The effect of zeta inhibitory peptide (ZIP) on cocaine induced neuroadaptations in the nucleus accumbens

• Applicant: Dr. Andre Deutschmann
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Anatomy and Physiology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 367294095

Cocaine addiction is a chronic, relapsing disorder characterized by continued use in the face of adverse consequences. However, a safe, efficacious pharmacological treatment for cocaine addiction remains to be discovered. Neuroadaptations within the corticolimbic glutamatergic system occur following cocaine use. Interactions between glutamatergic and dopaminergic projections to the nucleus accumbens (NAc) are thought to play a central role in the motivational aspects of drug seeking and may also shape vulnerability to relapse. The ability of these corticolimbic glutamate synapses to exhibit experience-dependent plasticity is essential for learning and updating information. Within the NAc, long-term depression (LTD) is critical for depotentiating synapses that have been enhanced during the acquisition of skill learning or conditioned-cue associations. Chronic cocaine administration leads to blunted LTD in the NAc of mice. Understanding how to reverse this anaplasticity may help in the development of treatments for addiction. Zeta-inhibitory peptide (ZIP) is a cell-penetrating peptide, that has been used extensively in the memory literature to support a role for PKMζ in maintaining memory. Additionally, ZIP is able to impair several types of memory in PKMζ knockouts suggesting that the actions of ZIP are independent of PKMζ. Our lab has shown that infusion of zeta-inhibitory peptide into the NAc persistently blocks the ability of cues to reinstate cocaine seeking, even when the peptide is no longer present in the brain. To date, no other studies have demonstrated a compound that blocks cocaine reinstatement in this type of persistent manner. Therefore, understanding the mechanism of action of ZIP could have significant impact on our understanding of cocaine relapse and provide clear avenues for novel therapeutic treatments. Cocaine self-administration leads to anaplasticity within the NAc, specifically impairing LTD. I hypothesize that the persistent behavioral effects of ZIP rely upon its ability to reverse cocaine-induced impairments in LTD. To test this hypothesis I propose to examine the ability of ZIP to rescue two forms of LTD in the NAc. Additionally, I will examine whether ZIP is effective in blunting reinstatement of cocaine seeking in a GluA2 phosphomutant mouse that does not exhibit LTD in the NAc. As LTD cannot be rescued by ZIP in this mouse line, this would allow us to demonstrate that the ability of ZIP to rescue LTD is necessary for the behavioral effects. Along with these changes in long-term synaptic plasticity, chronic cocaine also leads to changes in the synaptic strength. Therefore I will also examine the effect of ZIP on spontaneous excitatory postsynaptic currents and AMPA/NMDA ratio. These results will provide critical insights into the role of cocaine-induced synaptic plasticity in reinstatement behavior in general and more specifically provide information about the mechanism by which ZIP can block this reinstatement.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Lisa Briand, Ph.D.