CHEMOKINE MODULATION OF MDPV-INDUCED BEHAVIOR AND NEUROPLASTICITY

Abstract

Psychostimulant abuse is a major public health concern yet no FDA-approved medications exist. Synthetic cathinones (“bath salts”) are a class of psychostimulants that have emerged relatively recently worldwide. One synthetic cathinone, MDPV (3,4-methylenedioxypyrovalerone) is mechanistically similar to cocaine but is over ten times more potent, possesses high abuse potential, and is relatively understudied. Recent studies have revealed involvement of inflammatory proteins called chemokines in the rewarding effects of MDPV and the mechanistically similar drug, cocaine. We and others have shown that the chemokine-receptor ligand pair CXCL12-CXCR4 is recruited in the rewarding effects of cocaine and MDPV. Humans and animal models of cocaine addiction have dysregulated CXCL12 and the commercially-available CXCR4 antagonist, AMD3100, can reverse cocaine use and relapse in preclinical models of addiction. Specifically, AMD3100 reduces self-administration and reinstatement to cocaine-seeking with concomitant alterations in CXCL12 gene expression in the midbrain. Here, I employ several complementary methods to demonstrate that AMD3100 also reverses MDPV-elicited behaviors. I demonstrate that (i) AMD3100 reverses MDPV-induced hyperlocomotion, conditioned place preference (preclinical model of drug reward), self-administration and reinstatement to MDPV-seeking behavior; (ii) AMD3100 can rescue MDPV-induced deficits in measures of anxiety and recognition memory shortly after a binge; and (iii) repeated MDPV exposure upregulates CXCL12 gene expression in the nucleus accumbens with concomitant downregulation of dendrite morphometrics and a related synapse scaffolding protein gene expression. These findings implicate CXCR4-CXCL12 signaling in the modulation of MDPV-elicited behaviors, suggesting that AMD3100 is a viable therapeutic option for the effects of this synthetic cathinone.