Publications by authors named "Danny G Winder"

100 Publications

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
July 2021

Delineation of an insula-BNST circuit engaged by struggling behavior that regulates avoidance in mice.

Nat Commun 2021 06 11;12(1):3561. Epub 2021 Jun 11.

Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.

Active responses to stressors involve motor planning, execution, and feedback. Here we identify an insular cortex to BNST (insula) circuit recruited during restraint stress-induced active struggling that modulates affective behavior. We demonstrate that activity in this circuit tightly follows struggling behavioral events and that the size of the fluorescent sensor transient reports the duration of the struggle event, an effect that fades with repeated exposure to the homotypic stressor. Struggle events are associated with enhanced glutamatergic- and decreased GABAergic signaling in the insular cortex, indicating the involvement of a larger circuit. We delineate the afferent network for this pathway, identifying substantial input from motor- and premotor cortex, somatosensory cortex, and the amygdala. To begin to dissect these incoming signals, we examine the motor cortex input, and show that the cells projecting from motor regions to insular cortex are engaged shortly before struggle event onset. This study thus demonstrates a role for the insula pathway in monitoring struggling activity and regulating affective behavior.
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http://dx.doi.org/10.1038/s41467-021-23674-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196075PMC
June 2021

Alterations in connectivity of the bed nucleus of the stria terminalis during early abstinence in individuals with alcohol use disorder.

Alcohol Clin Exp Res 2021 05 8;45(5):1028-1038. Epub 2021 Apr 8.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: For individuals with Alcohol Use Disorder (AUD), long-term recovery is difficult in part due to symptoms of anxiety that occur during early abstinence and can trigger relapse. Research in rodent models of AUD has identified the bed nucleus of the stria terminalis (BNST), a small, sexually dimorphic, subcortical region, as critical for regulating anxiety-like behaviors during abstinence, particularly in female mice. Furthermore, prolonged alcohol use and subsequent abstinence alter BNST afferent and efferent connections to other brain regions. To our knowledge, however, no studies of early abstinence have investigated BNST structural connectivity in humans during abstinence; this study addresses that gap.

Methods: Nineteen participants with AUD currently in early abstinence and 20 healthy controls completed a diffusion tensor imaging (DTI) scan. BNST structural connectivity was evaluated using probabilistic tractography. A linear mixed model was used to test between-groups differences in BNST network connectivity. Exploratory analyses were conducted to test for correlations between BNST connectivity and alcohol use severity and anxiety within the abstinence group. Sex was included as a factor for all analyses.

Results: The BNST showed stronger structural connectivity with the BNST network in early abstinence women than in control women, which was not seen in men. Women also showed region-specific differences, with stronger BNST-hypothalamus structural connectivity but weaker vmPFC-BNST structural connectivity than men. Exploratory analyses also demonstrated a relationship between alcohol use severity and vmPFC-BNST structural connectivity that was moderated by sex.

Conclusions: This study is the first to demonstrate BNST structural connectivity differences in early abstinence and revealed key sex differences. The sex-specific differences in BNST structural connectivity during early abstinence could underlie known sex differences in abstinence symptoms and relapse risk and help to inform potential sex-specific treatments.
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http://dx.doi.org/10.1111/acer.14596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131245PMC
May 2021

Increased Synaptic Strength and mGlu Receptor Plasticity on Mouse Prefrontal Cortex Intratelencephalic Pyramidal Cells Following Intermittent Access to Ethanol.

Alcohol Clin Exp Res 2021 03 9;45(3):518-529. Epub 2021 Feb 9.

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

Background: The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus).

Methods: In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1 day after 4 to 5 weeks of intermittent access (IA) EtOH exposure.

Results: Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking.

Conclusions: Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu and/or mGlu receptor function as potential treatments for AUD.
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http://dx.doi.org/10.1111/acer.14546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969423PMC
March 2021

Contrasting sex-dependent adaptations to synaptic physiology and membrane properties of prefrontal cortex interneuron subtypes in a mouse model of binge drinking.

Neuropharmacology 2020 11 8;178:108126. Epub 2020 Aug 8.

Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA; Warren Center for Neuroscience Drug Discovery, Nashville, TN, 37232, USA; Vanderbilt Center for Addiction Research, Nashville, TN, 37232, USA.

