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Article ; Online: Opioid trail: Tracking contributions to opioid use disorder from host genetics to the gut microbiome.

Duffy, Eamonn P / Bachtell, Ryan K / Ehringer, Marissa A

2023 Volume 156, Page(s) 105487

Abstract: Opioid use disorder (OUD) is a worldwide public health crisis with few effective treatment options. Traditional genetics and neuroscience approaches have provided knowledge about biological mechanisms that contribute to OUD-related phenotypes, but the ... ...

Abstract	Opioid use disorder (OUD) is a worldwide public health crisis with few effective treatment options. Traditional genetics and neuroscience approaches have provided knowledge about biological mechanisms that contribute to OUD-related phenotypes, but the complexity and magnitude of effects in the brain and body remain poorly understood. The gut-brain axis has emerged as a promising target for future therapeutics for several psychiatric conditions, so characterizing the relationship between host genetics and the gut microbiome in the context of OUD will be essential for development of novel treatments. In this review, we describe evidence that interactions between host genetics, the gut microbiome, and immune signaling likely play a key role in mediating opioid-related phenotypes. Studies in humans and model organisms consistently demonstrated that genetic background is a major determinant of gut microbiome composition. Furthermore, the gut microbiome is susceptible to environmental influences such as opioid exposure. Additional work focused on gene by microbiome interactions will be necessary to gain improved understanding of their effects on OUD-related behaviors.
MeSH term(s)	Humans ; Gastrointestinal Microbiome/genetics ; Analgesics, Opioid ; Opioid-Related Disorders/genetics ; Microbiota ; Brain
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2023.105487
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Article ; Online: Adenosine receptor stimulation inhibits methamphetamine-associated cue seeking.

Bachtell, Ryan K / Larson, Tracey A / Winkler, Madeline C

Journal of psychopharmacology (Oxford, England)

2023 Volume 37, Issue 2, Page(s) 192–203

Abstract: Background: Methamphetamine (METH) is a psychostimulant drug that remains a popular and threatening drug of abuse with high abuse liability. There is no established pharmacotherapy to treat METH dependence, but evidence suggests that stimulation of ... ...

Abstract	Background: Methamphetamine (METH) is a psychostimulant drug that remains a popular and threatening drug of abuse with high abuse liability. There is no established pharmacotherapy to treat METH dependence, but evidence suggests that stimulation of adenosine receptors reduces the reinforcing properties of METH and could be a potential pharmacological target. This study examines the effects of adenosine receptor subtype stimulation on METH seeking using both a cue-induced reinstatement and cue-craving model of relapse. Methods: Male and female rats were trained to self-administer METH during daily 2-h sessions. Cue-induced reinstatement of METH seeking was evaluated after extinction training. A systemic pretreatment of an adenosine A1 receptor (A1R) or A2A receptor (A2AR) agonist was administered prior to an extinction or cue session to evaluate the effects of adenosine receptor subtype stimulation on METH seeking. The effects of a systemic pretreatment of A1R or A2AR agonists were also evaluated in a cue-craving model where the cued-seeking test was conducted after 21 days of forced home-cage abstinence without extinction training. Results: Cue-induced reinstatement was reduced in both male and female rats that received A1R or A2AR agonist pretreatments. Similarly, an A1R or A2AR agonist pretreatment also inhibited cue craving in both male and female rats. Conclusion: Stimulation of either adenosine A1R or A2AR subtypes inhibits METH-seeking behavior elicited by METH-associated cues. These effects may be attributed to the ability of A1R and A2AR stimulation to disrupt cue-induced dopamine and glutamate signaling throughout the brain.
MeSH term(s)	Rats ; Male ; Female ; Animals ; Methamphetamine/pharmacology ; Cues ; Extinction, Psychological ; Central Nervous System Stimulants/pharmacology ; Drug-Seeking Behavior ; Self Administration ; Receptors, Purinergic P1
Chemical Substances	Methamphetamine (44RAL3456C) ; Central Nervous System Stimulants ; Receptors, Purinergic P1
Language	English
Publishing date	2023-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639313-5
ISSN	1461-7285 ; 0269-8811
ISSN (online)	1461-7285
ISSN	0269-8811
DOI	10.1177/02698811221147157
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Zs.A 2311: Show issues

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Article ; Online: Genetic background and sex influence somatosensory sensitivity and oxycodone analgesia in the Hybrid Rat Diversity Panel.

Duffy, Eamonn P / Ward, J O / Hale, L H / Brown, K T / Kwilasz, Andrew J / Saba, Laura M / Ehringer, Marissa A / Bachtell, Ryan K

Genes, brain, and behavior

2024 Volume 23, Issue 2, Page(s) e12894

Abstract: Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide ... ...

