Publications by authors named "Cody A Siciliano"

40 Publications

Alcohol and the brain: from genes to circuits.

Trends Neurosci 2021 Oct 23. Epub 2021 Oct 23.

Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Alcohol use produces wide-ranging and diverse effects on the central nervous system. It influences intracellular signaling mechanisms, leading to changes in gene expression, chromatin remodeling, and translation. As a result of these molecular alterations, alcohol affects the activity of neuronal circuits. Together, these mechanisms produce long-lasting cellular adaptations in the brain that in turn can drive the development and maintenance of alcohol use disorder (AUD). We provide an update on alcohol research, focusing on multiple levels of alcohol-induced adaptations, from intracellular changes to changes in neural circuits. A better understanding of how alcohol affects these diverse and interlinked mechanisms may lead to the identification of novel therapeutic targets and to the development of much-needed novel and efficacious treatment options.
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http://dx.doi.org/10.1016/j.tins.2021.09.006DOI Listing
October 2021

Dopamine release in the nucleus accumbens core signals perceived saliency.

Curr Biol 2021 Sep 8. Epub 2021 Sep 8.

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA; Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN 37232, USA. Electronic address:

A large body of work has aimed to define the precise information encoded by dopaminergic projections innervating the nucleus accumbens (NAc). Prevailing models are based on reward prediction error (RPE) theory, in which dopamine updates associations between rewards and predictive cues by encoding perceived errors between predictions and outcomes. However, RPE cannot describe multiple phenomena to which dopamine is inextricably linked, such as behavior driven by aversive and neutral stimuli. We combined a series of behavioral tasks with direct, subsecond dopamine monitoring in the NAc of mice, machine learning, computational modeling, and optogenetic manipulations to describe behavior and related dopamine release patterns across multiple contingencies reinforced by differentially valenced outcomes. We show that dopamine release only conforms to RPE predictions in a subset of learning scenarios but fits valence-independent perceived saliency encoding across conditions. Here, we provide an extended, comprehensive framework for accumbal dopamine release in behavioral control.
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http://dx.doi.org/10.1016/j.cub.2021.08.052DOI Listing
September 2021

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models.

J Clin Invest 2021 Jul 22. Epub 2021 Jul 22.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, United States of America.

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.
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http://dx.doi.org/10.1172/JCI146861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409586PMC
July 2021

Regional and sex differences in spontaneous striatal dopamine transmission.

J Neurochem 2021 Jul 15. Epub 2021 Jul 15.

Neuroscience Center, Brigham Young University, Provo, UT, USA.

Striatal dopamine release is key for learning and motivation and is composed of subregions including the dorsal striatum (DS), nucleus accumbens core, and the nucleus accumbens shell. Spontaneously occurring dopamine release was compared across these subregions. Dopamine release/uptake dynamics differ across striatal subregions, with dopamine transient release amplitude and release frequency greatest in male mice, and the largest signals observed in the DS. Surprisingly, female mice exhibited little regional differences in dopamine release for DS and nucleus accumbens core regions, but lower release in the nucleus accumbens shell. Blocking voltage-gated K channel (Kv channels) with 4-aminopyridine enhanced dopamine detection without affecting reuptake. The 4-aminopyridine effects were greatest in ventral regions of female mice, suggesting regional differences in Kv channel expression. The dopamine transporter blocker cocaine also enhanced detection across subregions in both sexes, with greater overall increased release in females than males. Thus, sex differences in dopamine transmission are apparent and likely include differences in the Kv channel and dopamine transporter function. The lack of regional differences in dopamine release observed in females indicates differential regulation of spontaneous and evoked dopamine release.
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http://dx.doi.org/10.1111/jnc.15473DOI Listing
July 2021

Neurobiology of novelty seeking.

Science 2021 05;372(6543):684-685

Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA.

