Publications by authors named "Andrew D Gaulden"

8 Publications

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Effects of fentanyl on acute locomotor activity, behavioral sensitization, and contextual reward in female and male rats.

Drug Alcohol Depend 2021 Sep 24;229(Pt A):109101. Epub 2021 Sep 24.

Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States; Translational Neuroscience Program, Wayne State University School of Medicine, Detroit, MI, United States; Research Services, John D. Dingell VA Medical Center, Detroit, MI, United States. Electronic address:

Background: Although fentanyl has gained widespread prominence, there remains a lack of knowledge on this opioid synthetic agonist, particularly related to sex effects. Therefore, we conducted behavioral tests in female and male rats to measure drug abuse-related responses to fentanyl hypothesizing sex-specific responses.

Methods: Using female and male rats, we measured the effects of acute or repeated administration of fentanyl (20 μg/kg) on locomotor activity (LMA) and behavioral sensitization in an open field test. We further measured contextual-reward and associated locomotor activity during training in a conditioned place preference (CPP) paradigm using a low (4 μg/kg) or high (16 μg/kg) dose of fentanyl. Vaginal lavage samples were collected from female rats in the CPP study, and the estrous phase was determined based on the cytological characterization.

Results: Female, but not male, rats showed elevated LMA in response to acute fentanyl and behavioral sensitization to repeated administration of fentanyl. Fentanyl produced significant CPP in both sexes, but it was more potent in males. Finally, our secondary investigation of the estrous cycle on fentanyl-CPP suggests that non-estrus phases, likely reflecting high estradiol, may predict the degree of fentanyl preference in females.

Conclusions: Fentanyl was more potent and/or effective to produce LMA and LMA sensitization in females but more potent to produce CPP in males. Furthermore, the role of sex in fentanyl responses varied across endpoints, and sex differences in LMA were not predictive of sex differences in CPP.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.109101DOI Listing
September 2021

CaMKII Modulates Diacylglycerol Lipase-α Activity in the Rat Nucleus Accumbens after Incubation of Cocaine Craving.

eNeuro 2021 Sep-Oct;8(5). Epub 2021 Oct 8.

Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064-3095

Relapse is a major challenge to the treatment of substance use disorders. A progressive increase in cue-induced drug craving, termed incubation of craving, is observed after withdrawal from multiple drugs of abuse in humans and rodents. Incubation of cocaine craving involves the strengthening of excitatory synapses onto nucleus accumbens (NAc) medium spiny neurons via postsynaptic accumulation of high-conductance Ca-permeable AMPA receptors. This enhances reactivity to drug-associated cues and is required for the expression of incubation. Additionally, incubation of cocaine craving is associated with loss of the synaptic depression normally triggered by stimulation of metabotropic glutamate receptor 5 (mGlu5), leading to endocannabinoid production, and expressed presynaptically via cannabinoid receptor 1 activation. Previous studies have found alterations in mGlu5 and Homer proteins associated with the loss of this synaptic depression. Here we conducted coimmunoprecipitation studies to investigate associations of diacylglycerol lipase-α (DGL), which catalyzes formation of the endocannabinoid 2-arachidonylglycerol (2-AG), with mGlu5 and Homer proteins. Although these interactions were unchanged in the NAc core at incubation-relevant withdrawal times, the association of DGL with total and phosphorylated Ca/calmodulin-dependent protein kinase IIα (CaMKIIα) and CaMKIIβ was increased. This would be predicted, based on other studies, to inhibit DGL activity and therefore 2-AG production. This was confirmed by measuring DGL enzymatic activity. However, the magnitude of DGL inhibition did not correlate with the magnitude of incubation of craving for individual rats. These results suggest that CaMKII contributes to the loss of mGlu5-dependent synaptic depression after incubation, but the functional significance of this loss remains unclear.
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http://dx.doi.org/10.1523/ENEURO.0220-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503962PMC
October 2021

Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening.

Neuron 2020 03 13;105(6):1062-1076.e6. Epub 2020 Jan 13.

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

Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.
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http://dx.doi.org/10.1016/j.neuron.2019.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992313PMC
March 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

Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.

ACS Chem Neurosci 2018 07 9;9(7):1552-1559. Epub 2018 May 9.

Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
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http://dx.doi.org/10.1021/acschemneuro.7b00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081739PMC
July 2018

Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.

Transl Psychiatry 2018 04 26;8(1):92. Epub 2018 Apr 26.

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

Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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http://dx.doi.org/10.1038/s41398-018-0141-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917016PMC
April 2018

Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

Biol Psychiatry 2017 Oct 15;82(7):488-499. Epub 2017 Mar 15.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address:

Background: Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood.

Methods: We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice.

Results: Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation.

Conclusions: Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.
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http://dx.doi.org/10.1016/j.biopsych.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585044PMC
October 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
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