The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

Kupchik, Yonatan M.; Kalivas, Peter W.

doi:10.1038/npp.2016.160

Cited by 36 publications

(34 citation statements)

References 7 publications

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“…While part of MSNs expressing dopamine D1‐like receptors participate in a indirect pathway, targeting ventral pallidum neurons that send projections to the ventral mesencephalon, a portion of MSNs expressing dopamine D2‐like receptors contribute to a direct pathway and synapse on ventral pallidum neurons that directly project to the thalamus (Kupchik et al . ; Kupchik and Kalivas ). Moreover, a similar organization has also been suggested in the dorsal striatum (Cazorla et al .…”

Section: Dopamine and Darpp‐32 Signaling Pathwaysmentioning

confidence: 98%

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DARPP‐32 in the orchestration of responses to positive natural stimuli

Scheggi

Montis

Gambarana

2018

Journal of Neurochemistry

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Dopamine- and cAMP-regulated phosphoprotein (M 32 kDa, DARPP-32) is an integrator of multiple neuronal signals and plays a crucial role particularly in mediating the dopaminergic component of the systems involved in the evaluation of stimuli and the ensuing elaboration of complex behavioral responses (e.g., responses to reinforcers and stressors). Dopamine neurons can fire tonically or phasically in distinct timescales and in specific brain regions to code different behaviorally relevant information. Dopamine signaling is mediated mainly through the regulation of adenylyl cyclase activity, stimulated by D1-like or inhibited by D2-like receptors, respectively, that modulates cAMP-dependent protein kinase (PKA) function. The activity of DARPP-32 is finely regulated by its phosphorylation at multiple sites. Phosphorylation at the threonine (Thr) 34 residue by PKA converts DARPP-32 into an inhibitor of protein phosphatase 1, while the phosphorylation at the Thr75 residue turns it into an inhibitor of PKA. Thus, DARPP-32 is critically implicated in regulating striatal output in response to the convergent pathways that influence signaling of the cAMP/PKA pathway. This review summarizes some of the landmark and recent studies of DARPP-32-mediated signaling in the attempt to clarify the role played by DARPP-32 in the response to rewarding natural stimuli. Particularly, the review deals with data derived from rodents studies and discusses the involvement of the cAMP/PKA/DARPP-32 pathway in: 1) appetitive food-sustained motivated behaviors, 2) motivated behaviors sustained by social reward, 3) sexual behavior, and 4) responses to environmental enrichment.

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Section: Dopamine and Darpp‐32 Signaling Pathwaysmentioning

confidence: 98%

“…Moreover, recent evidences suggest novel more complex views of the regulation of the neuronal circuitries involved in the processing and execution of motivated behaviors by ventral striatal outputs and sustain a crucial role of the ventral pallidum (Kupchik et al . ; Kupchik and Kalivas ).…”

Section: Dopamine and Darpp‐32 Signaling Pathwaysmentioning

confidence: 98%

DARPP‐32 in the orchestration of responses to positive natural stimuli

Scheggi

Montis

Gambarana

2018

Journal of Neurochemistry

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“…DA released from ventral tegmental area (VTA) efferents into the NA binds to these G-protein coupled receptors (GPCRs) on MSNs (Gerfen et al, 1987 ; Jimenez-Castellanos and Graybiel, 1987 ; Davidson and Stamford, 1993 ; Sesack et al, 2003 ). Although historically it was thought that D 1 and D 2 -expressing MSNs were exclusively part of the direct and indirect basal ganglia pathways (Gerfen et al, 1990 ) and that manipulation of D 1 or D 2 MSNs specifically illustrates pathway specificity (Bock et al, 2013 ; MacAskill et al, 2014 ), recent studies have shown that this subdivision of cell type is not synonymous with these distinct pathways in projections of the NA (Smith et al, 2013 ; Kupchik et al, 2015 ; Kupchik and Kalivas, 2017 ). DAergic neurons in the VTA respond during conditioned behavior (Ljungberg et al, 1992 ) and, as described in detail below, conditioned and discriminative cues incorporate distinct DAergic mechanisms to modulate drug-induced neurobehavioral plasticity.…”

Section: Introductionmentioning

confidence: 99%

The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms

Namba

Tomek

Olive

et al. 2018

Front. Behav. Neurosci.

