Abstract

Exposure to psychostimulants increases brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the cerebral cortex and subcortical structures. Because BDNF is co-localized with dopamine and glutamate in afferents to the striatum of rats, it may be co-released with those neurotransmitters upon stimulation. Further, there may be an interaction between the intracellular signaling cascades activated by dopamine, glutamate, and TrkB receptors in medium spiny striatal neurons. In the present study, the effect of acute amphetamine administration on TrkB phosphorylation, as an indirect indicator of activation, and striatal gene expression, was evaluated. In Experiment 1, 15 min or 2 h after a single saline or amphetamine (2.5 mg/kg, i.p.) injection, the caudate–putamen (CPu), nucleus accumbens (NAc), and dorsomedial prefrontal cortex (dmPFC) were extracted and processed for phospho (p)-TrkB immunoreactivity. Immunoprecipitation analyses indicated that neither the tyrosine phosphorylation (p-Tyr) or autophosphorylation sites of TrkB (706) were changed in NAc, CPu, or dmPFC 15 min after amphetamine administration. In contrast, p-Tyr and the PLCγ phosphorylation site of TrkB (816) were increased in the NAc and CPu 2 h after amphetamine. In Experiment 2, intra-striatal infusion of the tyrosine kinase inhibitor, K252a, increased amphetamine-induced vertical activity but not total distance traveled. In addition, K252a inhibited amphetamine-induced preprodynorphin, but not preproenkephalin, mRNA expression in the striatum. These data indicate that acute amphetamine administration induces p-TrkB activation and signaling in a time- and brain region-dependent manner and that TrkB/BDNF signaling plays an important role in amphetamine-induced behavior and striatal gene expression.

Highlights

  • Amphetamine (AMPH) triggers behavioral activation and gene expression in the striatum by integrating dopamine and glutamate inputs to medium spiny neurons (MSNs) that project to the dorsal and ventral pallidum and ventral midbrain

  • P-Tyr, p-TrkB 706, and p-TrkB 816 (PLCγ phosphorylation site) immunoreactivities were significantly increased in the CPu 2 h after amphetamine (Figures 1A–D)

  • No differences were detected in the dorsomedial prefrontal cortex (dmPFC) 2 h after AMPH injection

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Summary

Introduction

Amphetamine (AMPH) triggers behavioral activation and gene expression in the striatum by integrating dopamine and glutamate inputs to medium spiny neurons (MSNs) that project to the dorsal and ventral pallidum and ventral midbrain. Activation of genes/proteins that mediate or temper the psychomotor response to stimulants is triggered primarily by D1 dopamine–Gs-coupledPKA signaling (McGinty et al, 2008). Dopamine and glutamatergic afferents to the striatum express brain-derived neurotrophic factor (BDNF) that activates TrkB receptors present on all MSNs (Freeman et al, 2003). Overlapping signaling cascades activated by these MSN inputs suggest that the striatum responds to an initial, moderate dose of AMPH with a complex repertoire that both mediates psychomotor effects and simultaneously functions to bring the network back to homeostasis.

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