Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse

Abstract

Drug addiction is defined as a compulsive pattern of drug-seeking- and taking- behavior, with recurrent episodes of abstinence and relapse, and a loss of control despite negative consequences. Addictive drugs promote reinforcement by increasing dopamine in the mesocorticolimbic system, which alters excitatory glutamate transmission within the reward circuitry, thereby hijacking reward processing. Within the reward circuitry, the striatum is a key target structure of drugs of abuse since it is at the crossroad of converging glutamate inputs from limbic, thalamic and cortical regions, encoding components of drug-associated stimuli and environment, and dopamine that mediates reward prediction error and incentive values. These signals are integrated by medium-sized spiny neurons (MSN), which receive glutamate and dopamine axons converging onto their dendritic spines. MSN primarily form two mostly distinct populations based on the expression of either DA-D1 (D1R) or DA-D2 (D2R) receptors. While a classical view is that the two MSN populations act in parallel, playing antagonistic functional roles, the picture seems much more complex. Herein, we review recent studies, based on the use of cell-type-specific manipulations, demonstrating that dopamine differentially modulates dendritic spine density and synapse formation, as well as glutamate transmission, at specific inputs projecting onto D1R-MSN and D2R-MSN to shape persistent pathological behavioral in response to drugs of abuse. We also discuss the identification of distinct molecular events underlying the detrimental interplay between dopamine and glutamate signaling in D1R-MSN and D2R-MSN and highlight the relevance of such cell-type-specific molecular studies for the development of innovative strategies with potential therapeutic value for addiction. Because drug addiction is highly prevalent in patients with other psychiatric disorders when compared to the general population, we last discuss the hypothesis that shared cellular and molecular adaptations within common circuits could explain the co-occurrence of addiction and depression. We will therefore conclude this review by examining how the nucleus accumbens (NAc) could constitute a key interface between addiction and depression.

Integrative multi-dimensional characterization of striatal projection neuron heterogeneity in adult brain

“…Traditionally, SPNs have been segregated into two subpopulations based on expression of D1like or D2-like receptors [12][13][14] . Indeed, SPNs expressing D1-like receptors differ from SPNs that express D2-like receptors at cellular, circuit, and behavioral levels [15][16][17][18][19][20][21] . However, many questions remain concerning this dichotomous separation.…”

Male DAT Val559 Mice Exhibit Compulsive Behavior under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

“…Given evidence of baseline and drug-stimulated compulsive behaviors in DAT Val559 mice and the ability of DA to modulate spine density of striatal medium spiny neurons (MSNs) [ 47 ], we hypothesized that DAT Val559-driven ADE might drive neuroadaptations in key brain regions linked to compulsions. Our prior studies demonstrated that perturbations in DAT trafficking and function were confined in DAT Val559 males to the dorsal striatum [ 30 ].…”

Sex differences in chronic pain-induced mental disorders: Mechanisms of cerebral circuitry

“…In recent years, it has become a consensus that there are sex differences in the incidence of dopamine-related neuropsychiatric disorders and sensitivity to dopamine-enhancing drugs such as stimulants, and previous studies have shown that dopaminergic circuits often act through dopamine receptors D1 and D2 (Fasano et al, 2013 ; Stalter et al, 2020 ; Allichon et al, 2021 ). It has been shown in the chronic constriction injury (CCI) pain model of the sciatic nerve in mice that dopaminergic projections from the VTA to the nucleus accumbens (NAc) are involved in pain modulation (Ding et al, 2021 ).…”