Abstract
Dopamine–glutamate co-release is a unique property of midbrain neurons primarily located in the ventral tegmental area (VTA). Dopamine neurons of the VTA are important for behavioral regulation in response to rewarding substances, including natural rewards and addictive drugs. The impact of glutamate co-release on behaviors regulated by VTA dopamine neurons has been challenging to probe due to lack of selective methodology. However, several studies implementing conditional knockout and optogenetics technologies in transgenic mice have during the past decade pointed towards a role for glutamate co-release in multiple physiological and behavioral processes of importance to substance use and abuse. In this review, we discuss these studies to highlight findings that may be critical when considering mechanisms of importance for prevention and treatment of substance abuse.
Highlights
Substance use disorder is a chronic, relapsing neuropsychiatric disease that occurs in a minority of recreational drug users [1]
Med. 2019, 8, 1887 of Vglut2 (A,B) and Th (C,D) mRNA in midbrain sections of wildtype adult mouse at two rostro-caudal levels. (A,B) Vglut2 mRNA is abundant throughout the midbrain with strong signals in e.g., the red nucleus (RN), retrosplenial group of the cortex (RSG) and dentate gyrus (DG), and weaker signals in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). (C,D) Th mRNA is selectively localized in dopaminergic neurons of the VTA and SNc; its mRNA signal is implemented to visualize these areas
Dotted square around the VTA and SNc presented as closeups in (A’–D’; scale bar 200 mm). (C’,D’) SNc, substantia nigra pars reticulata (SNr) and subregions of VTA outlined in Th closeups and superimposed on Vglut2 closeups (A’,B’). (C’,D’) Th mRNA was strongly localized in the SNc and within the parabrachial pigmented area (PBP) and paranigral nucleus (PN) of the VTA with a weaker signal in the rostral linear nucles (RLi) and caudal aspect of the interfascicular nucleus (IF). (A’,B’) Within the VTA, Vglut2 mRNA was detected in the PBP, PN, RLi, and IF as well as within the medially-located subzone of the PBP while no Vglut2 mRNA was detected in the GABAergic SNr area
Summary
Substance use disorder is a chronic, relapsing neuropsychiatric disease that occurs in a minority of recreational drug users [1]. The mesolimbic DA system, containing DA neurons located within the ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc) [9], has been shown to be important for reward processing. Abusive drugs increase DA levels preferentially in the NAc mSh as compared to the NAc core or the dorsal aspect of the striatum [1,13,14] While these increases are related to the reinforcing properties of the drugs, the behavioral patterns observed in addicts after chronic drug use are related to more persistent neuroadaptations in the glutamatergic system. (A,B) Vglut mRNA is abundant throughout the midbrain with strong signals in e.g., the red nucleus (RN), retrosplenial group of the cortex (RSG) and dentate gyrus (DG), and weaker signals in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Reprinted from Papathanou et al, 2018 [24]
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