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http://dx.doi.org/10.1126/science.abi7270DOI Listing
May 2021

Toward Standardized Guidelines for Investigating Neural Circuit Control of Behavior in Animal Research.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Apr 28.

Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232.

With the advent of tools for recording and manipulating activity with high spatiotemporal resolution in defined neural circuits in behaving animals, behavioral neuroscience is now tasked with establishing field-wide standards for implementing and interpreting these powerful approaches. Theoretical frameworks for what constitute proof of fundamental neurobiological principles is an ongoing and frequently debated topic. On the other hand, standardizing interpretation of individual experimental findings to avoid spurious conclusions in practice has received less attention. Even within subfields, similar assays are often used to support widely disparate conclusions which in part has contributed to a slew of studies claiming highly specified functions for cell types and circuits which are often in direct disagreement with one another. In this opinion piece, we discuss common pitfalls in design and interpretation of approaches for recording or manipulating neural activity in animal models of motivated behavior. We emphasize the importance of integrating findings across multiple behavioral assays concomitant with tempered inference regarding specialized neuronal functions as a standardized starting point for parsing circuit control of behavior. Our aim is to stimulate an open and accessible discourse in the literature to address issues of continuity across behavioral neurosciences.
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http://dx.doi.org/10.1523/ENEURO.0498-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174055PMC
July 2021

Bidirectional causality between addiction and cognitive deficits.

Int Rev Neurobiol 2021 30;157:371-407. Epub 2020 Dec 30.

Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, United States. Electronic address:

Cognitive deficits are highly comorbid with substance use disorders. Deficits span multiple cognitive domains, are associated with disease severity across substance classes, and persist long after cessation of substance use. Furthermore, recovery of cognitive function during protracted abstinence is highly predictive of treatment adherence, relapse, and overall substance use disorder prognosis, suggesting that addiction may be best characterized as a disease of executive dysfunction. While the association between cognitive deficits and substance use disorders is clear, determining causalities is made difficult by the complex interplay between these variables. Cognitive dysfunction present prior to first drug use can act as a risk factor for substance use initiation, likelihood of pathology, and disease trajectory. At the same time, substance use can directly cause cognitive impairments even in individuals without preexisting deficits. Thus, parsing preexisting risk factors from substance-induced adaptations, and how they may interact, poses significant challenges. Here, focusing on psychostimulants and alcohol, we review evidence from clinical literature implicating cognitive deficits as a risk factor for addiction, a consequence of substance use, and the role the prefrontal cortex plays in these phenomena. We then review corresponding preclinical literature, highlighting the high degree of congruency between animal and human studies, and emphasize the unique opportunity that animal models provide to test causality between cognitive phenotypes and substance use, and to investigate the underlying neurobiology at a cellular and molecular level. Together, we provide an accessible resource for assessing the validity and utility of forward- and reverse-translation between these clinical and preclinical literatures.
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http://dx.doi.org/10.1016/bs.irn.2020.11.001DOI Listing
December 2020

Sex differences in dopamine release regulation in the striatum.

Neuropsychopharmacology 2021 02 14;46(3):491-499. Epub 2020 Dec 14.

Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.

The mesolimbic dopamine system-which originates in the ventral tegmental area and projects to the striatum-has been shown to be involved in the expression of sex-specific behavior and is thought to be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters-as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.
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http://dx.doi.org/10.1038/s41386-020-00915-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027008PMC
February 2021

Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington's Disease Model.

Cell 2020 11 27;183(4):918-934.e49. Epub 2020 Oct 27.

McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington's disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.
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http://dx.doi.org/10.1016/j.cell.2020.09.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932131PMC
November 2020

An optimized procedure for robust volitional cocaine intake in mice.

Exp Clin Psychopharmacol 2021 Aug 13;29(4):319-333. Epub 2020 Jul 13.

Department of Pharmacology, Vanderbilt University/Vanderbilt University School of Medicine.

