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Article ; Online: Break the net, break the cycle: removal of perineuronal nets in the lateral hypothalamus decreases cocaine relapse.

Marchant, Nathan J

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2018 Volume 44, Issue 5, Page(s) 835–836

MeSH term(s)	Cocaine ; Cues ; Humans ; Hypothalamic Area, Lateral ; Nerve Net ; Receptors, N-Acetylglucosamine ; Recurrence
Chemical Substances	Receptors, N-Acetylglucosamine ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2018-10-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-018-0245-z
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Article ; Online: The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats.

Campbell, Erin J / Marchant, Nathan J

British journal of pharmacology

2018 Volume 175, Issue 7, Page(s) 994–1003

Abstract: The last decade has seen major advances in neuroscience tools allowing us to selectively modulate cellular pathways in freely moving animals. Chemogenetic approaches such as designer receptors exclusively activated by designer drugs (DREADDs) permit the ... ...

Abstract	The last decade has seen major advances in neuroscience tools allowing us to selectively modulate cellular pathways in freely moving animals. Chemogenetic approaches such as designer receptors exclusively activated by designer drugs (DREADDs) permit the remote control of neuronal function by systemic drug administration. These approaches have dramatically advanced our understanding of the neural control of behaviour. Here, we review the different techniques and genetic approaches available for the restriction of chemogenetic receptors to defined neuronal populations. We highlight the use of a dual virus approach to target specific circuitries and the effectiveness of different routes of administration of designer drugs. Finally, we discuss the potential caveats associated with DREADDs including off-target effects of designer drugs, the effects of chronic chemogenetic receptor activation and the issue of collateral projections associated with DREADD activation and inhibition.
MeSH term(s)	Animals ; Behavior/drug effects ; Brain/drug effects ; Brain/physiology ; Designer Drugs/administration & dosage ; Humans ; Neurons/drug effects ; Neurons/physiology ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Designer Drugs ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2018-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.14146
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Article ; Online: Lateral hypothalamic GABAergic neurons encode alcohol memories.

Alonso-Lozares, Isis / Wilbers, Pelle / Asperl, Lina / Teijsse, Sem / van der Neut, Charlotte / Schetters, Dustin / van Mourik, Yvar / McDonald, Allison J / Heistek, Tim / Mansvelder, Huibert D / De Vries, Taco J / Marchant, Nathan J

Current biology : CB

2024 Volume 34, Issue 5, Page(s) 1086–1097.e6

Abstract: In alcohol use disorder, the alcohol memories persist during abstinence, and exposure to stimuli associated with alcohol use can lead to relapse. This highlights the importance of investigating the neural substrates underlying not only relapse but also ... ...

Abstract	In alcohol use disorder, the alcohol memories persist during abstinence, and exposure to stimuli associated with alcohol use can lead to relapse. This highlights the importance of investigating the neural substrates underlying not only relapse but also encoding and expression of alcohol memories. GABAergic neurons in the lateral hypothalamus (LH-GABA) have been shown to be critical for food-cue memories and motivation; however, the extent to which this role extends to alcohol-cue memories and motivations remains unexplored. In this study, we aimed to describe how alcohol-related memories are encoded and expressed in LH GABAergic neurons. Our first step was to monitor LH-GABA calcium transients during acquisition, extinction, and reinstatement of an alcohol-cue memory using fiber photometry. We trained the rats on a Pavlovian conditioning task, where one conditioned stimulus (CS+) predicted alcohol (20% EtOH) and another conditioned stimulus (CS-) had no outcome. We then extinguished this association through non-reinforced presentations of the CS+ and CS- and finally, in two different groups, we measured relapse under non-primed and alcohol-primed induced reinstatement. Our results show that initially both cues caused increased LH-GABA activity, and after learning only the alcohol cue increased LH-GABA activity. After extinction, this activity decreases, and we found no differences in LH-GABA activity during reinstatement in either group. Next, we inhibited LH-GABA neurons with optogenetics to show that activity of these neurons is necessary for the formation of an alcohol-cue association. These findings suggest that LH-GABA might be involved in attentional processes modulated by learning.
MeSH term(s)	Rats ; Animals ; Hypothalamic Area, Lateral/physiology ; Learning ; Ethanol ; GABAergic Neurons ; Cues ; Recurrence ; gamma-Aminobutyric Acid
Chemical Substances	Ethanol (3K9958V90M) ; gamma-Aminobutyric Acid (56-12-2)
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2024.01.076
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Article ; Online: A sleeping giant: Suvorexant for the treatment of alcohol use disorder?

