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NutriNeuro, Unité Mixte de Recherche (UMR) 1286, Institut National de la Recherche Agronomique, Bordeaux Institut Polytechnique, University of Bordeaux, Bordeaux, France
Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Sorbonne Université, Faculty of Sciences, Paris, FranceCentre National de la Recherche Scientifique, UMR8246, Paris, FranceInstitut National de la Santé et de la Recherche Médicale, U1130, Paris France
Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Sorbonne Université, Faculty of Sciences, Paris, FranceCentre National de la Recherche Scientifique, UMR8246, Paris, FranceInstitut National de la Santé et de la Recherche Médicale, U1130, Paris France
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.
Drug addiction is defined as a compulsive pattern of drug-seeking and drug-taking behavior, with recurrent episodes of abstinence and relapse, and a loss of control despite negative consequences. A current hypothesis is that persistent behavioral alterations characterizing addiction result from drug-evoked long-term changes in synaptic efficacy involving the early recruitment of specific signaling cascade and gene expression (
). This continuum between synaptic and nuclear events shapes an enduring remodeling of the reward circuitry likely involved in the transition from casual drug use to addiction (
). This drug-induced memory trace is persistent and tightly related to the context of drug consumption, partly explaining the high risk of relapse even after long periods of abstinence. Addictive drugs promote reinforcement by increasing dopamine (DA) in the mesocorticolimbic system (
). The striatum is a key target structure of drugs of abuse because it is at the crossroad of converging glutamate inputs from limbic, thalamic, and cortical regions, which encode components of drug-associated stimuli and environment, and DA, which mediates reward prediction error and incentive values. These signals are integrated in gamma-aminobutyric acidergic striatal projection neurons (SPNs), which receive glutamate and DA axons converging onto their dendritic spines (
D1 and D2 dopamine receptor gene expression in the rat striatum: Sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAS in distinct neuronal populations of the dorsal and ventral striatum.
) which are G protein–coupled receptors positively and negatively modulating adenylyl cyclase though their respective coupling to Gs/olf and Gi/o subtypes (
A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release.
). While a classical view is that the two populations of SPNs act in parallel, playing antagonistic functional roles, the picture seems much more complex, as discussed below.
Initial studies based on the use of DA receptor agonists or antagonists led to somewhat confounding results on the role of D1R-SPNs and D2R-SPNs in drug-evoked adaptations (
). A major limitation of such strategies is the widespread effect of these compounds in the brain, with different specificity, pharmacokinetics, and downstream effects relative to presynaptic and postsynaptic receptors. Analyzing molecular events in identified neuronal populations was made possible by the development of reporter mouse lines expressing fluorescent proteins or Cre-recombinase under the control of cell-specific promoters drd1a and drd2/adora2a for D1R-SPNs and D2R-SPNs, respectively (
). From circuits to molecules, cell-type–specific manipulations are now achievable owing to targeted chemogenetic and optogenetic technologies, conditional knockout, or acting on specific protein-protein interactions. This deepened our understanding of the differential impact of drug exposure on these two neuronal populations, from alterations of the inputs they receive to the pattern of signaling cascades and transcriptional landscape they exhibit at various stages of addiction. Focusing on studies using the psychostimulants cocaine and amphetamine, which constitute the vast majority of the work regarding cell-specific functions in addiction, we discuss the literature linking drug-induced behavioral alterations with adaptations in D1R-SPNs and D2R-SPNs at the circuit, cellular, and molecular levels.
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 (
), few preclinical studies support the intriguing possibility that individuals who develop behavioral traits of addiction display plasticity-related alterations in the striatum (
). Nonetheless, most studies have focused on remodeling of neural circuits in the ventral striatum (i.e., nucleus accumbens [NAc]) and dorsomedial striatum (DMS) induced by early drug exposure (Supplemental Table S1), which does not reflect addiction per se but might constitute a main trigger toward drug abuse.
SPNs constitute 95% of striatal neurons, the remaining 5% being local interneurons, which include large tonically active cholinergic interneurons. Even though cholinergic interneurons are major players in the modulation of striatal microcircuits (
), their implication in drug responses is beyond the scope of the current review.
