Publications by authors named "Toni A Patrick"

6 Publications

  • Page 1 of 1

In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity.

Neuron 2021 08;109(15):2398-2403.e4

Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.

The brain's endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling in vivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling in vivo.
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http://dx.doi.org/10.1016/j.neuron.2021.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351909PMC
August 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

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

Auditory Event-Related Potentials in the Interictal Phase of Migraine Indicate Alterations in Automatic Attention.

Appl Psychophysiol Biofeedback 2017 Dec;42(4):323-333

Department of Psychology, University of Memphis, 400 Innovation Dr., Memphis, TN, 38104, USA.

Migraine has been characterized by interictal cortical hyperresponsivity. We compared event-related brain potentials (ERPs) to unattended tone pairs in migraineurs (interictal) versus non-headache controls, with particular interest in attention-related activity (i.e., the N1 component). Electroencephalograms were recorded from 11 interictal migraineurs and 14 headache-free controls while they watched a silent video. Pairs of 50-ms tones with 500-ms inter-tone intervals were presented with inter-pair intervals of 1 or 5 s. P1, N1, P2, and N2 components were analyzed. N1 peak amplitudes were larger in migraineurs than in controls, especially after the 5-s inter-pair interval. However, there was no difference between groups in the attenuation of the N1 (i.e., no interaction). P2 peak amplitudes were larger in migraineurs, but only after the first tone in the pair. The three migraineurs without aura had larger N1s than the eight with aura. Our findings are consistent with interictal hyperresponsivity of cortical generators of these ERPs in migraineurs. However, areas that inhibit the responses with stimulus repetition do not seem to be affected.
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http://dx.doi.org/10.1007/s10484-017-9378-9DOI Listing
December 2017

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
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