Roles of dopamine and glutamate co‐release in the nucleus accumbens in mediating the actions of drugs of abuse

Abstract

Projections of ventral tegmental area dopamine (DA) neurons to the medial shell of the nucleus accumbens have been increasingly implicated as integral to the behavioral and physiological changes involved in the development of substance use disorders (SUDs). Recently, many of these nucleus accumbens-projecting DA neurons were found to also release the neurotransmitter glutamate. This glutamate co-release from DA neurons is critical in mediating the effect of drugs of abuse on addiction-related behaviors. Potential mechanisms underlying the role(s) of dopamine/glutamate co-release in contributing to SUDs are unclear. Nevertheless, an important clue may relate to glutamate's ability to potentiate loading of DA into synaptic vesicles within terminals in the nucleus accumbens in response to drug-induced elevations in neuronal activity, enabling a more robust release of DA after stimulation. Here, we summarize how drugs of abuse, particularly cocaine, opioids, and alcohol, alter DA release in the nucleus accumbens medial shell, examine the potential role of DA/glutamate co-release in mediating these effects, and discuss future directions for further investigating these mechanisms.

UHPLC–electrospray ionization–mass spectrometric analysis of brain cell-specific glucogenic and neurotransmitter amino acid content

“…However, proof obtained here that GABA is measurable in VMN nitrergic neurons, albeit at substantially lower levels relative to GAD-immunoreactive nerve cells, was unforeseen. While it is well established that neurons that co-express multiple transmitters, including GABA, occur in the brain 32 – 36 , there has been a lack of active contemplation of the possibility of co-release of gluco-regulatory transmitters. Current work advances the novel concept that NO and GABA, which impose pharmacological evidence-based antagonistic effects on glucose counter-regulation, are co-localized in VMN nitrergic neurons.…”

Dopamine Neurons That Cotransmit Glutamate, From Synapses to Circuits to Behavior

“…The only DA-neuron-specific VGluT2 cKO study without an impaired response to acute psychostimulants used a TH IRES–Cre transgene instead of a DAT Cre or DAT IRES–Cre transgene to establish the DA-neuron-specific VGluT2 cKO ( Nordenankar et al, 2015 ). Subsequent reviews have cautioned about comparisons between TH Cre and DAT Cre induced conditional gene expression ( Pupe and Wallén-Mackenzie, 2015 ; Stuber et al, 2015 ; Lammel et al, 2015 ; Buck et al, 2020 ; Fischer et al, 2020 ). Briefly, TH Cre mice cause more developmental effects than DAT Cre mice, because TH expression begins earlier in development than DAT (see above), and is more widespread and ectopic (i.e., neurons that are positive for TH mRNA but not TH protein) ( Di Porzio et al, 1990 ).…”

“…Selectively targeting DA neuron GLU cotransmission may thus serve as a potential treatment for addiction ( Bimpisidis and Wallén-Mackenzie, 2019 ), especially psychostimulant use disorders perhaps by facilitating behavioral switching ( Mingote et al, 2019 ). Further discussion about DA-GLU neurons and addiction is found in recent reviews ( Trudeau et al, 2014 ; Steinkellner et al, 2018 ; Bimpisidis and Wallén-Mackenzie, 2019 ; Buck et al, 2020 ; Fischer et al, 2020 ).…”

Parental Education, Ethnicity, and Functional Connectivity between Nucleus Accumbens and Frontoparietal Network

“…This suggests that as parts of the brain reward system, the right and left NAcc function reflects how individuals respond to cues that signal a potential reward [1]. The right and left NAcc have also been implicated in obesity [2,6], food addiction [7], tobacco, alcohol, and drug-seeking behaviors [8][9][10], obsessive-compulsive disorder [11,12], depression [13], and anxiety [12].…”