Relapse to cocaine use, the highest among commonly abused illicit drugs, is a serious public problem and represents the primary challenge that exists for the treatment of cocaine addicts. Despite extensive investigation, molecular substrates that can serve as potential therapeutic targets to prevent relapse are limited. Thus, understanding the mechanisms of relapse and identifying new molecular targets for developing pharmacological treatments will greatly aid the field of addiction research. Recent preclinical rodent studies have suggested that craving and drug-induced relapse is mediated by enhanced synaptic AMPAR transmission in the nucleus accumbens (NAc) via GluA2-lacking-, GluA1-containinng-Ca2+-permeable AMPA receptors (CP-AMPARs). Work from our laboratory has identified the Cav1.2 L-type Ca2+ channel (LTCC) as a promising candidate for mediating cocaine-induced long-term behavioral responses and in regulating cell surface AMPARs. Using psychomotor sensitization, we find that Cav1.2 channels in the NAc, mediates cocaine-induced expression of sensitization following extended periods of withdrawal. Using the reinstatement of cocaine CPP model, we find that the LTCC antagonist, diltiazem delivered directly into the NAc blocks cocaine-induced reinstatement of cocaine CPP. Furthermore, we have found that Cav1.2-activated kinase pathways (CaMKII and ERK) regulate cocaine-induced increase in cell surface GluA1, but not GluA2 in the NAc. Thus, in this RO1 application we aim to capitalize on the knowledge we have gained to further explore molecular targets that mediate relapse to cocaine. We will test the central hypothesis that Cav1.2- activated kinase pathways in the NAc mediate cocaine-induced reinstatement of cocaine seeking via increase in NAc synaptic CP-AMPARs. To circumvent the challenge of the lack of Cav1.2-specific blockers, we propose to use the cutting edge Cre-lox P technology to generate local Cav1.2 knockout in the mouse NAc. Kinases will be manipulated by the use of viral vectors.
In Aim 1. 1, adenoassociated viral (AAV) vectors expressing Cre recombinase will be stereotaxically delivered into the NAc of Cav1.2 floxed mice. Mice will be behaviorally tested in cocaine-induced reinstatement of cocaine CPP.
In Aim 1. 2, molecular studies will be pursued to examine Cav1.2-induced AMPAR trafficking.
In Aim 1. 3, electron microscopy will be utilized to examine GluA1 trafficking in dopamine D1 neurons in the NAc shell.
In Aim 2. 1, viral vectors expressing kinase inhibitors will be stereotaxically delivered into the NAc of C57BL/6 mice. Mice will be behaviorally tested in cocaine-induced reinstatement of cocaine CPP.
In Aim 2. 2, role of kinases in AMPAR trafficking will be examined.
In Aim 3, the functional significance of NAc CP-AMPARs, GluA1 trafficking and GluA1 phosphorylation in cocaine-induced reinstatement will be examined using pharmacology and genetic mutant mice. The results obtained from this study could greatly advance the field of cocaine addiction by identifying discrete molecular targets for developing pharmacological treatments for cocaine addicts.

Public Health Relevance

The results of this study have the potential to identify the Cav1.2 L-type Ca2+ channel and its downstream molecular targets as substrates that mediate relapse to cocaine-seeking behavior. These findings will greatly advance our understanding of the molecular basis of cocaine's addictive properties, which has the potential to form the basis for developing novel treatment approaches to benefit cocaine addicts.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Satterlee, John S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Addy, Nii A; Nunes, Eric J; Hughley, Shannon M et al. (2018) The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway. Neuropsychopharmacology 43:2361-2372
Bavley, Charlotte C; Rice, Richard C; Fischer, Delaney K et al. (2018) Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase-mTORC1 Translational Pathway. J Neurosci 38:2780-2795
Kabir, Z D; Che, A; Fischer, D K et al. (2017) Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2?. Mol Psychiatry 22:1096-1109
Marrone, Gina F; Le Rouzic, Valerie; Varadi, Andras et al. (2017) Genetic dissociation of morphine analgesia from hyperalgesia in mice. Psychopharmacology (Berl) 234:1891-1900
Xu, Jin; Lu, Zhigang; Narayan, Ankita et al. (2017) Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine. J Clin Invest 127:1561-1573
Bavley, Charlotte C; Fischer, Delaney K; Rizzo, Bryant K et al. (2017) Cav1.2 channels mediate persistent chronic stress-induced behavioral deficits that are associated with prefrontal cortex activation of the p25/Cdk5-glucocorticoid receptor pathway. Neurobiol Stress 7:27-37
Martínez-Rivera, A; Hao, J; Tropea, T F et al. (2017) Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens. Mol Psychiatry 22:1735-1745
Kabir, Zeeba D; Lee, Anni S; Burgdorf, Caitlin E et al. (2017) Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1. Neuropsychopharmacology 42:2032-2042
Burgdorf, Caitlin E; Schierberl, Kathryn C; Lee, Anni S et al. (2017) Extinction of Contextual Cocaine Memories Requires Cav1.2 within D1R-Expressing Cells and Recruits Hippocampal Cav1.2-Dependent Signaling Mechanisms. J Neurosci 37:11894-11911
Kabir, Zeeba D; Martínez-Rivera, Arlene; Rajadhyaksha, Anjali M (2017) From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms. Neurotherapeutics 14:588-613

Showing the most recent 10 out of 19 publications