Alcohol use disorder (AUD) affects all sexes, however women who develop AUD may be particularly susceptible to cravings and other components of the disease. While many brain regions are involved in AUD etiology, proper prefrontal cortex (PFC) function is particularly important for top-down craving management and the moderation of drinking behaviors. Essential regulation of PFC output is provided by local inhibitory interneurons, yet how drinking affects interneuron physiology remains poorly understood, particularly in female individuals. To address this gap, we generated fluorescent reporter transgenic mice to label the two major classes of interneuron in deep layer prelimbic PFC, based on expression of parvalbumin (PV-IN) or somatostatin (SST-IN). We then interrogated PV-IN and SST-IN membrane and synaptic physiology in a rodent model of binge drinking. Beginning in late adolescence, mice received 3-4 weeks of intermittent access (IA) ethanol. We prepared acute brain slices one day after the last drinking session. PV-INs but not SST-INs from IA ethanol mice displayed increased excitability relative to controls, regardless of sex. On the contrary, synaptic adaptations to PV-INs differed based on sex. While drinking decreased excitatory synaptic strength onto PV-INs from female mice, PV-INs from IA ethanol male mice exhibited potentiated excitatory transmission relative to controls. In contrast, decreased synaptic strength onto SST-INs was observed following IA ethanol in all groups of mice. Together, these findings illustrate novel sex differences in drinking-related PFC pathophysiology. Discovering means to restore PV-IN and SST-IN dysfunction following extended drinking provides opportunities for developing new treatments for all AUD patients.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544622PMC
November 2020

BNST GluN2D-Containing NMDA Receptors Influence Anxiety- and Depressive-like Behaviors and ModulateCell-Specific Excitatory/Inhibitory Synaptic Balance.

J Neurosci 2020 05 10;40(20):3949-3968. Epub 2020 Apr 10.

Department of Molecular Physics & Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, 37212

Excitatory signaling mediated by NMDARs has been shown to regulate mood disorders. However, current treatments targeting NMDAR subtypes have shown limited success in treating patients, highlighting a need for alternative therapeutic targets. Here, we identify a role for GluN2D-containing NMDARs in modulating emotional behaviors and neural activity in the bed nucleus of the stria terminalis (BNST). Using a GluN2D KO mouse line (GluN2D), we assessed behavioral phenotypes across tasks modeling emotional behavior. We then used a combination of electrophysiology and fiber photometry to assess changes in BNST plasticity, cell-specific physiology, and cellular activity profiles. GluN2D male mice exhibit evidence of exacerbated negative emotional behavior, and a deficit in BNST synaptic potentiation. We also found that GluN2D is functionally expressed on corticotropin-releasing factor (CRF)-positive BNST cells implicated in driving negative emotional states, and recordings in mice of both sexes revealed increased excitatory and reduced inhibitory drive onto GluN2D BNST-CRF cells and increased activity Using a GluN2D conditional KO line (GluN2D) to selectively delete the subunit from the BNST, we find that BNST-GluN2D male mice exhibit increased depressive-like behaviors, as well as altered NMDAR function and increased excitatory drive onto BNST-CRF neurons. Together, this study supports a role for GluN2D-NMDARs in regulating emotional behavior through their influence on excitatory signaling in a region-specific manner, and suggests that these NMDARs may serve as a novel target for selectively modulating glutamate signaling in stress-responsive structures and cell populations. Excitatory signaling mediated through NMDARs plays an important role in shaping emotional behavior; however, the receptor subtypes/brain regions through which this occurs are poorly understood. Here, we demonstrate that loss of GluN2D-containing NMDARs produces an increase in anxiety- and depressive-like behaviors in mice, deficits in BNST synaptic potentiation, and increased activity in BNST-CRF neurons known to drive negative emotional behavior. Further, we determine that deleting GluN2D in the BNST leads to increased depressive-like behaviors and increased excitatory drive onto BNST-CRF cells. Collectively, these results demonstrate a role for GluN2D-NMDARs in regulating the activity of stress-responsive structures and neuronal populations in the adult brain, suggesting them as a potential target for treating negative emotional states in mood-related disorders.
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http://dx.doi.org/10.1523/JNEUROSCI.0270-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219300PMC
May 2020

α-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference.

