A Role for p38 Mitogen-activated Protein Kinase Mediated Threonine 30 Dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference [Neurobiology]

February 27th, 2015 by Mannangatti, P., Narasimha Naidu, K., Damaj, M. I., Ramamoorthy, S., Jayanthi, L. D.

The noradrenergic and p38 mitogen activated protein kinase (p38 MAPK) systems are implicated in cocaine-elicited behaviors. Previously, we demonstrated a role for p38 MAPK-mediated norepinephrine transporter (NET) T30-phosphorylation in cocaine-induced NET upregulation (1). The present study explored the functional interaction between p38 MAPK-mediated NET regulation and cocaine-induced behaviors. In-vitro cocaine treatment of mouse prefrontal cortex (PFC) synaptosomes resulted in enhanced NET function, surface expression and phosphorylation. Pretreatment with PD169316, a p38 MAPK inhibitor completely blocked cocaine-mediated NET upregulation and phosphorylation. In mice, in-vivo administration of p38 MAPK inhibitor SB203580 completely blocked cocaine-induced NET upregulation and p38 MAPK activation in the PFC and nucleus accumbens (NAc). When tested for cocaine-induced locomotor sensitization and conditioned place preference (CPP), mice receiving SB203580 on cocaine challenge day or on post conditioning test day exhibited significantly reduced cocaine sensitization and CPP. TAT-peptide strategy was utilized to test the involvement of NET-T30 motif. In-vitro treatment of synaptosomes with TAT-NET-T30 (wild-type peptide) completely blocked cocaine-mediated NET upregulation and phosphorylation. In-vivo administration of TAT-NET-T30 peptide but not TAT-NET-T30A (mutant peptide) completely blocked cocaine-mediated NET upregulation and phosphorylation. In cocaine CPP paradigm, mice receiving TAT-NET-T30, but not TAT-NET-T30A on post-conditioning test day exhibited significantly reduced cocaine CPP. Following extinction, TAT-NET-T30 when given prior to cocaine challenge, significantly reduced reinstatement of cocaine-CPP. These results demonstrate that the direct inhibition of p38 MAPK or the manipulation of NET-T30 motif/phosphorylation via TAT-peptide strategy prevents cocaine-induced NET upregulation, locomotor sensitization and CPP suggesting a role for T30-linked NET regulation in cocaine-elicited behaviors.
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