Abstract
Adolescent psychostimulant abuse has been on the rise over the past decade. This trend has demonstrable ramifications on adolescent behavior and brain morphology, increasing risk for development of addiction during adolescence and in later adulthood. Neuroimmune substrates are implicated in the etiology of substance use disorders. To add to this body of work, the current study was developed to explore the role of a chemokine receptor, CXC Chemokine Receptor 4 (CXCR4), in the development of amphetamine (AMPH) sensitization. We targeted CXCR4 as it is implicated in developmental processes, dopaminergic transmission, neuroimmune responses, and the potentiation of psychostimulant abuse pathology. To evaluate the role of CXCR4 activity on the development of AMPH sensitization, a CXCR4 antagonist (Plerixafor; AMD3100) was administered to rats as a pretreatment variable. Specifically, adolescent Long Evans male rats (N = 37) were divided into four groups: (1) AMD3100 (IP, 4.0 mg/kg) + AMPH (IP, 4.0 mg/kg), (2) saline (SAL; 0.9% NaCl) + AMPH, (3) AMD3100 + SAL, and (4) SAL + SAL. Animals were first habituated to locomotor activity (LMA) chambers, then injected with a pretreatment drug (AMD3100 or SAL) followed by AMPH or SAL every other for four days. After a one-week withdrawal period, all animals were administered a low challenge dose of AMPH (IP, 1.0 mg/kg). AMPH-injected rats displayed significantly more locomotor activity compared to controls across all testing days. CXCR4 antagonism significantly attenuated AMPH-induced locomotor activity. On challenge day, AMD3100 pre-treated animals exhibited diminutive AMPH-induced locomotor activity compared to SAL pre-treated animals. Postmortem analyses of brain tissue revealed elevated CXCR4 protein levels in the striatum of all experimental groups. Our results implicate CXCR4 signaling in the development of AMPH sensitization and may represent an important therapeutic target for future research in psychostimulant abuse.
Highlights
Psychostimulant drug abuse during adolescence potentiates the risk for progression to drug dependence in adulthood for human [1, 2] and rodent [3, 4] populations
The present study examined the role of CXC Chemokine Receptor 4 (CXCR4) antagonism on the development of AMPH sensitization in a cohort of adolescent male Long Evans rats
The current study evaluated the role of CXCR4 signaling in the development of AMPHinduced locomotor sensitization in adolescent male Long Evans rats
Summary
Psychostimulant drug abuse during adolescence potentiates the risk for progression to drug dependence in adulthood for human [1, 2] and rodent [3, 4] populations. Preclinical and clinical models implicate adolescence, compared to adulthood, as a vulnerable developmental period for the development of psychostimulant-induced neurobehavioral alterations [1, 7, 8, as reviewed by 9]. In rodent and human neural in vitro [24] and in vivo models [25], CXCR4 may determine cell fate by activating secondary messengers like extracellular signal-regulated kinases 1/2 and Jun N-terminal kinase to reduce cyclic adenosine monophosphate and increase intracellular calcium levels. These activities lower the threshold for action potentials, altering neuronal and glial signaling. Clinical and rodent models demonstrate anti-inflammatory agents as effective therapies for psychiatric and substance use disorders [as reviewed by 39, 40]
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