Substance use disorder (SUD) is a behavioral disorder characterized by volitional drug consumption. Mouse models of SUD allow for the use of molecular, genetic, and circuit-level tools, providing enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends on the validity of the mouse models used. Self-administration models have long been the preferred preclinical model for SUD as they allow for volitional drug consumption, thus providing strong face validity. While previous work has defined the parameters that influence intravenous cocaine self-administration in other species-such as rats and primates-many of these parameters have not been explicitly assessed in mice. In a series of experiments, we showed that commonly used mouse models of self-administration, where behavior is maintained on a fixed-ratio schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery-demonstrating that it is impossible to determine when drug consumption is and is not volitional. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pretrained on sucrose and behavior is maintained on a variable-ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and results in clearer delineation between drug-reinforced and saline conditions. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple approach to minimize these confounds with variable-ratio schedules of reinforcement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pha0000399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890946PMC
August 2021

Precision Calcium Imaging of Dense Neural Populations via a Cell-Body-Targeted Calcium Indicator.

Neuron 2020 08 26;107(3):470-486.e11. Epub 2020 Jun 26.

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.

Methods for one-photon fluorescent imaging of calcium dynamics can capture the activity of hundreds of neurons across large fields of view at a low equipment complexity and cost. In contrast to two-photon methods, however, one-photon methods suffer from higher levels of crosstalk from neuropil, resulting in a decreased signal-to-noise ratio and artifactual correlations of neural activity. We address this problem by engineering cell-body-targeted variants of the fluorescent calcium indicators GCaMP6f and GCaMP7f. We screened fusions of GCaMP to natural, as well as artificial, peptides and identified fusions that localized GCaMP to within 50 μm of the cell body of neurons in mice and larval zebrafish. One-photon imaging of soma-targeted GCaMP in dense neural circuits reported fewer artifactual spikes from neuropil, an increased signal-to-noise ratio, and decreased artifactual correlation across neurons. Thus, soma-targeting of fluorescent calcium indicators facilitates usage of simple, powerful, one-photon methods for imaging neural calcium dynamics.
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http://dx.doi.org/10.1016/j.neuron.2020.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415598PMC
August 2020

A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies.

Neuropsychopharmacology 2020 08 6;45(9):1463-1472. Epub 2020 May 6.

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.

A large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus. Thus, delineating neural control of behavior requires a dissociation between stimulus valence and stimulus-driven behavior. We developed the Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence in mice. First, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. Next, discriminative stimuli are presented concurrently allowing for parsing innate behavioral strategies based on reward seeking and avoidance. Lastly, responding in the face of punishment is assessed, thus examining  how positive and negative outcomes are relatively valued. First, we identified sex-specific behavioral strategies, showing that females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. Next, we show that chemogenetically inhibiting D1 medium spiny neurons (MSNs) in the nucleus accumbens-a population that has been linked to reward-driven behavior-reduces positive and increases negative reinforcement learning rates. Thus, D1 MSNs modulate stimulus processing, rather than motivated responses or the reinforcement process itself. Together, the MCOAT has broad utility for understanding complex behaviors as well as the definition of the discrete information encoded within cellular populations.
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http://dx.doi.org/10.1038/s41386-020-0692-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360782PMC
August 2020

Direct dopamine terminal regulation by local striatal microcircuitry.

J Neurochem 2020 12 19;155(5):475-493. Epub 2020 Jun 19.

Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.

Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward-related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters - as well heterosynaptic mechanisms such as retrograde signaling from postsynaptic cholinergic and dynorphin systems, among others. Additionally, modulation of dopamine release via diffusible messengers, such as nitric oxide and hydrogen peroxide, allows for various metabolic factors to quickly and efficiently regulate dopamine release and subsequent signaling. Here we review how these mechanisms work in concert to influence the timing and magnitude of striatal dopamine signaling, independent of action potential activity at the level of dopaminergic cell bodies in the midbrain, thereby providing a parallel pathway by which dopamine can be modulated. Understanding the complexities of local regulation of dopamine signaling is required for building comprehensive frameworks of how activity throughout the dopamine system is integrated to drive signaling and control behavior.
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http://dx.doi.org/10.1111/jnc.15034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606645PMC
December 2020

A cortical-brainstem circuit predicts and governs compulsive alcohol drinking.

