VGLUT3 gates psychomotor effects induced by amphetamine

Abstract

Several subtypes of modulatory neurons co‐express vesicular glutamate transporters (VGLUTs) in addition to their cognate vesicular transporters. These neurons are believed to establish new forms of neuronal communication. The atypical VGLUT3 is of particular interest since in the striatum this subtype is found in tonically active cholinergic interneurons (TANs) and in a subset of 5‐HT fibers. The striatum plays a major role in psychomotor effects induced by amphetamine. Whether and how VGLUT3‐operated glutamate/ACh or glutamate/5HT co‐transmissions modulates psychostimulants‐induced maladaptive behaviors is still unknown. Here, we investigate the involvement of VGLUT3 and glutamate co‐transmission in amphetamine‐induced psychomotor effects and stereotypies. Taking advantage of constitutive and cell‐type specific VGLUT3‐deficient mouse lines, we tackled the hypothesis that VGLUT3 could gate psychomotor effects (locomotor activity and stereotypies) induced by acute or chronic administration of amphetamine. Interestingly, VGLUT3‐null mice demonstrated blunted amphetamine‐induced stereotypies as well as reduced striatal ∆FosB expression. VGLUT3‐positive varicosities within the striatum arise in part from 5HT neurons. We tested the involvement of VGLUT3 deletion in serotoninergic neurons in amphetamine‐induced stereotypies. Mice lacking VGLUT3 specifically in 5HT fibers showed no alteration to amphetamine sensitivity. In contrast, specific deletion of VGLUT3 in cholinergic neurons partially phenocopied the effects observed in the constitutive knock‐out mice. Our results show that constitutive deletion of VGLUT3 modulates acute and chronic locomotor effects induced by amphetamine. They point to the fact that the expression of VGLUT3 in multiple brain areas is pivotal in gating amphetamine‐induced psychomotor adaptations. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Psychostimulant Drugs Activate Cell-type Specific and Topographic cFos Expression in the Lumbar Spinal Cord

“…In rodents, a single administration of d-amphetamine induces a broad repertoire of motor behaviors ranging from increased locomotion (from 2 to 5 mg/kg) to repetitive/stereotyped motor sequences (above 5 mg/kg) (Crittenden et al, 2014;Mansouri-Guilani et al, 2019;Valjent et al, 2010;Yates et al, 2007). Our results indicate that the latter are correlated with an increased expression of pS32-cFos in neurons in the ventral horn of the spinal cord, a spinal region harboring neural circuits dedicated to execution and generation of rhythmic motor behaviors (Grillner and El Manira, 2020).…”

Sucrose Consumption Alters Serotonin/Glutamate Co-localisation Within the Prefrontal Cortex and Hippocampus of Mice

“…These non-serotonergic neurons have also been implicated in reward ( McDevitt et al, 2014 ) and have even been shown to mimic addictive phenotypes produced by VGLUT3 knockout. For example, the knockout of specifically cholinergic, but not serotonergic VGLUT3 neurons, is responsible for the aforementioned amphetamine-sensitisation ( Mansouri-Guilani et al, 2019 ). It is therefore important that future studies be performed which immunologically dissect these VGLUT3 projections, for example by additionally probing for acetylcholine axons.…”

Targeting VGLUT Machinery: Implications on mGluR5 Signaling and Behavior

“…Given its involvement in striatal circuitry, VGLUT3 signaling regulates the phenotypic behavior induced by drugs of abuse. Global loss of VGLUT3 blunted acute and chronic amphetamine-induced stereotypies, an effect coupled with marked reduction in ΔFosB expression levels in murine striatal tissues (Mansouri-Guilani et al, 2019). Furthermore, striatal VGLUT3 signaling regulates cocaine rewarding properties, albeit in a manner different from mGluR5.…”