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Article ; Online: Association of dopamine D2-like and D

Czoty, Paul W / Tryhus, Aaron M / Solingapuram Sai, Kiran K / Nader, Susan H / Epperly, Phillip M

2023 Volume 1807, Page(s) 148323

Abstract: Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are ... ...

Abstract	Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [
MeSH term(s)	Humans ; Animals ; Male ; Cocaine/pharmacology ; Dopamine ; Quinpirole/pharmacology ; Macaca mulatta ; Receptors, Dopamine D3 ; Dopamine Agonists/pharmacology ; Receptors, Dopamine D2/physiology ; Self Administration ; Dose-Response Relationship, Drug
Chemical Substances	Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X) ; Quinpirole (20OP60125T) ; Receptors, Dopamine D3 ; Dopamine Agonists ; Receptors, Dopamine D2
Language	English
Publishing date	2023-03-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2023.148323
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Article ; Online: Influence of social rank on the development of long-term ethanol drinking trajectories in cynomolgus monkeys.

Galbo-Thomma, Lindsey K / Davenport, April T / Epperly, Phillip M / Czoty, Paul W

Alcohol, clinical & experimental research

2023 Volume 47, Issue 10, Page(s) 1943–1951

Abstract: Background: Chronic stress contribute to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ... ...

Abstract	Background: Chronic stress contribute to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ethical constraints. Group-housed nonhuman primates develop social dominance hierarchies that represent a continuum of social experiences from enrichment in higher-ranked (dominant) monkeys to chronic social stress in lower-ranked (subordinate) individuals. This framework provides a translationally relevant model of chronic social stress that can be used to characterize its effects on vulnerability to AUD. Methods: Twelve male cynomolgus monkeys living in three social groups with established social dominance hierarchies were provided access to ethanol and water for 22 h/day, 4-5 days/week, for 1 year. Ethanol-free periods (2- or 3-day "weekends" or longer periods up to 10 days) were spent in social groups to maintain the stability of the social hierarchies. Observational studies conducted 6 months into the year of drinking assessed signs of ethanol withdrawal. After 1 year, monkeys were individually housed 24 h/day, 7 days/week for four consecutive weeks to examine the effect of eliminating the "weekends" spent socially housed. Results: Subordinate monkeys had significantly higher mean daily ethanol intakes than dominant monkeys across 1 year of open access. Subordinates also had higher intakes on the first day back drinking following ethanol-free periods of 9-10 days. Moreover, during the last 4 weeks of open access, intakes on the first drinking day after an ethanol-free weekend increased significantly in subordinate monkeys. This effect diminished when all monkeys were individually housed for 4 weeks, indicating that the increased intake in subordinates was driven by the social environment. Conclusions: These data demonstrate that social subordination, which is associated with chronic social stress, results in increased vulnerability to the development and maintenance of heavy drinking trajectories.
Language	English
Publishing date	2023-08-27
Publishing country	United States
Document type	Journal Article
ISSN	2993-7175
ISSN (online)	2993-7175
DOI	10.1111/acer.15163
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Article ; Online: Cognitive-enhancing effects of acetylcholine receptor agonists in group-housed cynomolgus monkeys who drink ethanol.

Galbo-Thomma, Lindsey K / Epperly, Phillip M / Blough, Bruce E / Landavazo, Antonio / Saldaña, Santiago J / Carroll, F Ivy / Czoty, Paul W

The Journal of pharmacology and experimental therapeutics

2023

Abstract: The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and ... ...

Abstract	The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and reward-related behavior and their distribution can be altered by long-term heavy drinking. Therefore, AChRs are promising pharmacotherapeutic targets for treating the cognitive symptoms of AUD. In the present study, the pro-cognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than one year. The muscarinic AChR antagonist scopolamine was used to disrupt performance of a serial stimulus discrimination and reversal (SDR) task designed to probe cognitive flexibility, defined as the ability to modify a previously learned behavior in response to a change in reinforcement contingencies. The ability of xanomeline and varenicline to remediate the disruptive effects of scopolamine was compared between dominant and subordinate monkeys, with lighter and heavier drinking histories, respectively. We hypothesized that subordinate monkeys would be more sensitive to all three drugs. Scopolamine dose-dependently impaired performance on the serial SDR task in all monkeys at doses lower than those that produced non-specific impairments (e.g, sedation); its potency did not differ between dominant and subordinate monkeys. However, both AChR agonists were effective in remediating the scopolamine-induced deficit in subordinate monkeys, but not in dominant monkeys. These findings suggest xanomeline and varenicline may be effective for enhancing cognitive flexibility in individuals with a history of heavy drinking.
Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.123.001854
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Article ; Online: Effect of chronic binge-like ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys.

Tryhus, Aaron M / Epperly, Phillip M / Davenport, April T / Galbo, Lindsey K / Czoty, Paul W

Drug and alcohol dependence

2021 Volume 223, Page(s) 108707

Abstract: Background: Although most individuals with cocaine use disorder also abuse alcohol, little is known about the behavioral and pharmacological mechanisms that promote co-abuse. For example, it is unclear whether prior experience with alcohol renders ... ...

