue memories and inhibited subsequent cue‐induced GSK‐3β activity in the BLA. Basolateral amygdala, but not central amygdala, injections of SB216763, a selective inhibitor of GSK‐3β, immediately after the reactivation of cocaine cue memories also disrupted cocaine cue memory reconsolidation and prevented cue‐induced increases in GSK‐3β activity in the BLA. The effect of SB216763 on the reconsolidation of cocaine cue memories lasted at least 2 weeks and was not recovered by a cocaine priming injection. These results indicate that GSK‐3β activity in the BLA mediates the reconsolidation of cocaine cue memories.

The roles of protein kinases in learning and memory

“…Consistently, pharmacological inhibition of GSK-3b enhances fear LTM formation, whereas transgenic overexpression of GSK-3b impairs spatial memory formation (Hernandez et al 2002). Additionally, GSK-3b has also been implicated in reconsolidation (Kimura et al 2008b;Wu et al 2011) and memory retrieval (Hong et al 2012).…”

Counterconditioning During Reconsolidation Prevents Relapse of Cocaine Memories

“…Interestingly, it was recently shown that administration of LiCl immediately after memory retrieval abolished the expression of cocaine-CPP (Wu et al, 2011). The authors suggested that LiCl disrupted the reconsolidation of cocaine-associated memories via its pharmacological properties, namely, inhibition of glycogen synthase kinase 3β (GSK3β) (Wu et al, 2011), which is implicated in synaptic plasticity, learning, and memory formation (Dewachter et al, 2009).…”

“…Interestingly, it was recently shown that administration of LiCl immediately after memory retrieval abolished the expression of cocaine-CPP (Wu et al, 2011). The authors suggested that LiCl disrupted the reconsolidation of cocaine-associated memories via its pharmacological properties, namely, inhibition of glycogen synthase kinase 3β (GSK3β) (Wu et al, 2011), which is implicated in synaptic plasticity, learning, and memory formation (Dewachter et al, 2009). However, we show here that the mere administration of LiCl after memory retrieval without a counterconditioning indeed decreases the expression of cocaine-CPP, but it does not prevent the reinstatement of CPP triggered by a cocaine prime (Experiment 2), implying that memory reconsolidation is not affected by LiCl per se in the absence of the behavioral, aversive counterconditioning.…”

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

“…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].…”

“…Although GSK-3 exists as two isoforms, GSK-3α and GSK-3β, the majority of research has focused on GSK-3β as a result of its involvement in neuropsychiatric diseases such as schizophrenia and addiction [40,41,42,79,80,81], as well as neurodegenerative disease [82,83]. GSK-3β is a constitutively active kinase that can be inhibited by its phosphorylation at Ser9 [84].…”