Vesicular monoamine transporter 2 mediates fear behavior in mice

A subset of people exposed to a traumatic event develops post‐traumatic stress disorder (PTSD), which is associated with dysregulated fear behavior. Genetic variation in SLC18A2, the gene that encodes vesicular monoamine transporter 2 (VMAT2), has been reported to affect risk for the development of PTSD in humans. Here, we use transgenic mice that express either 5% (VMAT2‐LO mice) or 200% (VMAT2‐HI mice) of wild‐type levels of VMAT2 protein. We report that VMAT2‐LO mice have reduced VMAT2 protein in the hippocampus and amygdala, impaired monoaminergic vesicular storage capacity in both the striatum and frontal cortex, decreased monoamine metabolite abundance and a greatly reduced capacity to release dopamine upon stimulation. Furthermore, VMAT2‐LO mice showed exaggerated cued and contextual fear expression, altered fear habituation, inability to discriminate threat from safety cues, altered startle response compared with wild‐type mice and an anxiogenic‐like phenotype, but displayed no deficits in social function. By contrast, VMAT2‐HI mice exhibited increased VMAT2 protein throughout the brain, higher vesicular storage capacity and greater dopamine release upon stimulation compared with wild‐type controls. Behaviorally, VMAT2‐HI mice were similar to wild‐type mice in most assays, with some evidence of a reduced anxiety‐like responses. Together, these data show that presynaptic monoamine function mediates PTSD‐like outcomes in our mouse model, and suggest a causal link between reduced VMAT2 expression and fear behavior, consistent with the correlational relationship between VMAT2 genotype and PTSD risk in humans. Targeting this system is a potential strategy for the development of pharmacotherapies for disorders like PTSD.     

Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens

Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study, we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is, the measurement of dopamine 'transients'. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to ～500?nM, presumably by inducing reverse transport by dopamine transporter (DAT). Taken together, data presented here show that average extracellular dopamine in the NAc is low (20-30?nM) and largely arises from phasic dopamine transients.