Abstract	Background: Although most individuals with cocaine use disorder also abuse alcohol, little is known about the behavioral and pharmacological mechanisms that promote co-abuse. For example, it is unclear whether prior experience with alcohol renders individuals more sensitive to cocaine when it is subsequently experienced. Methods: This study examined the effects of chronic ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys. Six monkeys consumed 2.0 g/kg ethanol in a binge-drinking paradigm and 6 monkeys drank a non-alcoholic solution 5 days per week. After 9 months, each monkey's sensitivity to acquiring cocaine self-administration was determined. Monkeys performed an operant response resulting in food pellet delivery under a fixed-ratio 30 schedule of reinforcement. Saline, then ascending doses of cocaine, were substituted for food pellets until a cocaine dose was reached at which the number of cocaine injections delivered differed significantly from saline injections delivered. Following acquisition, a complete cocaine dose-effect curve was generated to determine whether ethanol consumption altered the reinforcing potency of cocaine determined by calculating the ED Results: Although individual variability was observed, the cocaine dose which initially served as a reinforcer did not differ between ethanol-drinking and control groups and, within the ethanol-drinking group, was not related to the amount of ethanol consumed. Moreover, the reinforcing potency of cocaine did not differ between groups. Conclusion: Taken together, the data suggest that a history of binge-like alcohol consumption does not affect sensitivity to cocaine when it is subsequently first experienced.
MeSH term(s)	Alcohol Drinking ; Animals ; Cocaine ; Conditioning, Operant ; Dose-Response Relationship, Drug ; Ethanol ; Macaca mulatta ; Reinforcement Schedule ; Self Administration
Chemical Substances	Ethanol (3K9958V90M) ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2021-04-10
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2021.108707
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Article ; Online: Priming the pump? Evaluating the effect of multiple intermittent theta burst sessions on cortical excitability in a nonhuman primate model.

Hanlon, Colleen A / Smith, Hilary R / Epperly, Phillip M / Collier, Miracle / Galbo, Lindsey K / Czoty, Paul W

Brain stimulation

2022 Volume 15, Issue 3, Page(s) 676–677

MeSH term(s)	Animals ; Cortical Excitability ; Evoked Potentials, Motor ; Primates ; Theta Rhythm ; Transcranial Magnetic Stimulation
Language	English
Publishing date	2022-04-07
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	2394410-9
ISSN	1876-4754 ; 1935-861X
ISSN (online)	1876-4754
ISSN	1935-861X
DOI	10.1016/j.brs.2022.04.004
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Article ; Online: Punishment of ethanol choice in rhesus monkeys.

Stinson, Benjamin T / Galbo, Lindsey K / Flynn, Shawn M / Gouin, Angelique / Epperly, Phillip M / Davenport, April T / Czoty, Paul W

Behavioural pharmacology

2022 Volume 33, Issue 6, Page(s) 395–401

Abstract: A defining characteristic of individuals diagnosed with alcohol use disorder (AUD) is that negative outcomes related to drinking do not lead them to reduce their alcohol use. In rodent models of AUD, this characteristic has been studied by adding the ... ...

Abstract	A defining characteristic of individuals diagnosed with alcohol use disorder (AUD) is that negative outcomes related to drinking do not lead them to reduce their alcohol use. In rodent models of AUD, this characteristic has been studied by adding the bitter tastant quinine to an ethanol solution. In this study, we extended this approach to a nonhuman primate model in which the ability of quinine to decrease the choice of a 4% ethanol solution vs. water was measured. Five adult female rhesus monkeys with 7.3 years of experience drinking ethanol were given access to a 4% ethanol solution and water for 3 h per day. When ethanol choice was stable, a single quinine concentration (0.03-5.6 g /L) was added to the ethanol solution for 1 day until a quinine concentration-effect curve was generated. After determining the quinine concentration that reduced ethanol choice by half (the quinine EC 50 ), the relative reinforcing strength of ethanol was manipulated by adding quinine or sucrose to the water alternative depending on the monkey's baseline choice. Adding quinine to ethanol produced a concentration-dependent decrease in ethanol choice and intake. Importantly, water intake increased, indicating an effect on response allocation rather than simply a decrease in fluid consumption. Consistent with this conclusion, the addition of quinine or sucrose to the water alternative resulted in predictable increases and decreases, respectively, in ethanol choice. These studies establish a model of punishment of ethanol choice in nonhuman primates that can be used to understand the contextual, biologic and pharmacologic factors that influence sensitivity to the punishment of alcohol drinking.
MeSH term(s)	Alcohol Drinking/drug therapy ; Alcoholism ; Animals ; Ethanol/pharmacology ; Female ; Macaca mulatta ; Punishment ; Quinine/pharmacology ; Sucrose ; Water
Chemical Substances	Water (059QF0KO0R) ; Ethanol (3K9958V90M) ; Sucrose (57-50-1) ; Quinine (A7V27PHC7A)
Language	English
Publishing date	2022-08-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1027374-8
ISSN	1473-5849 ; 0955-8810
ISSN (online)	1473-5849
ISSN	0955-8810
DOI	10.1097/FBP.0000000000000683
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Article ; Online: Cortical excitability in a nonhuman primate model of TMS.