Neuropsychopharmacology 2020 08 19;45(9):1473-1481. Epub 2020 Feb 19.

Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Basic Sciences, Nashville, TN, United States.

The α-adrenergic receptor (α-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α-AR autoreceptors, it also activates excitatory G-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α-AR heteroreceptors and BNST G-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST G-coupled α-AR heteroreceptor signaling using a G-coupled designer receptor exclusively activated by designer drug (G-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST G-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α-AR heteroreceptors and BNST G-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.
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http://dx.doi.org/10.1038/s41386-020-0641-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360592PMC
August 2020

Anxiety during abstinence from alcohol: A systematic review of rodent and human evidence for the anterior insula's role in the abstinence network.

Addict Biol 2021 03 28;26(2):e12861. Epub 2020 Jan 28.

Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.

Alcohol Use Disorder (AUD) is a chronic, relapsing disease that impacts almost a third of Americans. Despite effective treatments for attaining sobriety, the majority of patients relapse within a year, making relapse a substantial barrier to long-term treatment success. A major factor contributing to relapse is heightened negative affect that results from the combination of abstinence-related increases in stress-reactivity and decreases in reward sensitivity. Substantial research has contributed to the understanding of reward-related changes in AUD. However, less is known about anxiety during abstinence, a critical component of understanding addiction as anxiety during abstinence can trigger relapse. Most of what we know about abstinence-related negative affect comes from rodent studies which have identified key brain regions responsible for abstinence-related behaviors. This abstinence network is composed of brain regions that make up the extended amygdala: the nucleus accumbens (NAcc), the central nucleus of the amygdala (CeA), and the bed nucleus of the stria terminalis (BNST). More recently, emerging evidence from rodent and human studies suggests a fourth brain region, the anterior insula, might be part of the abstinence network. Here, we review current rodent and human literature on the extended amygdala's role in alcohol abstinence and anxiety, present evidence for the anterior insula's role in the abstinence network, and provide future directions for research to further elucidate the neural underpinnings of abstinence in humans. A better understanding of the abstinence network is critical toward understanding and possibly preventing relapse in AUD.
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http://dx.doi.org/10.1111/adb.12861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384950PMC
March 2021

BNST-insula structural connectivity in humans.

Neuroimage 2020 04 16;210:116555. Epub 2020 Jan 16.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA; Research and Development, Department of Veterans Affairs Medical Center, Nashville, TN, USA. Electronic address:

The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089680PMC
April 2020

mGlu and mGlu Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Neuron 2020 01 14;105(1):46-59.e3. Epub 2019 Nov 14.

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Nashville, TN 37232, USA. Electronic address:

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu) and 3 (mGlu) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu or mGlu potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu or mGlu NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu and mGlu NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu and mGlu NAMs induce antidepressant-like effects through related but divergent mechanisms of action.
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http://dx.doi.org/10.1016/j.neuron.2019.09.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952546PMC
January 2020

Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states.

Nat Neurosci 2019 12 11;22(12):2000-2012. Epub 2019 Nov 11.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.

Acquisition and extinction of learned fear responses utilize conserved but flexible neural circuits. Here we show that acquisition of conditioned freezing behavior is associated with dynamic remodeling of relative excitatory drive from the basolateral amygdala (BLA) away from corticotropin releasing factor-expressing (CRF) centrolateral amygdala neurons, and toward non-CRF (CRF) and somatostatin-expressing (SOM) neurons, while fear extinction training remodels this circuit back toward favoring CRF neurons. Importantly, BLA activity is required for this experience-dependent remodeling, while directed inhibition of the BLA-centrolateral amygdala circuit impairs both fear memory acquisition and extinction memory retrieval. Additionally, ectopic excitation of CRF neurons impairs fear memory acquisition and facilities extinction, whereas CRF neuron inhibition impairs extinction memory retrieval, supporting the notion that CRF neurons serve to inhibit learned freezing behavior. These data suggest that afferent-specific dynamic remodeling of relative excitatory drive to functionally distinct subcortical neuronal output populations represents an important mechanism underlying experience-dependent modification of behavioral selection.
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http://dx.doi.org/10.1038/s41593-019-0528-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884697PMC
December 2019

Driving the Downward Spiral: Alcohol-Induced Dysregulation of Extended Amygdala Circuits and Negative Affect.

