Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3−/− mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3−/− mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

We have previously demonstrated that exposure to high fat (HF) during early development alters the presynaptic regulation of mesolimbic dopamine (DA), and increases incentive motivation for HF food rewards. The goal of the present experiments was to examine the long-term consequences of early exposure to HF on anticipatory and consumatory nucleus accumbens (NAc) DA responses to HF food rewards. Mothers were maintained on a HF (30% fat) or control diet (CD; 5% fat) from gestation day 13 to postnatal day 22 when offspring from both diet groups were weaned and maintained on the CD until adulthood. In vivo NAc DA responses to food anticipation and consumption were measured in a Pavlovian conditioning paradigm using voltammetry in freely moving rats. HF-exposed offspring displayed reduced NAc DA responses to a tone previously paired with the delivery of HF food rewards. In an unconditioned protocol, consumatory NAc DA responses could be isolated, and were similar in HF and control offspring. These data demonstrate that exposure to HF through maternal diet during early development might program behavioral and functional responses associated with mesolimbic DA neurotransmission, thus leading to an increased HF feeding and obesity.

Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out. We investigate here whether apoE is involved in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory reinnervation mechanisms. We examined the modifications in gene expression and protein levels of apoE and its key receptors, the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), as well as the reactive astrocyte marker glial fibrillary acidic protein (GFAP) in different brain structures throughout the degenerative and reactive regenerative period. In the striatum, upregulations of GFAP, apoE and LRP mRNAs at 1 day post-treatment were associated with marked decreases in dopamine (DA) levels, loss in tyrosine hydroxylase protein content, as well as to a compensatory increase in dopaminergic metabolism. Subsequent return to near control levels coincided with indications of reinnervation in the striatum: all consistent with a role of apoE during the degenerative process and regenerative period. We also found that this cascade was activated in the hippocampus and more so than in the striatum, with a particular contribution of LDLR expression. The hippocampal activation did not correlate with substantial neurochemical reductions but appears to reflect local subtle alteration of DA metabolism and the regulation of plasticity-related event in this structure. This study provides first evidence of an activation of the apoE/apoE receptors cascade in a mouse model of PD, specifically in the MPTP-induced deafferentation of the striatum. Results are also quite consistent with the postulated role of apoE in brain repair but, raise the issue of possible lesion- and region-specific alterations in gene expression.

High caloric intake during early postnatal development can have long term consequences for the offspring. We previously reported that the adult offspring of dams fed a high-fat diet during the last week of gestation and throughout lactation display blunted locomotor response to amphetamine (AMP) and reduced sensitization to the drug compared to offspring of control diet dams. Here, we report that the subsensitivity of high-fat offspring to AMP's locomotor stimulant action reflects, at least in part, altered regulation of nucleus accumbens (NAc) dopamine (DA) transmission. When compared to controls, the DA response of high-fat animals to AMP, as measured with microdialysis, was attenuated in the NAc, but unaffected in the prefrontal cortex (PFC). A relatively higher activity of NAc synaptosomal DA transporter sites without changes in vesicular monoamine transporter (VMAT) uptake capacity was also observed in high-fat offspring. Moreover, ventral tegmental area (VTA) D2 receptor mRNA levels were decreased in high-fat offspring, suggesting a reduction in DA release-regulating D2 autoreceptors in terminal regions such as the NAc. The magnitude of locomotor response to D2/3 receptor activation (with quinpirole) was greater in high-fat than in control animals despite having comparable postsynaptic D2 mRNA levels in the NAc. Finally, while operant responding for a sugar-enriched food reward did not differ between diet groups, high-fat offspring displayed increased operant responding for a fat-enriched reward compared to controls. These findings add to mounting evidence that early life exposure to elevated dietary maternal fat can lead to long lasting changes in DA-mediated behavioral responses to stimulant drugs and fat-enriched foods.