Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5

Abstract

Repeated exposure to cocaine produces an enduring increase in dendritic spine density in adult rat nucleus accumbens. It has been shown previously that chronic cocaine administration increases the expression of cyclin-dependent kinase-5 in this brain region and that this neuronal protein kinase regulates cocaine-induced locomotor activity. Moreover, cyclin-dependent kinase-5 has been implicated in neuronal function and synaptic plasticity. Therefore, we studied the involvement of this enzyme in cocaine's effect on dendritic spine density. Adult male rats, receiving intra-accumbens infusion of the cyclin-dependent kinase-5 inhibitor roscovitine or saline, were administered a 28-day cocaine treatment regimen. Animals were killed 24-48 h after the final cocaine injection and their brains removed and processed for Golgi-Cox impregnation. Our findings demonstrate that roscovitine attenuates cocaine-induced dendritic spine outgrowth in nucleus accumbens core and shell and such inhibition reduces spine density in nucleus accumbens shell of control animals. These data indicate that cyclin-dependent kinase-5 is involved in regulation of, as well as cocaine-induced changes in, dendritic spine density. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2015 January 16. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLong-term exposure to psychostimulant drugs produces enduring neuronal alterations in intracellular signaling pathways and structural changes in dendritic morphology (Nestler, 2001). For example, repeated exposure to cocaine increases spine density on dendrites of dopaminoceptive medium spiny neurons in the shell (but not core) division of nucleus accumbens (NAc) (Robinson and Kolb, 1999;Robinson et al., 2001) and increases the expression of several transcription factors that mediate gene expression in these neurons (Nestler, 2001). Recently, cyclin-dependent kinase-5 (Cdk5) was identified as a downstream target of the transcription factor ΔFosB which is persistently expressed in NAc of mice repeatedly treated with cocaine. Overexpression of ΔFosB increases Cdk5 expression and activity (Kelz et al., 1999;Bibb et al., 2001). Cdk5 is a protein serine/threonine kinase that regulates neurite outgrowth (Dhavan and Tsai, 2001) and modulates dopamine signaling (Bibb et al., 1999a). Interestingly, acute inhibition of Cdk5 activity in NAc potentiates the locomotor effects of chronic cocaine (Bibb et al., 2001). The purpose of the present study was to determine if this neuronal protein kinase is involved in cocaine-induced dendritic spine proliferation in rat NAc.The potent Cdk5 inhibitor roscovitine (or vehicle) was bilaterally infused into NAc shell via ALZET mini-pump. The effect of a 4-week regimen of repeated i.p. injections of cocaine (or saline) on dendritic spine density was assessed by a modified Golgi staining technique. Detailed anatomical features along dendrites were easily discernible and dendritic spines were readily resolved (Fig. 1). Re...

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…As observed for psychomotor stimulants, nicotine also increases spine density in both PFC and the shell subregion of the NAC [208,209]. The structural changes induced by the above drugs are detectable at 24-48 hrs following discontinuation of chronic drug treatment [207] and can be observed for up 3.5 months [202,209]. Similar to nicotine and psychomotor stimulants, the structural plasticity associated with morphine treatment has been described a month after the last treatment [210,211].…”

“…In all studies to date, both non-contingent and contingent cocaine or amphetamine administration were found to increase spine density, as well as dendritic branching on medium spiny GABAergic neurons within both the shell and core subregions of the NAC [198][199][200][201][202][203][204][205][206][207]. Similarly, repeated treatment with both psychomotor stimulants increase spine density and branching of the apical, and to a lesser extent the basalar, dendrites of glutamatergic pyramidal neurons within the PFC [198][199][200][201]204,205].…”

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

“…Importantly, manipulations, such as inhibiting cyclindependent kinase 5 (cdk5), which are known to prevent drug-induced spine proliferation in the NAcc (Norrholm et al, 2003), also prevent the development of conditioning but spare sensitization (Singer et al, 2014b). Although we did not observe spine alterations in ΔFosB+ neurons in the present study, it remains possible under some conditions for changes to occur in these neurons that enable the development of conditioned associations, as ΔFosB is a transcription factor for the cdk5 gene.…”

Transcriptional mechanisms of addiction: role of ΔFosB

“…Cdk5 is also induced by chronic cocaine in the nucleus accumbens, an effect blocked upon DcJun expression, and DFosB binds to and activates the Cdk5 gene through an AP-1 site in its promoter (Chen et al 2000;Peakman et al 2003). Cdk5 is an important target of DFosB since its expression has been directly linked to changes in the phosphorylation state of numerous synaptic proteins including glutamate receptor subunits (Bibb et al 2001), as well as increases in dendritic spine density (Norrholm et al 2003;Lee et al 2006), in the nucleus accumbens, which are associated with chronic cocaine administration (Robinson & Kolb 2004). Recently, the regulation of Cdk5 activity in nucleus accumbens has been directly linked to alterations in the behavioural effects of cocaine (Taylor et al 2007).…”