Alcohol Clin Exp Res 2019 10 30;43(10):2000-2013. Epub 2019 Aug 30.

Vanderbilt Center for Addiction Research, Nashville, Tennessee.

Alcohol use disorder (AUD) afflicts a large number of individuals, families, and communities globally. Affective disturbances, including stress, depression, and anxiety, are highly comorbid with AUD, contributing in some cases to initial alcohol use and continued use. Negative affect has a particularly strong influence on the withdrawal/abstinence stage of addiction as individuals with AUD frequently report stressful events, depression, and anxiety as key factors for relapse. Treatment options for negative affect associated with AUD are limited and often ineffective, highlighting the pressing need for preclinical studies examining the underlying neural circuitry driving AUD-associated negative affect. The extended amygdala (EA) is a set of brain areas collectively involved in generating and regulating affect, and extensive research has defined a critical role for the EA in all facets of substance use disorder. Here, we review the expansive historical literature examining the effects of ethanol exposure on the EA, with an emphasis on the complex EA neural circuitry driving negative affect in all phases of the alcohol addiction cycle. Specifically, this review focuses on the effects of alcohol exposure on the neural circuitry in 2 key components of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Additionally, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and neural circuitry in the EA, with the long-term goal of developing better diagnostic tools and new pharmacological targets aimed at treating negative affect in AUD. The concepts detailed here will serve as the foundation for a companion review focusing on the potential for the endogenous cannabinoid system in the EA as a novel target for treating the stress, anxiety, and negative emotional state driving AUD.
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http://dx.doi.org/10.1111/acer.14178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779502PMC
October 2019

Endocannabinoid Signaling in the Central Amygdala and Bed Nucleus of the Stria Terminalis: Implications for the Pathophysiology and Treatment of Alcohol Use Disorder.

Alcohol Clin Exp Res 2019 10 21;43(10):2014-2027. Epub 2019 Aug 21.

Vanderbilt Center for Addiction Research, Nashville, Tennessee.

High rates of relapse are a chronic and debilitating obstacle to effective treatment of alcohol use disorder (AUD); however, no effective treatments are available to treat symptoms induced by protracted abstinence. In the first part of this 2-part review series, we examine the literature supporting the effects of alcohol exposure within the extended amygdala (EA) neural circuitry. In Part 2, we focus on a potential way to combat negative affect associated with AUD, by exploring the therapeutic potential of the endogenous cannabinoid (eCB) system. The eCB system is a potent modulator of neural activity in the brain, and its ability to mitigate stress and negative affect has long been an area of interest for developing novel therapeutics. This review details the recent advances in our understanding of eCB signaling in 2 key regions of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), and their role in regulating negative affect. Despite an established role for EA eCB signaling in reducing negative affect, few studies have examined the potential for eCB-based therapies to treat AUD-associated negative affect. In this review, we present an overview of studies focusing on eCB signaling in EA and cannabinoid modulation on EA synaptic activity. We further discuss studies suggesting dysregulation of eCB signaling in models of AUD and propose that pharmacological augmentation of eCB could be a novel approach to treat aspects of AUD. Lastly, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and the EA eCB system that could yield new pharmacotherapies targeting negative affective symptoms associated with AUD.
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http://dx.doi.org/10.1111/acer.14159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779484PMC
October 2019

Acute Negative Allosteric Modulation of M Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception.

ACS Chem Neurosci 2019 08 24;10(8):3740-3750. Epub 2019 Jul 24.

Opioid use disorder (OUD) is a debilitating neuropsychiatric condition characterized by compulsive opioid use, dependence, and repeated relapse after periods of abstinence. Given the high risk of developing OUD following prescription opioid use, the continued need for opioid-induced analgesia, and the limitations of current OUD treatments, it is necessary to develop novel, non-opioid-based treatments for OUD and decrease abuse potential of prescription opioids. Recent evidence suggests that negative allosteric modulation (NAM) of the M muscarinic acetylcholine receptor (M mAChR) may provide an alternative therapeutic approach for the treatment of OUD. Previous studies demonstrated localization of M mAChR expression within the mesocorticolimbic reward circuitry and that the selective M NAM ML375 attenuates both cocaine and alcohol self-administration in rats. In the present study, the effects of ML375 were evaluated in rats self-administering the μ-opioid agonists oxycodone or remifentanil on a progressive ratio (PR) schedule or on cue reactivity (a rodent model of relapse) in the absence of oxycodone following 72 h of abstinence. ML375 reduced the PR break point for oxycodone and remifentanil self-administration and attenuated cue-elicited responding. Importantly, ML375 did not affect sucrose pellet-maintained responding on a PR schedule or opioid-induced antinociception using the hot-plate and tail-flick assays. We also confirm expression of M mAChR mRNA in the ventral tegmental area and show that this is primarily on dopamine (tyrosine hydroxylase mRNA-positive) neurons. Taken together, these findings suggest that selective functional antagonism of the M mAChR may represent a novel, non-opioid-based treatment for OUD.
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http://dx.doi.org/10.1021/acschemneuro.9b00274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383364PMC
August 2019

Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling.

Alcohol Clin Exp Res 2019 08 18;43(8):1695-1701. Epub 2019 Jun 18.

From the, Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania.

Background: Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.

Methods: Adult male CRF-tomato reporter mice were treatment-naïve, or either exposed to CIE for 2 weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques.

Results: We found that NE depolarized BNST CRF neurons in naïve mice in a β-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE- or stress-exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α-AR-dependent.

Conclusions: Altogether, these findings suggest that stress and CIE interact with β-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β-AR balance of BNST CRF neuronal excitability. Restoration of α/β-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.
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http://dx.doi.org/10.1111/acer.14118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677590PMC
August 2019

Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

Sci Signal 2019 02 19;12(569). Epub 2019 Feb 19.

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

G protein-coupled receptors (GPCRs) that couple to G proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP25Δ3 homozygote mice exhibited normal presynaptic inhibition by GABA receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT receptors and adrenergic α receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25Δ3 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by G-coupled GPCRs through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.
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http://dx.doi.org/10.1126/scisignal.aat8595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758873PMC
February 2019

α-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity .

J Neurosci 2019 01 26;39(3):472-484. Epub 2018 Nov 26.

Vanderbilt Center for Addiction Research,

Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α-AR is a G-linked GPCR, we assessed the impact of activating the G-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced in BNST neurons. Further, using as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α-AR activation suppresses the activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons. Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α-AR agonist guanfacine reduces activity of these cells , and reduces excitatory PBN inputs onto these cells Additionally, we uncover a novel sex-dependent coexpression of with in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.
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http://dx.doi.org/10.1523/JNEUROSCI.1035-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335747PMC
January 2019

Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence.

Neuropsychopharmacology 2019 02 2;44(3):526-537. Epub 2018 Nov 2.

Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.

Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a G-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.
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http://dx.doi.org/10.1038/s41386-018-0257-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333805PMC
February 2019

Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

Biol Psychiatry 2019 02 17;85(3):237-247. Epub 2018 Aug 17.

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

Background: Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAG cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown.

Methods: This study combined designer receptors exclusively activated by designer drugs (DREADDs), behavioral pharmacology, electrophysiology, and immunoelectron microscopy in male and female mice to elucidate mechanisms in the vPAG that promote arousal.

Results: Activation of locus coeruleus projections to the vPAG or vPAG neurons induced by DREADDs promoted arousal. Similarly, agonist stimulation of vPAG alpha1-adrenergic receptors (α1ARs) increased latency to fall asleep, whereas α1AR blockade had the opposite effect. α1AR stimulation drove vPAG activity in a glutamate-dependent, action potential-independent manner. Compared with other dopaminergic brain regions, α1ARs were enriched on astrocytes in the vPAG, and mimicking α1AR transmission specifically in vPAG astrocytes via Gq-DREADDS was sufficient to increase arousal. In general, the wake-promoting effects observed were not accompanied by hyperactivity.

Conclusions: These experiments revealed that vPAG α1ARs increase arousal, promote glutamatergic input onto vPAG neurons, and are abundantly expressed on astrocytes. Activation of locus coeruleus inputs, vPAG astrocytes, or vPAG neurons increase sleep latency but do not produce hyperactivity. Together, these results support an arousal circuit whereby noradrenergic transmission at astrocytic α1ARs activates wake-promoting vPAG neurons via glutamate transmission.
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http://dx.doi.org/10.1016/j.biopsych.2018.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326840PMC
February 2019

Dorsal BNST α-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.