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In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self-administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence.

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“…Moreover, alcohol-induced increases in neuronal complexity in the dorsal striatum are correlated with increased AMPA receptor activity specifically in the dopamine D1 receptor expressing MSNs (medium spiny neurons), suggesting that alcohol enhances the activity of D1 MSNs in the direct pathway [52]. Notably, striatal circuits associated with D1-and D2-expressing MSNs are not equivalent for the dorsal and ventral striatum [53]. The role of D1-and D2-expressing MSNs of the NAc core in binge-like drinking is currently under study in our laboratory.…”

Section: Effects Of Binge-drinking and Dreadds On Nac Neuronal Morphomentioning

confidence: 99%

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

et al. 2020

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Binge drinking is a dangerous pattern of behavior. We tested whether chronically manipulating nucleus accumbens (NAc) activity (via clozapine-N-oxide (CNO) and Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) could produce lasting effects on ethanol binge-like drinking in mice selectively bred to drink to intoxication. We found chronically increasing NAc activity (4 weeks, via CNO and the excitatory DREADD, hM3Dq) decreased binge-like drinking, but did not observe CNO-induced changes in drinking with the inhibitory DREADD, hM4Di. The CNO/hM3Dq-induced reduction in ethanol drinking persisted for at least one week, suggesting adaptive neuroplasticity via transcriptional and epigenetic mechanisms. Therefore, we defined this plasticity at the morphological and transcriptomic levels. We found that chronic binge drinking (6 weeks) altered neuronal morphology in the NAc, an effect that was ameliorated with CNO/hM3Dq. Moreover, we detected significant changes in expression of several plasticity-related genes with binge drinking that were ameliorated with CNO treatment (e.g., Hdac4). Lastly, we found that LMK235, an HDAC4/5 inhibitor, reduced binge-like drinking. Thus, we were able to target specific molecular pathways using pharmacology to mimic the behavioral effects of DREADDs.Brain Sci. 2020, 10, 109 2 of 22 (DID) paradigm, mice are offered an ethanol solution early into the active period of their circadian cycle and can achieve BALs >80 mg%, suggesting they drink to intoxication [1]. C57BL/6J mice are typically reported as high drinking and can achieve BALs >80mg% in the DID paradigm; however, significant inbred strain differences have been observed suggesting there exists a genetic contribution to this phenotype [2,3]. The DID assay was used to independently create two lines of mice, HDID-1 and HDID-2, that were selectively bred (from genetically heterogeneous HS/Npt progenitors) for high BALs after DID [4,5]. HDID and HS/Npt mice have been extensively characterized and HDID mice represent a unique genetic animal model of risk for drinking to intoxication [6][7][8][9][10][11][12][13][14]. FDA approved compounds for treatment of AUD, as well as several investigational compounds, have been tested for efficacy in reducing binge-like drinking using the DID paradigm in C57BL/6J and HDID mice, as well as other genotypes, with mixed results [15][16][17][18][19][20]. Together, the results of these studies suggest that testing potential therapies in more than one inbred strain may represent a more beneficial strategy for clinical translation.Koob and Volkow (2010) reviewed decades of clinical and pre-clinical studies to address the neural circuitry associated with the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation [21]. The nucleus accumbens (NAc) is identified as an important region for each of these three stages. There is also extensive evidence that altering activity in the NAc reduces alcohol drinking, craving, and relapse. To achiev...

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The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

Cited by 36 publications

References 7 publications

DARPP‐32 in the orchestration of responses to positive natural stimuli

DARPP‐32 in the orchestration of responses to positive natural stimuli

The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

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