Science 2019 11;366(6468):1008-1012

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

What individual differences in neural activity predict the future escalation of alcohol drinking from casual to compulsive? The neurobiological mechanisms that gate the transition from moderate to compulsive drinking remain poorly understood. We longitudinally tracked the development of compulsive drinking across a binge-drinking experience in male mice. Binge drinking unmasked individual differences, revealing latent traits in alcohol consumption and compulsive drinking despite equal prior exposure to alcohol. Distinct neural activity signatures of cortical neurons projecting to the brainstem before binge drinking predicted the ultimate emergence of compulsivity. Mimicry of activity patterns that predicted drinking phenotypes was sufficient to bidirectionally modulate drinking. Our results provide a mechanistic explanation for individual variance in vulnerability to compulsive alcohol drinking.
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http://dx.doi.org/10.1126/science.aay1186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989100PMC
November 2019

Activity-Dependent Epigenetic Remodeling in Cocaine Use Disorder.

Handb Exp Pharmacol 2020 ;258:231-263

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Substance use disorder (SUD) is a behavioral disorder characterized by cycles of abstinence, drug seeking, and relapse. SUD is characterized by aberrant learning processes which develop after repeated exposure to drugs of abuse. At the core of this phenotype is the persistence of symptoms, such as craving and relapse to drug seeking, long after the cessation of drug use. The neural basis of these behavioral changes has been linked to dysfunction in neural circuits across the brain; however, the molecular drivers that allow for these changes to persist beyond the lifespan of any individual protein remain opaque. Epigenetic adaptations - where DNA is modified to increase or decrease the probability of gene expression at key genes - have been identified as a mechanism underlying the long-lasting nature of drug-seeking behavior. Thus, to understand SUD, it is critical to define the interplay between neuronal activation and longer-term changes in transcription and epigenetic remodeling and define their role in addictive behaviors. In this review, we discuss the current understanding of drug-induced changes to circuit function, recent discoveries in epigenetic mechanisms that mediate these changes, and, ultimately, how these adaptations drive the persistent nature of relapse, with emphasis on adaptations in models of cocaine use disorder. Understanding the complex interplay between epigenetic gene regulation and circuit activity will be critical in elucidating the neural mechanisms underlying SUD. This, with the advent of novel genetic-based techniques, will allow for the generation of novel therapeutic avenues to improve treatment outcomes in SUD.
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http://dx.doi.org/10.1007/164_2019_257DOI Listing
September 2020

Capturing the complexity of sex differences requires multidimensional behavioral models.

Authors:
Cody A Siciliano

Neuropsychopharmacology 2019 11 4;44(12):1997-1998. Epub 2019 Jun 4.

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

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http://dx.doi.org/10.1038/s41386-019-0424-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887867PMC
November 2019

Modulation of striatal dopamine dynamics by cocaine self-administration and amphetamine treatment in female rats.

Eur J Neurosci 2019 08 1;50(4):2740-2749. Epub 2019 Jun 1.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self-administration and returned to pre-cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self-administration (1.5 mg kg  inj , 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast-scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate-putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self-administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate-putamen, neither cocaine self-administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self-administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.
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http://dx.doi.org/10.1111/ejn.14437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742524PMC
August 2019

Dopamine tunes prefrontal outputs to orchestrate aversive processing.

Brain Res 2019 06 1;1713:16-31. Epub 2018 Dec 1.