Abstract	Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified "up-down" von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug-naïve animals to record baseline thermal sensitivity across the strains. Oxycodone-induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h
MeSH term(s)	Rats ; Animals ; Oxycodone/pharmacology ; Analgesics, Opioid/pharmacology ; Analgesia ; Opioid-Related Disorders
Chemical Substances	Oxycodone (CD35PMG570) ; Analgesics, Opioid
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2075819-4
ISSN	1601-183X ; 1601-1848
ISSN (online)	1601-183X
ISSN	1601-1848
DOI	10.1111/gbb.12894
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Article ; Online: Activation of the Immune System During a Developmental Window May Provide a Link Between Early Life Stress and Future Susceptibility to Cocaine Abuse.

Brown, Kyle T / Bachtell, Ryan K

Biological psychiatry

2018 Volume 84, Issue 12, Page(s) 865–866

MeSH term(s)	Child ; Cocaine ; Cocaine-Related Disorders ; Humans ; Immune System ; Stress, Psychological
Chemical Substances	Cocaine (I5Y540LHVR)
Language	English
Publishing date	2018-11-19
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2018.10.002
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Zs.A 720: Show issues

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Article ; Online: Toll-like receptor 4 antagonists reduce cocaine-primed reinstatement of drug seeking.

Brown, Kyle T / Levis, Sophia C / O'Neill, Casey E / Levy, Catherine / Rice, Kenner C / Watkins, Linda R / Bachtell, Ryan K

Psychopharmacology

2023 Volume 240, Issue 7, Page(s) 1587–1600

Abstract: Rationale: Cocaine can increase inflammatory neuroimmune markers, including chemokines and cytokines characteristic of innate inflammatory responding. Prior work indicates that the Toll-like receptor 4 (TLR4) initiates this response, and administration ... ...

Abstract	Rationale: Cocaine can increase inflammatory neuroimmune markers, including chemokines and cytokines characteristic of innate inflammatory responding. Prior work indicates that the Toll-like receptor 4 (TLR4) initiates this response, and administration of TLR4 antagonists provides mixed evidence that TLR4 contributes to cocaine reward and reinforcement. Objective: These studies utilize (+)-naltrexone, the TLR4 antagonist, and mu-opioid inactive enantiomer to examine the role of TLR4 on cocaine self-administration and cocaine seeking in rats. Methods: (+)-Naltrexone was continuously administered via an osmotic mini-pump during the acquisition or maintenance of cocaine self-administration. The motivation to acquire cocaine was assessed using a progressive ratio schedule following either continuous and acute (+)-naltrexone administration. The effects of (+)-naltrexone on cocaine seeking were assessed using both a cue craving model and a drug-primed reinstatement model. The highly selective TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides (LPS-Rs), was administered into the nucleus accumbens to determine the effectiveness of TLR4 blockade on cocaine-primed reinstatement. Results: (+)-Naltrexone administration did not alter the acquisition or maintenance of cocaine self-administration. Similarly, (+)-naltrexone was ineffective at altering the progressive ratio responding. Continuous administration of (+)-naltrexone during forced abstinence did not impact cued cocaine seeking. Acute systemic administration of (+)-naltrexone dose-dependently decreased cocaine-primed reinstatement of previously extinguished cocaine seeking, and administration of LPS-Rs into the nucleus accumbens shell also reduced cocaine-primed reinstatement of cocaine seeking. Discussion: These results complement previous studies suggesting that the TLR4 plays a role in cocaine-primed reinstatement of cocaine seeking, but may have a more limited role in cocaine reinforcement.
MeSH term(s)	Animals ; Rats ; Cocaine/adverse effects ; Cocaine-Related Disorders/drug therapy ; Dose-Response Relationship, Drug ; Extinction, Psychological ; Lipopolysaccharides/pharmacology ; Naltrexone/pharmacology ; Naltrexone/therapeutic use ; Rats, Sprague-Dawley ; Self Administration ; Toll-Like Receptor 4/antagonists & inhibitors ; Drug-Seeking Behavior/drug effects
Chemical Substances	Cocaine (I5Y540LHVR) ; Lipopolysaccharides ; Naltrexone (5S6W795CQM) ; Toll-Like Receptor 4
Language	English
Publishing date	2023-06-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-023-06392-w
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Article: Viral-mediated expression of Erk2 in the nucleus accumbens regulates responses to rewarding and aversive stimuli.

Parise, Lyonna F / Iñiguez, Sergio D / Warren, Brandon L / Parise, Eric M / Bachtell, Ryan K / Dietz, David / Nestler, Eric J / Bolaños-Guzmán, Carlos A

bioRxiv : the preprint server for biology

2023

Abstract: Second-messenger signaling within the mesolimbic reward circuit is involved in both the long-lived effects of stress and in the underlying mechanisms that promote drug abuse liability. To determine the direct role of kinase signaling within the nucleus ... ...