J Neurosci 2018 10 27;38(42):8922-8942. Epub 2018 Aug 27.

Vanderbilt Center for Addiction Research,

Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α-adrenergic receptors (α-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine--oxide activation of the G-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction. Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.
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http://dx.doi.org/10.1523/JNEUROSCI.0963-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191524PMC
October 2018

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances.

Neuropsychopharmacology 2018 08 24;43(9):1915-1923. Epub 2018 May 24.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.

Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances. In parallel, we examined the impact of ketamine administration on long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST), a region implicated in affective disturbances. We administered ketamine (3 mg/kg i.p.) to female C57BL/6J mice with a history of chronic ethanol drinking at either the onset, two, or 6 days- post-abstinence and observed its impact on affective behavior in the elevated plus maze (EPM), the Novelty Suppressed Feeding Test (NSFT), and the Forced Swim Test (FST). In addition, we assessed BNST synaptic plasticity with field potential electrophysiology two to 3 weeks into abstinence. We found that early abstinence was associated with disrupted behavior on the EPM. Ketamine administered at the onset of forced abstinence prevented both the deficit in early EPM behavior, and the delayed deficits in NSFT and FST. However, ketamine administered either two or 6 days post-abstinence failed to prevent the abstinence-induced affective disturbances. To begin to explore potential alterations in neural circuit activity that accompanies these actions of ketamine, we assessed the impact of ketamine administration at the onset of forced abstinence and measured LTP induction in the BNST. We find that early ketamine administration persistently increased the capacity for LTP within the BNST. These findings suggest a critical period at the onset of forced abstinence in which ketamine inoculation can prevent the development of affective disturbances, in part by enhancing plasticity within the BNST.
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http://dx.doi.org/10.1038/s41386-018-0102-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046046PMC
August 2018

Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis: Underlying Mechanisms and Potential Ramifications for Reinstatement of Drug- and Alcohol-Seeking Behaviors.

ACS Chem Neurosci 2018 09 13;9(9):2173-2187. Epub 2018 Jun 13.

The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that shows significant changes in activity and plasticity through chronic exposure to drugs and stress. The region is critical for stress- and cue-induced reinstatement of drug-seeking behaviors and is thus a candidate region for the plastic changes that occur in abstinence that prime addicted patients for reinstatement behaviors. Here, we discuss the various forms of long-term potentiation (LTP) and long-term depression (LTD) in the rodent BNST and highlight the way that these changes in excitatory transmission interact with exposure to alcohol and other drugs of abuse, as well as other stressors. In addition, we highlight potential areas for future research in this area, including investigating input- and cell-specific bidirectional changes in activity. As we continue to accrue foundational knowledge in the mechanisms and effects of plasticity in the BNST, molecular targets and treatment strategies that are relevant to reinstatement behaviors will also begin to emerge. Here, we briefly discuss the effects of catecholamine receptor modulators on synaptic plasticity in the BNST due to the role of norepinephrine in LTD and dopamine on the short-term component of LTP as well as the role that signaling at these receptors plays in reinstatement of drug- and alcohol-seeking behaviors. We hope that insights gained on the specific changes in plasticity that occur within the BNST during abstinence from alcohol and other drugs of abuse will provide insight into the biological underpinnings of relapse behavior in human addicts and inform future treatment modalities for addiction that tackle this complex biological problem.
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http://dx.doi.org/10.1021/acschemneuro.8b00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146063PMC
September 2018

Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies.

ACS Chem Neurosci 2018 09 8;9(9):2188-2204. Epub 2018 Jun 8.

Department of Molecular Physiology and Biophysics , Vanderbilt University , Nashville , Tennessee 37212 , United States.