In the dorsal striatum (DS), a common view is that D1R-SPNs and D2R-SPNs exert opposite effects through distinct output projections, with D2R-SPN reaching the midbrain through polysynaptic projections via the external globus pallidus (indirect pathway), while D1R-SPN directly project onto the internal globus pallidus and the substantia nigra (direct pathway). However, a subset of D1R-SPNs displays projections to the globus pallidus (
), depending on the methodologies used. Moreover, even though there exists a recent controversy as to whether they constitute a distinct subpopulation or they form collaterals, a large proportion of NAc D1R-SPNs projects in the ventral pallidum (VP), which is the canonical output of D2R-SPNs (
Consistent with the so-called Go/NoGo model of basal ganglia in which D1R-SPN activity facilitates and D2R-SPN activity inhibits movement planning/initiation (
), cell-type–specific manipulations initially supported that SPNs from the NAc and DMS play antagonistic roles on reward processing, including drug-induced behaviors (
). Conversely, chemogenetic inhibition of D1R-SPNs in the DMS reduces cue-induced reinstatement of cocaine seeking while sparing escalation, maintenance, and incentive components (
Altogether, these studies support a binary model in which D1R-SPNs and D2R-SPNs primarily form two parallel pathways promoting and reducing psychostimulant-induced adaptations, respectively. However, this dichotomic view overlooks several anatomofunctional findings. Notably, selective inhibition of NAc D1R-SPN projections to the VP reduces cue-induced reinstatement of cocaine seeking, suggesting that specific D1R-SPN projections might control distinct components of addictive behaviors (
)] enhances the motivation to self-administer cocaine and facilitates drug seeking, while global NAc shell activation accelerates extinction of this behavior (
). This latter finding could result from the concomitant stimulation of both SPN populations, which is likely to differentially impact striatal microcircuits. Along the same line, the “lateral inhibition” of D2R-SPNs onto D1R-SPNs in the NAc appears as a major mechanism by which D2R-SPNs could participate to locomotor sensitization by favoring D1R-SPN activity (
), the behavioral consequences of which remain unknown. Functionally, other findings challenge the view of opposite actions of the two SPN populations on drug-induced behavioral adaptations. In the DMS, ablation of D1R-SPNs decreases acute amphetamine-induced locomotor response without affecting sensitization, whereas ablating D2R-SPNs decreases sensitization but spares acute locomotor responses (
Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions: Dorsal striatum D1R- and D2R-neuron motor functions.
). Similarly, the transient inhibition of synaptic transmission of D2R-SPNs in the DMS delays the development of locomotor sensitization, although to a lower extent than D1R-SPN inhibition does (
Studies on the control of nondrug reward processing reinforce the controversy regarding the antagonistic roles of the two SPN populations. Indeed, optogenetic-mediated manipulations of D1R-SPNs and D2R-SPNs suggest that they can mediate “pro-rewarding” effects (
Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion [published online ahead of print Aug 28; published correction Sep 18.].
). These studies highlight that D1R-SPNs and D2R-SPNs may rather act in a dynamic and concerted fashion to control behavior. Accordingly, both populations are activated at the same time in the dorsolateral striatum during initiation of a reward-oriented action (
). In addition to challenging the antagonism of both SPN populations, these findings call for caution regarding the interpretation of the results obtained by direct manipulations of SPNs on drug-related behaviors because they could result from perturbations of reward processing per se, rather than reflecting specific alterations of drug-induced behavioral adaptations.
