Inhibition of CaMKII in the nucleus accumbens shell decreases enhanced amphetamine intake in sensitized rats

Abstract

Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 into the nucleus accumbens (NAcc) shell impairs expression of the sensitized locomotion and NAcc dopamine (DA) overflow normally observed in psychostimulant-exposed rats. Based on these results, we investigated the effect of NAcc shell KN-93 on the enhanced amphetamine (AMPH) intake normally observed in AMPH-relative to saline-exposed rats. Rats were administered five injections of either AMPH (1.5 mg/kg, i.p.) or saline, one injection every two-three days. Fourteen days following the last injection, they were trained to self-administer AMPH (200 μg/kg/infusion, i.v.) first on fixed ratio schedules (FR) and then on a progressive ratio schedule of reinforcement (PR). As expected, AMPH-exposed rats worked harder and obtained significantly more drug infusions than saline-exposed rats on the PR schedule. After four days of stable responding, all rats were bilaterally microinjected with (1 or 10 nmol/0.5 μl/side) into the NAcc shell, two minutes prior to the beginning of the self-administration session. Inhibiting CaMKII in this site reduced the enhanced drug intake observed in AMPH-exposed rats to levels no longer significantly different from those of saline-exposed rats. Responding in these latter controls was not affected by KN-93 nor did KN-93 affect responding in AMPH-exposed rats when it was infused into the NAcc core. Thus, in a manner similar to what has been reported for sensitized locomotion and NAcc DA overflow, these results suggest that inhibiting CaMKII in the NAcc shell attenuates the enhanced motivation to obtain a drug reinforcer that is normally displayed in AMPH-exposed rats. KeywordsNucleus accumbens; CaMKII; sensitization; amphetamine; self-administration; Repeated exposure to psychostimulants such as amphetamine (AMPH) enhances the ability of these drugs to produce locomotor activation and nucleus accumbens (NAcc) dopamine (DA) overflow, and also leads to enhanced drug taking [5,10,12,25,26,27]. These enhanced responses, manifestations of behavioral and neurochemical sensitization, have been proposed to model the transition from casual drug use to drug abuse and addiction [21,28]. Consistent with this view, rats previously exposed to AMPH that work harder than saline-exposed controls *Correspondence: Jessica Loweth, 5841 South Maryland Avenue, MC 3077, Chicago, IL 60637, TEL: (773) 702-2891, FAX: (773) 702-0857, E-MAIL: E-mail: jloweth@uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Together, the above findings suggest that CaMKII may ...

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

“…The magnitude of these effects was similar to previous studies (Barak et al, 2013;Neasta et al, 2010). These findings are interesting given that dopamine D1-like agonists increase AMPAR insertion into NAC MSNs through a process involving CAMKIIa (Anderson et al, 2008;Sun et al, 2008) and that both dopamine and CAMKIIa have been shown to be important for the expression of psychostimulant sensitization and drugseeking behavior (Licata and Pierce, 2003;Loweth et al, 2008;Pierce et al, 1998). In fact, lentiviral-mediated knockdown of CAMKIIa in the NACsh reduced motivation to self-administer cocaine on a PR schedule (Wang et al, 2010a).…”

Psychostimulant-Induced Neuroadaptations in Nucleus Accumbens AMPA Receptor Transmission

“…Calcium influx through L-type channels activates a family of protein kinases including CaMKII, an enzyme that plays a critical role in several forms of neuronal plasticity including changes induced by repeated cocaine exposure (Licata and Pierce 2003;Giordano et al 2010;Loweth and Vezina 2011). Recent work specifically implicates CaMKII in nucleus accumbens AMPA receptor plasticity produced by repeated noncontingent psychostimulant exposure (Boudreau et al 2009;Loweth et al 2010;Schierberl et al 2011) as well as motivation to self-administer amphetamine (Loweth et al 2008(Loweth et al , 2010. After cocaine self-administration, stimulating D1-like dopamine receptors in the medial nucleus accumbens shell promotes the reinstatement of cocaine seeking by serially stimulating L-type calcium channels and phosphorylation of CaMKII (Anderson et al 2008).…”

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

“…The neuronally enriched calcium/calmodulin-dependent protein kinase II (CaMKII) was identified originally as a DFosB target in NAc after cocaine exposure using genomewide approaches (McClung and Nestler, 2003), and we have recently verified this finding by showing that DFosB binding to the CaMKIIa gene promoter is both necessary and sufficient for the kinase's induction in NAc by cocaine . CaMKII in NAc has been linked to altered synaptic function (Huang and Hsu, 2012;Kourrich et al, 2012) and behavioral responses to drugs of abuse (Loweth et al, 2008;Pierce et al, 1998;Robison et al, 2013), but the role of NAc CaMKII in antidepressant action is unknown. Here, we investigated the regulation of NAc CaMKII expression by the antidepressant fluoxetine in the context of chronic social defeat stress.…”