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

Decades of research suggest that the mesocortical dopamine system exerts powerful control over mPFC physiology and function. Indeed, dopamine signaling in the medial prefrontal cortex (mPFC) is implicated in a vast array of processes, including working memory, stimulus discrimination, stress responses, and emotional and behavioral control. Consequently, even slight perturbations within this delicate system result in profound disruptions of mPFC-mediated processes. Many neuropsychiatric disorders are associated with dysregulation of mesocortical dopamine, including schizophrenia, depression, attention deficit hyperactivity disorder, post-traumatic stress disorder, among others. Here, we review the anatomy and functions of the mesocortical dopamine system. In contrast to the canonical role of striatal dopamine in reward-related functions, recent work has revealed that mesocortical dopamine fine-tunes distinct efferent projection populations in a manner that biases subsequent behavior towards responding to stimuli associated with potentially aversive outcomes. We propose a framework wherein dopamine can serve as a signal for switching mPFC states by orchestrating how information is routed to the rest of the brain.
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http://dx.doi.org/10.1016/j.brainres.2018.11.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575248PMC
June 2019

Leveraging calcium imaging to illuminate circuit dysfunction in addiction.

Alcohol 2019 02 6;74:47-63. Epub 2018 Jun 6.

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; The Salk Institute for Biological Sciences, 10010 N Torrey Pines Road, La Jolla, CA 92037, United States. Electronic address:

Alcohol and drug use can dysregulate neural circuit function to produce a wide range of neuropsychiatric disorders, including addiction. To understand the neural circuit computations that mediate behavior, and how substances of abuse may transform them, we must first be able to observe the activity of circuits. While many techniques have been utilized to measure activity in specific brain regions, these regions are made up of heterogeneous sub-populations, and assessing activity from neuronal populations of interest has been an ongoing challenge. To fully understand how neural circuits mediate addiction-related behavior, we must be able to reveal the cellular granularity within brain regions and circuits by overlaying functional information with the genetic and anatomical identity of the cells involved. The development of genetically encoded calcium indicators, which can be targeted to populations of interest, allows for in vivo visualization of calcium dynamics, a proxy for neuronal activity, thus providing an avenue for real-time assessment of activity in genetically and anatomically defined populations during behavior. Here, we highlight recent advances in calcium imaging technology, compare the current technology with other state-of-the-art approaches for in vivo monitoring of neural activity, and discuss the strengths, limitations, and practical concerns for observing neural circuit activity in preclinical addiction models.
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http://dx.doi.org/10.1016/j.alcohol.2018.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575247PMC
February 2019

Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli.

Nature 2018 11 7;563(7731):397-401. Epub 2018 Nov 7.

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.

Dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioural functions; however, the precise circuit computations remain unknown. One potentially unifying model by which dopamine may underlie a diversity of functions is by modulating the signal-to-noise ratio in subpopulations of mPFC neurons, where neural activity conveying sensory information (signal) is amplified relative to spontaneous firing (noise). Here we demonstrate that dopamine increases the signal-to-noise ratio of responses to aversive stimuli in mPFC neurons projecting to the dorsal periaqueductal grey (dPAG). Using an electrochemical approach, we reveal the precise time course of pinch-evoked dopamine release in the mPFC, and show that mPFC dopamine biases behavioural responses to aversive stimuli. Activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviours. mPFC-dPAG neurons display robust shock-induced excitations, as visualized by single-cell, projection-defined microendoscopic calcium imaging. Finally, photostimulation of dopamine terminals in the mPFC reveals an increase in the signal-to-noise ratio in mPFC-dPAG responses to aversive stimuli. Together, these data highlight how dopamine in the mPFC can selectively route sensory information to specific downstream circuits, representing a potential circuit mechanism for valence processing.
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http://dx.doi.org/10.1038/s41586-018-0682-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645392PMC
November 2018

Double threat in striatal dopamine signaling.

Nat Neurosci 2018 10;21(10):1296-1297

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.