) demonstrated that repeated cocaine exposure potentiates and depresses NAc D1R-SPN and D2R-SPN synapses, respectively, onto VP neurons. Optogenetically mediated depotentiation of D1R-SPN transmission onto the VP abolishes sensitized locomotor response, while potentiation of D2R-SPN-to-VP projections restores operant responding for sucrose in animals under cocaine withdrawal. These data suggest that D1R-SPN and D2R-SPN projections onto VP neurons mediate behavioral sensitization and cocaine-induced anhedonia, respectively (
). Yet, either chemogenetic activation of D1R-SPN or inhibition of D2R-SPN potentiates cocaine self-administration, which is reversed by chemogenetic inhibition of VP neurons (
). In accordance, Luscher’s group showed that cocaine-induced locomotor sensitization is associated with a potentiation of excitatory cortical inputs onto D1R-SPNs, but not D2R-SPNs, of the NAc (
). Optogenetically induced depotentiation of these synapses established the causality between drug-evoked plasticity in D1R-SPNs and behavioral sensitization (
). They also showed that mice trained to self-administer cocaine and subjected to a 30-day withdrawal display a potentiation of transmission at ventral hippocampal and cortical, but not amygdalar, excitatory projections onto NAc D1R-SPNs. Specific optogenetically induced patterns of stimulation decrease vigor response and abolish cocaine seeking when hippocampal and cortical inputs, respectively, are depotentiated (
). The same group also showed that compulsive self-stimulation of DA transmission, which models drug addiction, relies on the potentiation of excitatory projections from the orbitofrontal cortex onto D1R-SPNs of the ventrocentral striatum (
). These studies highlight that distinct components of drug addiction rely on drug-evoked synaptic adaptations at specific input projections onto D1R-SPNs. Accordingly, repeated cocaine exposure strengthens afferences from the basolateral amygdala onto D1R-SPNs but not D2R-SPNs (
). Inputs onto D2R-SPNs also seem to be altered by drug exposure because cocaine-induced CPP correlates with a strengthening of the coupling between hippocampal place cells and D2R-SPNs (
). However, further studies are necessary to establish causality between neurobiological adaptations onto D2R-SPNs and addictive behavior.
Beyond the comprehension of the mechanisms that underlie addiction, unraveling the precise alterations in synaptic connectivity between SPNs and input areas could inspire therapeutic strategies to reverse drug-induced synaptic changes, for instance through deep-brain or transcranial magnetic stimulation (
). Moreover, the identification of specific drug-evoked synaptic changes highlights that addiction involves perturbation in the balance between glutamatergic inputs and DA modulatory signaling onto SPNs. This calls for a better understanding of the underlying molecular mechanisms as it may lead to identification of innovative molecular target (
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 (
). 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 a fast D1R-mediated Ca2+ increase in D1R-SPNs and a slow D2R-dependent deactivation of D2R-SPNs in the DS of anesthetized mice (
Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: In vivo optical microprobe [Ca2+]i imaging.
). In freely moving mice, acute cocaine administration does not influence global neuronal activity in either subpopulation of the DS, although compact clusters of activity were identified in discrete subregions of the DS (
). Thus, cocaine-induced hyperlocomotion correlates with increased activity in D1R-SPN clusters near the dorsolateral striatum and a decrease in D2R-SPN clusters near the DMS (
). During cocaine-induced CPP, a transient Ca2+ rise occurs in NAc D1R-SPNs before entry in the drug-paired compartment, while Ca2+ decreases in D2R-SPN when the animal stays in this compartment (
). The mechanisms by which DA controls Ca2+ signaling were initially investigated through cell-specific overexpression in D1R-SPNs of NMDA glutamate receptor (NMDAR) bearing reduced Ca2+ permeability, which prevents the sensitizing and rewarding effects of cocaine (
). NMDAR knockout in D1R-expressing cells also blocks amphetamine-induced sensitization, a phenotype that is rescued by restoring functional NMDAR in NAc D1R-SPNs or deleting NMDAR in all SPNs (
). By contrast, NMDAR knockout in either D1R cells or adenosine A2A receptor (A2AR) cells (overlapping with D2R-SPNs), or both, preserves the development and extinction of cocaine-induced CPP (
). These findings highlight the critical role of a balanced NMDAR activity in each cell type for drug-induced responses. Although constitutive, and not striatal specific, these manipulations support a critical role of striatal DA and NMDAR signaling crosstalk in drug-evoked responses.
Downstream from these receptors, the ERK (extracellular signal-regulated kinase) pathway is activated by virtually all drugs of abuse (
) (Figure 1). Nevertheless, inhibiting D1R-mediated potentiation of NMDAR targeting ERK activation in D1R-SPNs blocks the sensitizing and rewarding effects of cocaine (
). We also found that in NAc shell D1R-SPNs, acute cocaine triggers rapid de novo formation of dendritic spines contacting preexisting glutamate axon terminals (
Rapid synaptogenesis in the nucleus accumbens is induced by a single cocaine administration and stabilized by mitogen-activated protein kinase interacting kinase-1 activity.
). Stabilization of these newly formed synapses requires the targeting of the cytoplasmic MNK-1 (mitogen-activated protein kinase interacting protein-1) by ERK, which controls local translation independently of nuclear events, and likely influences responses to subsequent drug exposure (
Rapid synaptogenesis in the nucleus accumbens is induced by a single cocaine administration and stabilized by mitogen-activated protein kinase interacting kinase-1 activity.
