Reversing Cocaine-Induced Plasticity with Zeta Inhibitory Peptide

Cocaine-induced plasticity persists during abstinence and is thought to underlie cue-evoked craving. Reversing this plasticity could provide an opportunity for therapeutic intervention. Converging evidence suggest that zeta inhibitory peptide (ZIP) eliminates memories for experience-dependent behaviors, including conditioned drug associations. However, the effect of ZIP on reward seeking and drug-induced plasticity is unknown. The current study examined the effect of ZIP administration in the nucleus accumbens on reinstatement (RI) of cocaine seeking, a rodent model of relapse. We demonstrate that intra-accumbal ZIP administration blocks cocaine-primed RI in rats when administered 24 h or 1 week before testing. These effects of ZIP on drug seeking are specific, as we did not see any effect of ZIP on RI of sucrose seeking. ZIP is a synthetic compound designed to inhibit the atypical PKC, PKMζ, a protein implicated in learning and memory. However, recent evidence from PKMζ-knock-out (KO) mice suggests that ZIP may function through alternative mechanisms. In support of this, we found that ZIP was able to block cue-induced RI in PKMζ-KO mice. One possible mechanism underlying addictive phenotypes is the ability of cocaine to block further plasticity. We hypothesized that ZIP may be working to reverse this anaplasticity. Although ZIP has no effect on accumbal LTD in slices from naive or yoked saline mice, it is able to restore both NMDA-dependent and mGluR5-dependent LTD in animals after cocaine self-administration and withdrawal. These findings demonstrate that intra-accumbal ZIP persistently reverses cocaine-induced behavioral and synaptic plasticity in male and female rodents.SIGNIFICANCE STATEMENT Zeta-inhibitory peptide (ZIP) has been shown to disrupt memory maintenance for experience-dependent behaviors. We examined the effect of ZIP infused into the nucleus accumbens on the reinstatement (RI) of cocaine seeking. We found that intra-accumbal ZIP blocked RI of cocaine seeking 24 h and 1 week later. This effect was specific to RI of cocaine seeking as ZIP did not disrupt RI of food seeking. In conjunction with these behavioral studies we examined the ability of ZIP to reverse cocaine-induced deficits in LTD. We found that ZIP was able to rescue two forms of LTD in cocaine-experienced mice. These studies demonstrate that ZIP is able to reverse cocaine-induced behavioral and synaptic plasticity in a persistent manner.