Abstract	Second-messenger signaling within the mesolimbic reward circuit is involved in both the long-lived effects of stress and in the underlying mechanisms that promote drug abuse liability. To determine the direct role of kinase signaling within the nucleus accumbens, specifically mitogen-activated protein kinase 1 (ERK2), in mood- and drug-related behavior, we used a herpes-simplex virus to up- or down-regulate ERK2 in adult male rats. We then exposed rats to a battery of behavioral tasks including the elevated plus-maze, open field test, forced-swim test, conditioned place preference, and finally cocaine self-administration. Herein, we show that viral overexpression or knockdown of ERK2 in the nucleus accumbens induces distinct behavioral phenotypes. Specifically, over expression of ERK2 facilitated depression- and anxiety-like behavior while also increasing sensitivity to cocaine. Conversely, down-regulation of ERK2 attenuated behavioral deficits, while blunting sensitivity to cocaine. Taken together, these data implicate ERK2 signaling, within the nucleus accumbens, in the regulation of affective behaviors and modulating sensitivity to the rewarding properties of cocaine.
Language	English
Publishing date	2023-10-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.03.560689
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Article ; Online: Initial d2 dopamine receptor sensitivity predicts cocaine sensitivity and reward in rats.

Merritt, Kathryn E / Bachtell, Ryan K

PloS one

2013 Volume 8, Issue 11, Page(s) e78258

Abstract: The activation of dopamine receptors within the mesolimbic dopamine system is known to be involved in the initiation and maintenance of cocaine use. Expression of the D2 dopamine receptor subtype has been implicated as both a predisposing factor and ... ...

Abstract	The activation of dopamine receptors within the mesolimbic dopamine system is known to be involved in the initiation and maintenance of cocaine use. Expression of the D2 dopamine receptor subtype has been implicated as both a predisposing factor and consequence of chronic cocaine use. It is unclear whether there is a predictive relationship between D2 dopamine receptor function and cocaine sensitivity that would enable cocaine abuse. Therefore, we exploited individual differences in behavioral responses to D2 dopamine receptor stimulation to test its relationship with cocaine-mediated behaviors. Outbred, male Sprague-Dawley rats were initially characterized by their locomotor responsiveness to the D2 dopamine receptor agonist, quinpirole, in a within-session ascending dose-response regimen (0, 0.1, 0.3 & 1.0 mg/kg, sc). Rats were classified as high or low quinpirole responders (HD2 and LD2, respectively) by a median split of their quinpirole-induced locomotor activity. Rats were subsequently tested for differences in the psychostimulant effects of cocaine by measuring changes in cocaine-induced locomotor activity (5 and 15 mg/kg, ip). Rats were also tested for differences in the development of conditioned place preference to a low dose of cocaine (7.5 mg/kg, ip) that does not reliably produce a cocaine conditioned place preference. Finally, rats were tested for acquisition of cocaine self-administration and maintenance responding on fixed ratio 1 and 5 schedules of reinforcement, respectively. Results demonstrate that HD2 rats have enhanced sensitivity to the locomotor stimulating properties of cocaine, display greater cocaine conditioned place preference, and self-administer more cocaine compared to LD2 animals. These findings suggest that individual differences in D2 dopamine receptor sensitivity may be predictive of cocaine sensitivity and reward.
MeSH term(s)	Animals ; Behavior, Animal ; Cocaine/pharmacology ; Cocaine-Related Disorders/etiology ; Cocaine-Related Disorders/metabolism ; Cocaine-Related Disorders/psychology ; Conditioning, Operant ; Dopamine/metabolism ; Dopamine Agonists/pharmacology ; Dose-Response Relationship, Drug ; Gene Expression ; Male ; Motor Activity ; Quinpirole/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D2/genetics ; Receptors, Dopamine D2/metabolism ; Reinforcement, Psychology ; Reward ; Self Administration
Chemical Substances	Dopamine Agonists ; Receptors, Dopamine D2 ; Quinpirole (20OP60125T) ; Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2013-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0078258
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Article ; Online: Effects of adenosine A

Haynes, Nicholas S / O'Neill, Casey E / Hobson, Benjamin D / Bachtell, Ryan K

Psychopharmacology

2018 Volume 236, Issue 2, Page(s) 699–708

Abstract: Rationale and objectives: Adenosine signaling through adenosine A: Methods: Sprague-Dawley rats were used to assess the differential effects of SCH 442416 and istradefylline that antagonize presynaptic and postsynaptic A: Results: Neither ... ...