Figure 1Cell-type–specific cellular and molecular events recruited from the plasma membrane to the nucleus in striatal projection neurons (SPNs) in response to psychostimulants. Diagram depicting major striatal signaling pathways and epigenetic and genic responses taking place from the membrane to the nucleus in (left) dopamine D1 receptor (D1R)– or (right) D2 receptor (D2R)–expressing SPNs in response to psychostimulants. Green and red arrows and lanes represent mechanisms described in the main text that are activated and inhibited, respectively, on dopamine release induced by psychostimulants. Glutamate afferences impinging onto each cell type are represented on top of each SPN subtype. Green afferences represent the ones for which a modulation of glutamate transmission induced by psychostimulants has been causally linked to distinct components of behavioral responses. Gray afferences represent the ones for which psychostimulant-induced changes in glutamate transmission have been either correlated to behavioral responses or not modified. AC, adenylate cyclase; Ack, acetyl-lysine; Amg, amygdala; AMPc, cyclic adenosine monophosphate; AP-1, activator protein-1; arc, activity-regulated cytoskeleton-associated protein; β-arr, β-arrestin; cdk5, cyclin-dependent kinase 5; CPP, conditioned place preference; CRE, calcium- and cyclic-AMP responsive element; CREB, cyclic adenosine monophosphate–responsive element binding protein; DA, dopamine; DARPP-32, dopamine and cyclic adenosine monophosphate–regulated phosphoprotein; egr1, early growth response 1; Elk-1, ETS-like-1 protein; ERK, extracellular signal-regulated kinase; Glu, glutamate; IL mPFC, infralimbic medial prefrontal cortex; me1-3K9, mono-, di-, tri-methyl-lysine; me2-3K9, di- tri-methyl-lysine 9; MEK, MAPKinase/ERK kinase; MNK-1, mitogen-activated protein kinase interacting protein-1; MSK-1, mitogen and stress-activated protein kinase-1; P, phosphorylation; PKA, protein kinase A; PP1, protein phosphatase 1; PRMT6, protein arginine methyltransferase 6; Ras-GRF-1, ras-guanine releasing factor-1; SRE, serum response element; STEP, striatal-enriched protein tyrosine phosphatase; T, threonine residue; Thal, thalamus; vHC, ventral hippocampus.
). Although PKA cannot directly target ERK, it can indirectly amplify its activation, notably via the cAMP-regulated phosphoprotein DARPP-32 [described in (
). Deleting DARPP-32 in D1R-SPNs reduces basal locomotion and cocaine-induced hyperlocomotion, while its deletion in D2R-SPNs leads to an opposite phenotype (
), cAMP/PKA/DARPP-32 signaling seems to prevail in D1R-SPNs over D2R-SPNs. Other possible pathways linking the D1R and cAMP/PKA pathways to ERK activation include the striatal-enriched protein phosphatase STEP, a phosphatase of ERK that is inhibited by PKA (
PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif.
NCS-Rapgef2, the protein product of the neuronal Rapgef2 gene, is a specific activator of D1 dopamine receptor-dependent ERK phosphorylation in mouse brain.
Despite the importance of the crosstalk between striatal DA and glutamate signaling for drug-induced adaptations, targeting of cognate receptors in humans to alleviate addiction led to a lack of efficacy and/or side effects over time (
), likely due to perturbation of crucial physiological functions. The development of biased ligands, recruiting specific pathways, opens the way toward the modulation of specific behavioral components (
). Little is known about their relevance in addiction, notably whether they could alleviate specific drug-evoked behavioral components while sparing nondrug reward processing. Interestingly, transgenic approaches show that biasing D2R toward arrestin signaling in the NAc affects cocaine-induced locomotion but not reward processing (
The physical interaction of DA receptors with other receptors also appears as a powerful mechanism by which receptors can mutually modify their functions through allosteric interactions resulting in functional selectivity. Hence, receptor heteromers are emerging as promising targets for fine-tuning of specific signaling pathways (
Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A2A-dopamine D2 receptor heterotetramers and adenylyl cyclase.