Developing efficacious treatments for alcohol use disorder (AUD) has proven difficult. The insidious nature of the disease necessitates a deep understanding of its underlying biology as well as innovative approaches to ameliorate ethanol-related pathophysiology. Excessive ethanol seeking and relapse are generated by long-term changes to membrane properties, synaptic physiology, and plasticity throughout the limbic system and associated brain structures. Each of these factors can be modulated by metabotropic glutamate (mGlu) receptors, a diverse set of G protein-coupled receptors highly expressed throughout the central nervous system. Here, we discuss how different components of the mGlu receptor family modulate neurotransmission in the limbic system and other brain regions involved in AUD etiology. We then describe how these processes are dysregulated following ethanol exposure and speculate about how mGlu receptor modulation might restore such pathophysiological changes. To that end, we detail the current understanding of the behavioral pharmacology of mGlu receptor-directed drug-like molecules in animal models of AUD. Together, this review highlights the prominent position of the mGlu receptor system in the pathophysiology of AUD and provides encouragement that several classes of mGlu receptor modulators may be translated as viable treatment options.
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http://dx.doi.org/10.1021/acschemneuro.8b00200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192262PMC
September 2018

Dorsolateral Striatum Engagement Interferes with Early Discrimination Learning.

Cell Rep 2018 05;23(8):2264-2272

Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.

In current models, learning the relationship between environmental stimuli and the outcomes of actions involves both stimulus-driven and goal-directed systems, mediated in part by the DLS and DMS, respectively. However, though these models emphasize the importance of the DLS in governing actions after extensive experience has accumulated, there is growing evidence of DLS engagement from the onset of training. Here, we used in vivo photosilencing to reveal that DLS recruitment interferes with early touchscreen discrimination learning. We also show that the direct output pathway of the DLS is preferentially recruited and causally involved in early learning and find that silencing the normal contribution of the DLS produces plasticity-related alterations in a PL-DMS circuit. These data provide further evidence suggesting that the DLS is recruited in the construction of stimulus-elicited actions that ultimately automate behavior and liberate cognitive resources for other demands, but with a cost to performance at the outset of learning.
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http://dx.doi.org/10.1016/j.celrep.2018.04.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015733PMC
May 2018

Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior.

Biol Psychiatry 2018 08 28;84(4):304-315. Epub 2017 Dec 28.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.

Background: Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored.

Methods: Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum.

Results: Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming.

Conclusions: These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.
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http://dx.doi.org/10.1016/j.biopsych.2017.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023784PMC
August 2018

The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

Alcohol Clin Exp Res 2017 Dec 25;41(12):1986-1999. Epub 2017 Oct 25.

Institute for Neuroscience, the University of Texas at Austin, Austin, Texas.

Corticotropin releasing factor (CRF) is a neuropeptide that plays a key role in behavioral and physiological responses to stress. A large body of animal literature implicates CRF acting at type 1 CRF receptors (CRFR1) in consumption by alcohol-dependent subjects, stress-induced reinstatement of alcohol seeking, and possibly binge alcohol consumption. These studies have encouraged recent pilot studies of CRFR1 antagonists in humans with alcohol use disorder (AUD). It was a great disappointment to many in the field that these studies failed to show an effect of these compounds on stress-induced alcohol craving. Here, we examine these studies to explore potential limitations and discuss preclinical and human literature to ask whether CRFR1 is still a valid drug target to pursue for the treatment of AUD.
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http://dx.doi.org/10.1111/acer.13507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711524PMC
December 2017

The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective.

Neuropharmacology 2017 Aug 27;122:100-106. Epub 2017 Mar 27.

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

The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components. Such recent developments are largely owed to methodological advances, which have made possible efforts previously deemed intractable, such as tracing of long-range cell-type specific projections and identifying functional efferent and afferent connections. In this review, we integrate earlier foundational work with more recent and advanced studies to construct a broad overview of the molecular neurocircuitry of the BNST in drug-associated behavior and affect. This article is part of the Special Issue entitled "Alcoholism".
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http://dx.doi.org/10.1016/j.neuropharm.2017.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481847PMC
August 2017

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

Nat Commun 2017 03 28;8:14782. Epub 2017 Mar 28.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.
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http://dx.doi.org/10.1038/ncomms14782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379055PMC
March 2017

Changes in the Adult GluN2B Associated Proteome following Adolescent Intermittent Ethanol Exposure.

PLoS One 2016 23;11(5):e0155951. Epub 2016 May 23.

Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, United States of America.

Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in non-synaptic proteins suggests that AIE may prime this signaling pathway for future ethanol exposures in adulthood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155951PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877005PMC
July 2017

Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking.

Neuropsychopharmacology 2016 07 11;41(8):2062-71. Epub 2016 Jan 11.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders.
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http://dx.doi.org/10.1038/npp.2016.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908652PMC
July 2016
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