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http://dx.doi.org/10.1038/s41593-018-0243-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683097PMC
October 2018

Granulocyte Colony Stimulating Factor Enhances Reward Learning through Potentiation of Mesolimbic Dopamine System Function.

J Neurosci 2018 10 27;38(41):8845-8859. Epub 2018 Aug 27.

Department of Pharmacology,

Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocyte-colony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor α. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli. Emerging evidence has highlighted the importance of the immune system in psychiatric diseases states. However, the effects of peripheral cytokines on motivation and cognitive function are largely unknown. Here, we report that granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine with known trophic and neuroprotective properties in the brain, acts directly on dopaminergic circuits to enhance their function. These changes in dopaminergic dynamics enhance reward learning and motivation for natural stimuli. Together, these results suggest that targeting immune factors may provide a new avenue for therapeutic intervention in the multiple psychiatric disorders that are characterized by motivational and cognitive deficits.
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http://dx.doi.org/10.1523/JNEUROSCI.1116-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181308PMC
October 2018

Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure.

Handb Exp Pharmacol 2018 ;248:213-238

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Alcohol use disorders are a leading public health concern, engendering enormous costs in terms of both economic loss and human suffering. These disorders are characterized by compulsive and excessive alcohol use, as well as negative affect and alcohol craving during abstinence. Extensive research has implicated the dopamine system in both the acute pharmacological effects of alcohol and the symptomology of alcohol use disorders that develop after extended alcohol use. Preclinical research has shed light on many mechanisms by which chronic alcohol exposure dysregulates the dopamine system. However, many of the findings are inconsistent across experimental parameters such as alcohol exposure length, route of administration, and model organism. We propose that the dopaminergic alterations driving the core symptomology of alcohol use disorders are likely to be relatively stable across experimental settings. Recent work has been aimed at using multiple model organisms (mouse, rat, monkey) across various alcohol exposure procedures to search for commonalities. Here, we review recent advances in our understanding of the effects of chronic alcohol use on the dopamine system by highlighting findings that are consistent across experimental setting and species.
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http://dx.doi.org/10.1007/164_2018_106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195853PMC
June 2019

Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation.

J Neurosci 2018 01 24;38(2):484-497. Epub 2017 Nov 24.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157,

Cocaine abuse disrupts dopamine system function, and reduces cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criterion for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were twofold; we sought to (1) identify the molecular mechanisms by which cocaine exposure produces tolerance and (2) determine whether amphetamine-induced reductions in cocaine intake are connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats, we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed cocaine tolerance. Amphetamine treatment also reversed escalated cocaine intake and decreased motivation to obtain cocaine as measured in a behavioral economics task, thereby linking tolerance to multiple facets of cocaine use. Finally, using fluorescence resonance energy transfer imaging, we found that cocaine tolerance is associated with the formation of DAT-DAT complexes, and that amphetamine disperses these complexes. In addition to extending our basic understanding of DATs and their role in cocaine reinforcement, we serendipitously identified a novel therapeutic target: DAT oligomer complexes. We show that dispersion of oligomers is concomitant with reduced cocaine intake, and propose that pharmacotherapeutics aimed at these complexes may have potential for cocaine addiction treatment. Tolerance to cocaine's subjective effects is a cardinal symptom of cocaine addiction and a DSM-V criterion for substance abuse disorders. However, elucidating the molecular adaptions that produce tolerance and determining its behavioral impact have proven difficult. Using cocaine self-administration in rats, we link tolerance to cocaine effects at the dopamine transporter (DAT) with aberrant cocaine-taking behaviors. Further, tolerance was associated with multi-DAT complexes, which formed after cocaine exposure. Treatment with amphetamine deconstructed DAT complexes, reversed tolerance, and decreased cocaine seeking. These data describe the behavioral consequence of cocaine tolerance, provide a putative mechanism for its development, and suggest that compounds that disperse DAT complexes may be efficacious treatments for cocaine addiction.
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http://dx.doi.org/10.1523/JNEUROSCI.2604-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761621PMC
January 2018

α6β2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty.