) makes these heteromers particularly relevant for addiction. Endogenous heteromers formed by D1R and the GluN1 NMDAR subunits are detected in the mouse striatum and act as a molecular bridge by which DA and glutamate exert their synergistic action on responses to cocaine in D1R-SPNs (
). Ex vivo electrophysiological recordings from D1R-SPN reporter mice show that the disruption of D1R/GluN1 interaction impedes D1R-mediated potentiation of NMDA postsynaptic currents; impedes long-term synaptic plasticity in D1R-SPNs, but not D2R-SPNs; and impedes cocaine-induced ERK activation (
). By contrast, D2R/GluN2B interaction mediates the inhibition of NMDA currents by DA in D2R-SPNs and alters the acute hyperlocomotor effect of cocaine (
). Hence, DA receptor/NMDAR heteromers may play a role in the imbalance between D1R-SPNs and D2R-SPNs induced by drugs of abuse, even though further work is needed to characterize their impact on downstream signaling toward the nucleus and long-lasting behavioral responses in vivo.
Genetic and Epigenetic Regulation
Like other forms of memory, addiction-related memories require changes in gene regulation and protein expression (
), 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) (
). Cocaine-triggered Elk-1 phosphorylation downstream of D1R regulates the induction of immediate early genes (IEG), including c-fos, zif268, Delta-fosB, and Arc (
)], exhibit a downregulation of c-Fos and dynorphin expression, but not of Zif268 expression, along with decreased locomotor sensitization but spared CPP (
The contribution of D1R-SPN-induced genes was initially established at the level of IEG through pharmacological studies and further confirmed using reporter mice (
). More comprehensive evidence came from the molecular profiling of FACS (fluorescence-activated cell sorting)–isolated c-Fos-positive neurons showing an enrichment of D1R-SPNs over D2R-SPN-specific genes, along with IEG (including Arc [activity-regulated cytoskeleton-associated protein] and FosB) in this cocaine-activated population (
). ΔFosB, the stable spliced version of FosB IEG, persistently accumulates in NAc D1R-SPNs after chronic psychostimulant exposure and plays a key role in cocaine addiction (
Psychostimulant exposure also affects IEG encoding effector proteins such as Arc, which is induced in the striatum downstream of D1R and ERK activation (
Activity-regulated cytoskeleton-associated protein accumulates in the nucleus in response to cocaine and acts as a brake on chromatin remodeling and long-term behavioral alterations.
). However, acute cocaine induces an enrichment of Arc in the nucleus, where it colocalizes with active transcription regions and phosphorylated histones H3 (
Activity-regulated cytoskeleton-associated protein accumulates in the nucleus in response to cocaine and acts as a brake on chromatin remodeling and long-term behavioral alterations.
Activity-regulated cytoskeleton-associated protein accumulates in the nucleus in response to cocaine and acts as a brake on chromatin remodeling and long-term behavioral alterations.
), revealing a homeostatic role of Arc in cocaine-induced gene expression. Other psychostimulant-regulated IEGs include genes encoding proteins involved in various cell functions, including mitochondrial or metabolic, which are differentially regulated in each SPN subpopulation after cocaine and play a key role in neuronal and behavioral adaptations to this drug (
), revealed major differences in transcriptional landscapes between each subpopulation. A similar approach based on the use of Ribotag mice identified the transcription factor Egr3 (early growth response 3) as differentially regulated by chronic cocaine use in the two SPN subtypes with an increase in D1R-SPNs and a decrease in D2R-SPNs (
). Chromatin immunoprecipitation demonstrated the binding of Egr3 to promoters of neuronal plasticity-associated genes CamK2α (calcium/calmodulin-dependent protein kinase IIα) and CREB, which were further shown increased in D1R-SPNs and decreased in D2R-SPNs (
The persistent and experience-dependent features of addiction have suggested a role for epigenetic modifications, as they mediate stable transcriptional alterations supporting long-term remodeling of neuronal networks (
Additive effects of histone deacetylase inhibitors and amphetamine on histone H4 acetylation, cAMP responsive element binding protein phosphorylation and ΔFosB expression in the striatum and locomotor sensitization in mice.
