Abstract

In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity.

Highlights

  • Acetylcholine is a key intercellular signaling molecule that is released from neurons in the central and peripheral nervous systems as well as from non-neuronal cell types such as immune and epithelial cells (Grando et al, 2007)

  • OVEREXPRESSION OF vesicular acetylcholine transporter (VAChT) IN THE STRIATUM OF ChAT-ChR2-enhanced yellow fluorescent protein (EYFP) BAC TRANSGENIC MICE VAChT protein products were elevated in striatum of ChATChR2-EYFP BAC transgenic mice, as illustrated by immunohistochemistry in brain slices (Figures 1A,B) and by immunoblot quantitation (Figure 1E)

  • Our results are consistent with reports that, relative to controls, mRNA for VAChT is elevated 20-fold and mRNA for ChAT is unchanged in the striatum of ChAT-ChR2-EYFP BAC transgenic mice (Kolisnyk et al, 2013b)

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Summary

Introduction

Acetylcholine is a key intercellular signaling molecule that is released from neurons in the central and peripheral nervous systems as well as from non-neuronal cell types such as immune and epithelial cells (Grando et al, 2007). Cholinergic interneurons are thought to correspond to the tonically active neurons (TANs) that undergo semi-synchronous patterns of firepause-rebound activity upon presentation of learned or salient sensory cues (Kawaguchi, 1993; Aosaki et al, 1995; Matsumoto et al, 2001; Inokawa et al, 2010; Schulz et al, 2011; Zhao et al, 2011; Doig et al, 2014) The activity of these interneurons is controlled by intrinsic membrane activity as well as a variety of inputs, including excitatory inputs from the cerebral cortex (Reynolds and Wickens, 2004; Doig et al, 2014) and the sensoryresponsive parafascicular nucleus of the thalamus (Lapper and Bolam, 1992), local inhibitory input (Gonzales et al, 2013; Doig et al, 2014), and modulatory inputs from cholinergic and dopaminergic fibers (Aosaki et al, 1994; Dautan et al, 2014). These data are consistent with the notion that the cuerelated activity of cholinergic interneurons of the striatum serves to re-bias action selection driven by cortico-basal ganglia circuits

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