Neuropharmacology 2017 Nov 27;126:281-291. Epub 2017 Jun 27.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States. Electronic address:

Determining neurobiological factors that contribute to individual variance in drug addiction vulnerability allows for identification of at-risk populations, use of preventative measures and personalized medicine in the treatment of substance use disorders. Rodents that exhibit high locomotor activity when exploring an inescapable novel environment (high-responder; HR) are more susceptible to the reinforcing effects of many abused compounds, including nicotine, as compared to animals that exhibit low locomotor activity (low-responder; LR). Given that nicotinic acetylcholine receptor (nAChR) modulation of reward-related dopamine signaling at accumbal dopamine terminals is critical for the acquisition of drug self-administration, we hypothesized that nAChR modulation of dopamine release would be predicted by an animal's novelty response. Using voltammetry in the nucleus accumbens core of rats, we found that nicotine produced opposite effects in HR and LR animals on stimulation frequencies that model phasic dopamine release, whereby release magnitude was either augmented or attenuated, respectively. Further, nicotine suppressed dopamine release elected by stimulation frequencies that model tonic release in LR animals, but had no effect in HR animals. The differential effects of nicotine were likely due to desensitization of nAChRs, since the nAChR antagonists mecamylamine (non-selective, 2 μM), dihydro-beta-erythroidine (β2-selective, 500 nM), and α-conotoxin MII [H9A; L15A] (α6-selective, 100 nM) produced effects similar to nicotine. Moreover, dihydro-beta-erythroidine failed to show differential effects in HR and LR rats when applied after α-conotoxin MII [H9A; L15A], suggesting a critical role of α6β2 compared non α6-containing nAChRs in the differential effects observed in these phenotypes. These results delineate a potential mechanism for individual variability in behavioral sensitivity to nicotine.
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http://dx.doi.org/10.1016/j.neuropharm.2017.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963689PMC
November 2017

Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration.

Neuropsychopharmacology 2017 Aug 31;42(9):1893-1904. Epub 2017 Jan 31.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Although the dopamine transporter (DAT) is the primary site of action for cocaine, and the dopamine system is known to mediate the reinforcing effects of cocaine, the dopaminergic variations underlying individual differences in cocaine self-administration behaviors are not fully understood. Recent advances in the application of economic principles to operant tasks in rodents have allowed for the within-subject, within-session determination of both consummatory and appetitive responding for reinforcers. Here we combined a behavioral economics approach with cocaine self-administration and ex vivo voltammetric recording of dopamine signaling in the core of the nucleus accumbens of rats to determine the relationship between dopamine signaling and discrete aspects of cocaine taking and seeking. We found neither dopamine release or uptake tracked individual differences in cocaine consumption or the reinforcing efficacy of cocaine. Cocaine potency at the DAT was correlated with reinforcing efficacy, but was not related to cocaine consumption. Further, we introduce a novel analysis that determines perseverative responding within the same procedure, and find that cocaine potency at the DAT also tracks differences in perseverative responding. Together, we demonstrate that cocaine effects at the DAT determine the reinforcing efficacy of cocaine, and perseverative responding for sub-threshold doses of cocaine that do not maintain responding when presented in isolation. Surprisingly, we find that variations in cocaine potency do not account for differences in cocaine consumption, suggesting that satiation for cocaine is determined by other targets or mechanisms. Finally, we outline a novel approach for relating drug-target interactions and potency to discrete motivational states during a single self-administration session.
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http://dx.doi.org/10.1038/npp.2017.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520781PMC
August 2017

Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine.

J Neurosci 2016 07;36(30):7807-16

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157

Unlabelled: Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a "primed" state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse.