). Chromatin immunoprecipitation–based analyses have been instrumental in understanding the contribution of these epigenetic changes to specific candidate gene regulation (
). A genome-wide analysis of H3 and H4 pan-acetylation extended the mapping of cocaine-induced histone acetylation alterations at many genes predominantly induced in D1R-SPNs including Arc, c-fos, and Egr3 (
) shows an increase in H3 and H4 acetylation in both populations after acute cocaine exposure, while H4 acetylation remain enriched only in D2R-SPNs after chronic exposure. This study also confirms the D1R-SPN-specific increase in Ser10-PH3 associated with c-fos transcriptional activation (
Histone lysine methylation is another cocaine-regulated modification that can either activate or repress transcription depending on the specific lysine (in this case, lysine K) residue targeted and its valence of methylation (
). In the NAc, chronic cocaine decreases the global level of dimethylation and trimethylation of H3K9 residue and downregulates its catalyzing enzymes, G9a histone methyltransferase (
). A ribosomal affinity purification approach shows that G9a expression is predominantly affected in D2R-SPNs in the whole striatum after cocaine exposure, and its specific knockdown in D2R-SPNs shifts these SPNs to a D1R-SPN phenotype, resulting in enhanced response to cocaine (
). Arginine methylation is decreased in D2R-SPNs together with downregulation of both PRMT6 (protein arginine methyltransferase 6) and its associated mark, asymmetric demethylation of R2 on histone H3 (H3R2me2a), after repeated exposure to cocaine (
Growing evidence suggests a critical role for persistent changes in chromatin architecture in modulating subsequent neuronal responses during drug reexposure via a mechanism referred to as “gene priming.” This process could be involved in cell-type–specific long-term transcriptional alterations as recent observations show differential changes in chromatin accessibility between D1R-SPNs and D2R-SPNs after chronic cocaine exposure (
). Overall these data indicate that epigenetic remodeling could be critical in shaping the transcriptional program of D1R-SPNs and D2R-SPNs, although further investigations are now required to understand the cell-specific contribution of these processes.
Finally, much attention has been paid to microRNAs (miRNAs), a category of 21- to 25-nucleotides-long noncoding RNAs, which are altered in several psychiatric conditions (
), are considered as “master regulators” of long-lasting transcriptional adaptations. miRNA-mediated gene regulation plays a role in cocaine-related changes in neurotransmission and behavior (
), but their cell-type–specific role in the striatum remains unknown. One study began to broadly address this issue by ablating a key protein in miRNA processing, Ago2, in D2R-SPNs (
). These mice showed loss of motivation to self-administer cocaine and a decrease of 23 (of 63) miRNAs induced by acute cocaine exposure. Questions as to whether and how miRNA regulation in D1R-SPNs occurs, along with the specific role of miRNAs in this neuronal population, remain to be answered.
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 interventions combined with genome-wide analysis of gene expression, epigenetic marks, and chromatin structure should deepen our understanding of the synergistic role of these two populations in drug-induced behavioral alterations. Establishing causality between drug-induced behavioral adaptations and discrete molecular and cellular mechanisms specific to each SPN population could allow the design of novel treatment strategies to alleviate selective behavioral components of addiction.
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 Recherche Agronomique, University of Bordeaux (to PT), Idex Bordeaux “chaire d’installation” (Grant No. ANR-10-IDEX-03-02) [to PT], and Région Aquitaine (Grant No. 2014-1R30301-00003023 [to PT]).
JC and PV disclose consulting fees from MELKin Pharmaceuticals but reported no potential conflicts of interest. The other authors report no biomedical financial interests or potential conflicts of interest.
D1 and D2 dopamine receptor gene expression in the rat striatum: Sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAS in distinct neuronal populations of the dorsal and ventral striatum.
A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release.
Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions: Dorsal striatum D1R- and D2R-neuron motor functions.
Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion [published online ahead of print Aug 28; published correction Sep 18.].
Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: In vivo optical microprobe [Ca2+]i imaging.
Rapid synaptogenesis in the nucleus accumbens is induced by a single cocaine administration and stabilized by mitogen-activated protein kinase interacting kinase-1 activity.
PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif.
NCS-Rapgef2, the protein product of the neuronal Rapgef2 gene, is a specific activator of D1 dopamine receptor-dependent ERK phosphorylation in mouse brain.
Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A2A-dopamine D2 receptor heterotetramers and adenylyl cyclase.
Activity-regulated cytoskeleton-associated protein accumulates in the nucleus in response to cocaine and acts as a brake on chromatin remodeling and long-term behavioral alterations.
Additive effects of histone deacetylase inhibitors and amphetamine on histone H4 acetylation, cAMP responsive element binding protein phosphorylation and ΔFosB expression in the striatum and locomotor sensitization in mice.
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