Authors: Kathryn Schierberl, Thomas Giordano, Shirish Satpute, Jin Hao, Gagandeep Kaur, Franz Hofmann, Sven Moosmang, Joerg Striessnig and Anjali Rajadhyaksha

Kathryn Schierberl

Graduate Program in Neuroscience; Weill Cornell Medical College; New York, NY USA

Thomas Giordano

Martinos Center for Biomedical Engineering; Massachusetts General Hospital; Harvard Medical School; Charlestown, MA USA; Department of Pediatrics; Division of Pediatric Neurology; Weill Cornell Medical College; New York, NY USA

Shirish Satpute

Martinos Center for Biomedical Engineering; Massachusetts General Hospital; Harvard Medical School; Charlestown, MA USA

Jin Hao

Department of Pediatrics; Division of Pediatric Neurology; Weill Cornell Medical College; New York, NY USA

Gagandeep Kaur

Department of Pediatrics; Division of Pediatric Neurology; Weill Cornell Medical College; New York, NY USA

Franz Hofmann

Research Group 923; Technical University Munich; Munich, Germany

Sven Moosmang

Institute for Pharmacology; Technical University Munich; Munich, Germany

Joerg Striessnig

Institute of Pharmacy, Pharmacology and Toxicology; University of Innsbruck; Innsbruck, Austria

Anjali Rajadhyaksha

Corresponding author: amr2011@med.cornell.edu
Graduate Program in Neuroscience; Weill Cornell Medical College; New York, NY USA; Martinos Center for Biomedical Engineering; Massachusetts General Hospital; Harvard Medical School; Charlestown, MA USA; Department of Pediatrics; Division of Pediatric Neurology; Weill Cornell Medical College; New York, NY USA

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Abstract:

AMPA receptor (AMPAR) plasticity at glutamatergic synapses in the mesostriatal dopaminergic pathway has been implicated in persistent cocaine-induced behavioral responses; however, the precise mechanism underlying these changes remains unknown. Utilizing cocaine psychomotor sensitization in mice we find that repeated cocaine results in a basal reduction of Ser 845 GluA1 and cell surface GluA1 levels in the dorsal striatum (dStr) following a protracted withdrawal period, an adaptation that is dependent on Ca_v1.3 channels but not those expressed in the VTA. We find that the basally-induced decrease in this phosphoprotein is the result of recruitment of the striatal dopamine D2 pathway, as evidenced by enhanced levels of D2 receptor (D2R) mRNA expression and D2R function as examined using the D2R antagonist, eticlopride, as well as alterations in the phosphorylation status of several downstream molecular targets of D2R’s, including CREB, DARPP-32, Akt and GSK3β. Taken together with our recently published findings examining similar phenomena in the nucleus accumbens (NAc), these results underscore the utilization of divergent molecular mechanisms in the dStr, in mediating cocaine-induced persistent behavioral changes.