Significance Statement: Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action, the dopamine transporter (DAT). Preclinical literature has shown that reduced cocaine potency at the DAT increases cocaine taking, highlighting the key role of tolerance in addiction. Addiction is characterized by cycles of abstinence, often for many months, followed by relapse, making it important to determine possible interactions between abstinence and subsequent drug re-exposure. Using a rodent model of cocaine abuse, we found long-lasting, possibly permanent, cocaine-induced alterations to the DAT, whereby cocaine tolerance is reinstated by minimal drug exposure, even after recovery of DAT function over prolonged abstinence periods.
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http://dx.doi.org/10.1523/JNEUROSCI.4652-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961771PMC
July 2016

Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains.

Alcohol 2017 Feb 11;58:25-32. Epub 2016 Jun 11.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address:

Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J × DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings show differential autoreceptor effects on dopamine synthesis between C57BL/6J and DBA/2J mice, and suggest that decreased dopaminergic activity is associated with excessive drinking.
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http://dx.doi.org/10.1016/j.alcohol.2016.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684872PMC
February 2017

Dopamine D3 autoreceptor inhibition enhances cocaine potency at the dopamine transporter.

J Neurochem 2016 09 15;138(6):821-9. Epub 2016 Aug 15.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Cocaine is a commonly abused central nervous system stimulant that enhances dopamine (DA) neurotransmission through its ability to block dopamine transporters (DATs). Recent evidence suggests there may be an interaction between DATs and D2/D3 autoreceptors that modulates cocaine's effects. The purpose of this study was to explore how D2/D3 autoreceptors modulate the ability of cocaine to inhibit DA uptake through DATs on pre-synaptic DA terminals. Using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core from male and female C57BL/6J mice, we first sought to examine the effects of global autoreceptor blockade using the non-selective D2/D3 autoreceptor antagonist, raclopride. We found that the ability of cocaine to inhibit DA uptake was increased by raclopride and that this effect was consistent across sexes. Furthermore, using D2 (L-741,626) or D3 (SB-277011-A) autoreceptor selective antagonists, we discovered that blockade of D3, but not D2, autoreceptors was responsible for the increased cocaine potency. Alterations in cocaine potency were attributable to alterations in uptake inhibition, rather than cocaine effects on vesicular DA release, suggesting that these results may be a product of a functional D3/DAT interaction apart from the canonical inhibitory actions of D3 autoreceptors on DA release. In addition, application of D2 (sumanirole) and D3 (PD 128907) autoreceptor-specific agonists had inverse effects, whereby D2 autoreceptor activation decreased cocaine potency and D3 autoreceptor activation had no effect. Together, these data show that DA autoreceptors dynamically regulate cocaine potency at the DAT, which is important for understanding cocaine's rewarding and addictive properties. We propose a model whereby presynaptic dopamine autoreceptors dynamically modulate cocaine potency through two separate mechanisms. We demonstrate that D2 agonists decrease cocaine potency, whereas D3 antagonists increase cocaine potency, likely through an allosteric mechanism outside of their canonical actions on dopamine release. These findings give important and novel insight into the contribution of D2/D3 autoreceptors to dopamine transporter function.
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http://dx.doi.org/10.1111/jnc.13732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017912PMC
September 2016

Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques.

Psychopharmacology (Berl) 2016 Apr 19;233(8):1435-43. Epub 2016 Feb 19.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.

Rationale: Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are not fully understood.

Objective: Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration.

Methods: Female rhesus macaques completed 1 year of daily (22 h/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa opioid receptor agonist) induced inhibition of dopamine release.

Results: Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa opioid receptors, which both act as negative regulators of presynaptic dopamine release, was moderately and robustly enhanced in ethanol drinkers.

Conclusions: Greater uptake rates and sensitivity to D2-type autoreceptor and kappa opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system and suggest that the dopamine and dynorphin/kappa opioid receptor systems may be efficacious pharmacotherapeutic targets in the treatment of alcohol use disorders.
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http://dx.doi.org/10.1007/s00213-016-4239-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814331PMC
April 2016
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