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

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Title: The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.
Authors: Sakae, D Y, Marti, F, Lecca, S, Vorspan, F, Martín-García, E, Morel, L J, Henrion, A, Gutiérrez-Cuesta, J, Besnard, A, Heck, N, Herzog, E, Bolte, S, Prado, V F, Prado, M A M, Bellivier, F, Eap, C B, Crettol, S, Vanhoutte, P, Caboche, J, Gratton, A
Source: Molecular Psychiatry. Nov2015, Vol. 20 Issue 11, p1448-1459. 12p.
Subjects: Cocaine abuse, Cholinergic mechanisms, Nucleus accumbens, Glutamate receptors, Dopamine receptors, Dopamine regulation, Signaling (Psychology), Psychology
Abstract: 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. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.
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  Data: <searchLink fieldCode="AR" term="%22Sakae%2C+D+Y%22">Sakae, D Y</searchLink><br /><searchLink fieldCode="AR" term="%22Marti%2C+F%22">Marti, F</searchLink><br /><searchLink fieldCode="AR" term="%22Lecca%2C+S%22">Lecca, S</searchLink><br /><searchLink fieldCode="AR" term="%22Vorspan%2C+F%22">Vorspan, F</searchLink><br /><searchLink fieldCode="AR" term="%22Martín-García%2C+E%22">Martín-García, E</searchLink><br /><searchLink fieldCode="AR" term="%22Morel%2C+L+J%22">Morel, L J</searchLink><br /><searchLink fieldCode="AR" term="%22Henrion%2C+A%22">Henrion, A</searchLink><br /><searchLink fieldCode="AR" term="%22Gutiérrez-Cuesta%2C+J%22">Gutiérrez-Cuesta, J</searchLink><br /><searchLink fieldCode="AR" term="%22Besnard%2C+A%22">Besnard, A</searchLink><br /><searchLink fieldCode="AR" term="%22Heck%2C+N%22">Heck, N</searchLink><br /><searchLink fieldCode="AR" term="%22Herzog%2C+E%22">Herzog, E</searchLink><br /><searchLink fieldCode="AR" term="%22Bolte%2C+S%22">Bolte, S</searchLink><br /><searchLink fieldCode="AR" term="%22Prado%2C+V+F%22">Prado, V F</searchLink><br /><searchLink fieldCode="AR" term="%22Prado%2C+M+A+M%22">Prado, M A M</searchLink><br /><searchLink fieldCode="AR" term="%22Bellivier%2C+F%22">Bellivier, F</searchLink><br /><searchLink fieldCode="AR" term="%22Eap%2C+C+B%22">Eap, C B</searchLink><br /><searchLink fieldCode="AR" term="%22Crettol%2C+S%22">Crettol, S</searchLink><br /><searchLink fieldCode="AR" term="%22Vanhoutte%2C+P%22">Vanhoutte, P</searchLink><br /><searchLink fieldCode="AR" term="%22Caboche%2C+J%22">Caboche, J</searchLink><br /><searchLink fieldCode="AR" term="%22Gratton%2C+A%22">Gratton, A</searchLink>
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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