The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

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.

Formation of a morphine-conditioned place preference does not change the size of evoked potentials in the ventral hippocampus-nucleus accumbens projection.

In opioid addiction, cues and contexts associated with drug reward can be powerful triggers for drug craving and relapse. The synapses linking ventral hippocampal outputs to medium spiny neurons of the accumbens may be key sites for the formation and storage of associations between place or context and reward, both drug-related and natural. To assess this, we implanted rats with electrodes in the accumbens shell to record synaptic potentials evoked by electrical stimulation of the ventral hippocampus, as well as continuous local-field-potential activity. Rats then underwent morphine-induced (10 mg/kg) conditioned-place-preference training, followed by extinction. Morphine caused an acute increase in the slope and amplitude of accumbens evoked responses, but no long-term changes were evident after conditioning or extinction of the place preference, suggesting that the formation of this type of memory does not lead to a net change in synaptic strength in the ventral hippocampal output to the accumbens. However, analysis of the local field potential revealed a marked sensitization of theta- and high-gamma-frequency activity with repeated morphine administration. This phenomenon may be linked to the behavioral changes-such as psychomotor sensitization and the development of drug craving-that are associated with chronic use of addictive drugs.