Hanlon, Colleen A / Czoty, Paul W / Smith, Hilary R / Epperly, Phillip M / Galbo, Lindsey K

Brain stimulation

2020 Volume 14, Issue 1, Page(s) 19–21

Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	2394410-9
ISSN	1876-4754 ; 1935-861X
ISSN (online)	1876-4754
ISSN	1935-861X
DOI	10.1016/j.brs.2020.10.008
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Article: Rich Club Characteristics of Alcohol-Naïve Functional Brain Networks Predict Future Drinking Phenotypes in Rhesus Macaques.

Rowland, Jared A / Stapleton-Kotloski, Jennifer R / Alberto, Greg E / Davenport, April T / Epperly, Phillip M / Godwin, Dwayne W / Daunais, James B

Frontiers in behavioral neuroscience

2021 Volume 15, Page(s) 673151

Abstract: ... ...

Abstract	Purpose
Language	English
Publishing date	2021-06-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2021.673151
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Article ; Online: Effects of chronic cocaine and ethanol self-administration on brain dopamine receptors in a rhesus monkey model of polysubstance abuse.

Say, Felicity M / Tryhus, Aaron M / Epperly, Phillip M / Nader, Susan H / Solingapuram Sai, Kiran K / George, Brianna E / Kirse, Haley A / Czoty, Paul W

Addiction biology

2022 Volume 27, Issue 5, Page(s) e13219

Abstract: Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of ... ...

Abstract	Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [
MeSH term(s)	Animals ; Brain/diagnostic imaging ; Brain/metabolism ; Cocaine/pharmacology ; Dose-Response Relationship, Drug ; Ethanol/pharmacology ; Humans ; Macaca mulatta/metabolism ; Male ; Receptors, Dopamine D2/metabolism ; Receptors, Dopamine D3/metabolism ; Self Administration ; Substance-Related Disorders
Chemical Substances	Receptors, Dopamine D2 ; Receptors, Dopamine D3 ; Ethanol (3K9958V90M) ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1324314-7
ISSN	1369-1600 ; 1355-6215
ISSN (online)	1369-1600
ISSN	1355-6215
DOI	10.1111/adb.13219
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Zs.A 4586: Show issues

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Article ; Online: Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys.

Flynn, Shawn M / Epperly, Phillip M / Davenport, April T / Cami-Kobeci, Gerta / Husbands, Stephen M / Ko, Mei-Chuan / Czoty, Paul W

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2019 Volume 44, Issue 8, Page(s) 1476–1484

Abstract: Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) ... ...

Abstract	Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) can decrease ethanol drinking. We characterized the effects of the mu opioid peptide (MOP) receptor agonist buprenorphine and the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028), which stimulates MOP and NOP receptors, in a translational nonhuman primate model of AUD. Rhesus monkeys drank a 4% ethanol solution 6 h per day, 5 days per week via an operant behavioral panel in their home cages. To assess behavioral selectivity, monkeys responded via a photo-optic switch to earn food pellets. After characterizing the acute effects of BU08028 (0.001-0.01 mg/kg, i.m.) and buprenorphine (0.003-0.056 mg/kg, i.m.), the drugs were administered chronically using a model of pharmacotherapy assessment that incorporates clinical aspects of AUD and treatment. Acutely, both drugs decreased ethanol drinking at doses that did not affect food-maintained responding. During chronic treatment, effects of BU08028 and buprenorphine were maintained for several weeks without development of tolerance or emergence of adverse effects. BU08028 was ~0.5 and 1.0 log units more potent in acute and chronic studies, respectively. The selective NOP receptor agonist SCH 221510 also selectively decreased ethanol intakes when given acutely (0.03-1.0 mg/kg, i.m.), whereas the MOP antagonist naltrexone (1.7-5.6 mg/kg, i.m.) decreased both ethanol intake and food pellets delivered. These data demonstrate that bifunctional MOP/NOP agonists, which may have therapeutic advantages to MOP-selective drugs, can decrease alcohol drinking in nonhuman primates.
MeSH term(s)	Alcohol Drinking/prevention & control ; Animals ; Azabicyclo Compounds/pharmacology ; Buprenorphine/analogs & derivatives ; Buprenorphine/pharmacology ; Dose-Response Relationship, Drug ; Eating/drug effects ; Macaca mulatta ; Male ; Naltrexone/pharmacology ; Receptors, Opioid/agonists ; Receptors, Opioid, mu/agonists
Chemical Substances	2-(N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl)-3,3-dimethylpentan-2-ol ; 8-(bis(2-methylphenyl)methyl)-3-phenyl-8-azabicyclo(3.2.1)octan-3-ol ; Azabicyclo Compounds ; Receptors, Opioid ; Receptors, Opioid, mu ; Buprenorphine (40D3SCR4GZ) ; Naltrexone (5S6W795CQM) ; nociceptin receptor (DVO6VKD7IJ)
Language	English
Publishing date	2019-04-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-019-0390-z
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