Elsevier

Biological Psychiatry

Volume 87, Issue 11, 1 June 2020, Pages 944-953
Biological Psychiatry

Review
From Signaling Molecules to Circuits and Behaviors: Cell-Type–Specific Adaptations to Psychostimulant Exposure in the Striatum

https://doi.org/10.1016/j.biopsych.2019.11.001Get rights and content

Abstract

Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal that are thought to result from persistent adaptations within brain reward circuits. Drugs of abuse increase dopamine (DA) concentration in these brain areas, including the striatum, which shapes an abnormal memory trace of drug consumption that virtually highjacks reward processing. Long-term neuronal adaptations of gamma-aminobutyric acidergic striatal projection neurons (SPNs) evoked by drugs of abuse are critical for the development of addiction. These neurons form two mostly segregated populations, depending on the DA receptor they express and their output projections, constituting the so-called direct (D1 receptor) and indirect (D2 receptor) SPN pathways. Both SPN subtypes receive converging glutamate inputs from limbic and cortical regions, encoding contextual and emotional information, together with DA, which mediates reward prediction and incentive values. DA differentially modulates the efficacy of glutamate synapses onto direct and indirect SPN pathways by recruiting distinct striatal signaling pathways, epigenetic and genetic responses likely involved in the transition from casual drug use to addiction. Herein we focus on recent studies that have assessed psychostimulant-induced alterations in a cell-type–specific manner, from remodeling of input projections to the characterization of specific molecular events in each SPN subtype and their impact on long-lasting behavioral adaptations. We discuss recent evidence revealing the complex and concerted action of both SPN populations on drug-induced behavioral responses, as these studies can contribute to the design of future strategies to alleviate specific behavioral components of addiction.

Section snippets

Cell-Type–Specific Modulation of SPN Activity

A current hypothesis is that the transition from recreational to compulsive drug use relies on a gradual recruitment from ventromedial to dorsolateral striatal subregions (18,19). Despite the existence of behavioral features of vulnerability toward addiction (19), few preclinical studies support the intriguing possibility that individuals who develop behavioral traits of addiction display plasticity-related alterations in the striatum (20). Nonetheless, most studies have focused on remodeling

Cell-Type–Specific Striatal Signaling From the Membrane Toward the Nucleus

Through differential coupling of DA receptors to Gs/olf and Gi/o, DA activates the cAMP (cyclic adenosine monophosphate)/downstream PKA (protein kinase A) pathway in D1R-SPNs, while repressing it in D2R-SPNs, leading to opposite regulations of ion channels, including glutamate receptors (69, 70, 71). The consensus is that DA increase facilitates glutamate-dependent activation of D1R-SPNs and inhibits glutamate-dependent activation of D2R-SPNs. Accordingly, acute cocaine administration triggers

Genetic and Epigenetic Regulation

Like other forms of memory, addiction-related memories require changes in gene regulation and protein expression (107,108) taking place downstream from the activation of cytoplasm-to-nucleus signaling. Once activated in D1R-SPNs (24), ERK directly targets the transcription factor Elk-1 (ETS-like-1 protein) and indirectly the Ca2+-binding protein and CREB (cAMP-responsive element binding protein) via the MSK-1 (mitogen and stress-activated protein kinase-1) (109, 110, 111). Cocaine-triggered

Conclusions and Perspectives

While converging data point at a critical role for D1R-SPN-specific plasticity, cell-type–specific approaches reveal evident molecular alterations in D2R-SPNs in favor of their active role in the reshaping of striatal circuits in addiction. However, we still lack a comprehensive model for the contribution of intracellular pathways involved in drug-induced transcriptional alterations in D1R-SPNs and D2R-SPNs at various stages of addiction. Cell-type–specific approaches and timed-controlled

Acknowledgments and Disclosures

The work is supported by the Centre National de la Recherche Scientifique (to MS, PV, and JC), Institut National de la Santé et de la Recherche Médicale (to PV and JC), Fondation pour la Recherche Médicale (Grant No. DEQ20150734352 [to JC]), and the Bio-Psy Labex cluster of excellence (to MS, JC, and PV); Sorbonne Université—Paris VI (to JC and PV), Agence Nationale pour la Recherche (Grant Nos. ANR-15-CE16-001 [to PT and PV] and ANR-18-CE37-0003-02 [to PV]); and the Institut National de la

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