Abstract	Rationale and objectives: Adenosine signaling through adenosine A Methods: Sprague-Dawley rats were used to assess the differential effects of SCH 442416 and istradefylline that antagonize presynaptic and postsynaptic A Results: Neither istradefylline nor SCH 442416 significantly altered basal locomotion. Istradefylline enhanced acute cocaine-induced locomotion but had no effect on the expression of locomotor sensitization. SCH 44216 had no effect on acute cocaine-induced locomotion but inhibited the expression of locomotor sensitization. Istradefylline was sufficient to induce cocaine seeking and augmented both cocaine-induced seeking and sucrose seeking. SCH 442416 inhibited cocaine-induced seeking, but had no effect on sucrose seeking and did not induce cocaine seeking when administered alone. Conclusions: These findings demonstrate differential effects of two A
MeSH term(s)	Adenosine A2 Receptor Antagonists/pharmacology ; Animals ; Cocaine/administration & dosage ; Cocaine-Related Disorders/psychology ; Dose-Response Relationship, Drug ; Drug-Seeking Behavior/drug effects ; Drug-Seeking Behavior/physiology ; Locomotion/drug effects ; Locomotion/physiology ; Male ; Motor Activity/drug effects ; Motor Activity/physiology ; Rats ; Rats, Sprague-Dawley ; Self Administration
Chemical Substances	Adenosine A2 Receptor Antagonists ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2018-11-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-018-5097-z
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Article ; Online: Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking.

Larson, Tracey A / O'Neill, Casey E / Palumbo, Michaela P / Bachtell, Ryan K

Journal of psychopharmacology (Oxford, England)

2018 , Page(s) 269881118812098

Abstract: Background:: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood.: Aim:: These experiments explore the effects of ... ...

Abstract	Background:: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. Aim:: These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. Methods:: Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62-82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. Results:: Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. Conclusions:: These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability.
Language	English
Publishing date	2018-11-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	639313-5
ISSN	1461-7285 ; 0269-8811
ISSN (online)	1461-7285
ISSN	0269-8811
DOI	10.1177/0269881118812098
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Article ; Online: Methamphetamine self-administration reduces alcohol consumption and preference in alcohol-preferring P rats.

Winkler, Madeline C / Greager, Emilee M / Stafford, Jacob / Bachtell, Ryan K

Addiction biology

2016 Volume 23, Issue 1, Page(s) 90–101

Abstract: Subclinical levels of polysubstance use are a prevalent and understudied phenomenon. Alcohol is a substance commonly co-used with other substances of other drug classes. These studies sought to determine the consumption effects of combining alcohol ... ...

Abstract	Subclinical levels of polysubstance use are a prevalent and understudied phenomenon. Alcohol is a substance commonly co-used with other substances of other drug classes. These studies sought to determine the consumption effects of combining alcohol drinking and methamphetamine (MA) self-administration. Male alcohol-preferring P rats had continuous access to a two-bottle alcohol drinking procedure in the home cage. Control rats remained alcohol naïve. Rats were also surgically implanted with intra-jugular catheters and trained to self-administer saline (control) or MA in daily 2-hour sessions. We first measured the acquisition and maintenance of MA intake in alcohol-consuming or control rats. MA intake was initially enhanced by alcohol consumption on a fixed ratio 1 schedule of reinforcement, but this effect did not prevail as the difficulty of the schedule (FR5 and progressive ratio) was increased. We next measured both alcohol consumption and preference before, during and after MA (or saline) self-administration. MA self-administration significantly reduced alcohol intake and preference ratios, a robust effect that persisted across several experimental variations. Interestingly, alcohol consumption rebounded following the cessation of MA self-administration. The effects of MA self-administration were specific to alcohol intake because it did not alter total fluid consumption or consumption of sucrose. MA self-administration did not impact blood-alcohol concentrations or alcohol-induced loss of righting reflex suggesting no effect of MA intake on the alcohol metabolism or sensitivity. Together, the results suggest that MA intake disrupts alcohol consumption and preferences but not the reverse in alcohol-preferring P rats.
MeSH term(s)	Alcohol Drinking ; Animals ; Behavior, Animal/drug effects ; Central Nervous System Depressants/administration & dosage ; Central Nervous System Stimulants/administration & dosage ; Central Nervous System Stimulants/pharmacology ; Conditioning, Operant ; Drinking Behavior/drug effects ; Ethanol/administration & dosage ; Extinction, Psychological ; Male ; Methamphetamine/administration & dosage ; Methamphetamine/pharmacology ; Rats ; Reinforcement, Psychology ; Self Administration
Chemical Substances	Central Nervous System Depressants ; Central Nervous System Stimulants ; Ethanol (3K9958V90M) ; Methamphetamine (44RAL3456C)
Language	English
Publishing date	2016-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1324314-7
ISSN	1369-1600 ; 1355-6215
ISSN (online)	1369-1600
ISSN	1355-6215
DOI	10.1111/adb.12476
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