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Three subtypes of vesicular transporters accumulate glutamate into synaptic vesicles to promote its vesicular release. One of the subtypes, VGLUT3, is expressed in neurons, including cholinergic striatal interneurons, that are known to release other classical transmitters. Here we showed that disruption of the Slc17a8 gene (also known as Vglut3) caused an unexpected hypocholinergic striatal phenotype. Vglut3−/− mice were more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates, and acetylcholine release was decreased in striatum slices lacking VGLUT3. These phenotypes were associated with a colocalization of VGLUT3 and the vesicular acetylcholine transporter (VAChT) in striatal synaptic vesicles and the loss of a synergistic effect of glutamate on vesicular acetylcholine uptake. We propose that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicular filling. Our study reveals a previously unknown effect of glutamate on cholinergic synapses with potential functional and pharmacological implications. [ABSTRACT FROM AUTHOR]

We previously reported that the CB1 cannabinoid receptor antagonist, rimonabant, impaired the acquisition and the short-term (24 h), but not long-term (3 weeks), expression of conditioned place preference (CPP) induced by nicotine in rats. To assess the time interval of efficacy of a single pretest injection of rimonabant to abolish nicotine–CPP, and the effects of chronic CB1 receptor blockade on long-term expression of nicotine–CPP. Wistar rats were conditioned to nicotine (0.06 mg/kg, subcutaneous) using an unbiased one-compartment procedure. Two test sessions were conducted 24 h (without injection) and 1, 2, or 3 weeks later. Rimonabant (3 mg/kg, intraperitoneal) or vehicle was administered daily between the two test sessions. In addition, the CB1-stimulated [35S]GTP-γ-S binding was assessed in rats from the 3-week experiment. The capacity of a single injection of rimonabant (3 mg/kg, 30 min pretest) to block the expression of nicotine–CPP disappeared within 1 week after conditioning. Daily administrations of rimonabant for 6, 13, or 20 days postacquisition did not impair nicotine–CPP but allowed an additional pretest injection of rimonabant to retain its capacity to abolish long-term expression of nicotine–CPP. The CB1 receptor-mediated G-protein signaling was not altered in various brain areas of rats given rimonabant for 3 weeks. The endocannabinoid system is essential to the expression of nicotine–CPP during less than 1 week after conditioning but not later. However, endocannabinoid-dependent mechanisms are critically involved in the development of the neuroadaptive changes responsible for the shift from CB1-dependent to CB1-independent expression of nicotine incentive learning. [ABSTRACT FROM AUTHOR]