Campbell, Erin J / Marchant, Nathan J / Lawrence, Andrew J

Brain research

2018 Volume 1731, Page(s) 145902

Abstract: There are currently 3 FDA approved treatments for alcohol use disorder (AUD) in the USA, opioid receptor antagonists such as naltrexone, disulfiram and acamprosate. To date, these have been largely inadequate at preventing relapse at a population level ... ...

Abstract	There are currently 3 FDA approved treatments for alcohol use disorder (AUD) in the USA, opioid receptor antagonists such as naltrexone, disulfiram and acamprosate. To date, these have been largely inadequate at preventing relapse at a population level and this may be because they only target certain aspects of AUD. Recently, suvorexant, a dual orexin receptor antagonist, has been FDA approved for the treatment of insomnia. Importantly, sleep disruptions occur during both acute and prolonged alcohol exposure and sleep deprivation is a potent factor promoting relapse to alcohol use. In this mini review article, we explore the therapeutic potential of suvorexant for the treatment of AUD. In particular, we highlight that in addition to altering the motivational properties of alcohol, suvorexant may also address key physiological components associated with alcohol withdrawal and abstinence, such as sleep disruptions, which should in turn help reduce or prevent relapse.
MeSH term(s)	Alcoholism/drug therapy ; Animals ; Azepines/therapeutic use ; Humans ; Orexin Receptor Antagonists/therapeutic use ; Sleep Wake Disorders/etiology ; Sleep Wake Disorders/prevention & control ; Substance Withdrawal Syndrome/etiology ; Substance Withdrawal Syndrome/prevention & control ; Triazoles/therapeutic use
Chemical Substances	Azepines ; Orexin Receptor Antagonists ; Triazoles ; suvorexant (081L192FO9)
Language	English
Publishing date	2018-08-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2018.08.005
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Article ; Online: Rats choose alcohol over social reward in an operant choice procedure.

Marchant, Nathan J / McDonald, Allison J / Matsuzaki, Rie / van Mourik, Yvar / Schetters, Dustin / De Vries, Taco J

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2022 Volume 48, Issue 4, Page(s) 585–593

Abstract: The interaction between social factors and alcohol addiction is complex, with potential for both positive and negative contributions to drug use and abstinence. Positive social connections are an important component in successful abstinence, and yet the ... ...

Abstract	The interaction between social factors and alcohol addiction is complex, with potential for both positive and negative contributions to drug use and abstinence. Positive social connections are an important component in successful abstinence, and yet the social context of alcohol use can also lead to relapse. Recently it was shown that rats overwhelmingly choose social reward over methamphetamine, cocaine, and heroin in a discrete choice procedure, and that prolonged choice for social reward attenuates incubation of drug craving. The extent to which this effect generalises to rats trained to self-administer alcohol is not known. In this study we aimed to test the effect of social reward on choice for alcohol in male and female rats. We first validated social reward self-administration in both male and female Long-Evans rats, and found that 60 s access to a social partner of the same sex can serve as an operant reinforcer. Next we trained rats to self-administer both social reward and alcohol (20% ethanol in water), and then used discrete choice trial based tests to determine whether there is a choice preference for alcohol or social reward. Our main finding is that both male and female rats showed persistent choice for alcohol over social reward, with only minor differences between the sexes. We also show that choice for alcohol could be reduced via increased response requirement for alcohol, pre-choice alcohol exposure, and also decreasing the alcohol percentage. This study shows that preference for social rewards over drugs may not generalise to rats self-administering alcohol, and we describe several conditions where choice for social reward can be developed. This study highlights the important contribution of social factors to alcohol abuse, and future studies can investigate the neurobiology underlying a shift in preference from alcohol to social rewards.
MeSH term(s)	Rats ; Male ; Female ; Animals ; Rats, Sprague-Dawley ; Rats, Long-Evans ; Reward ; Methamphetamine/pharmacology ; Ethanol/pharmacology ; Conditioning, Operant ; Self Administration
Chemical Substances	Methamphetamine (44RAL3456C) ; Ethanol (3K9958V90M)
Language	English
Publishing date	2022-09-15
Publishing country	England
Document type	Journal Article
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-022-01447-6
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Article ; Online: A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence.

Marchant, Nathan J / Kaganovsky, Konstantin

Behavioral neuroscience

2015 Volume 129, Issue 3, Page(s) 281–291

Abstract: In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol ...

Abstract	In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.
MeSH term(s)	Alcohol-Related Disorders/metabolism ; Animals ; Benzazepines/pharmacology ; Central Nervous System Depressants/administration & dosage ; Conditioning, Operant/drug effects ; Conditioning, Operant/physiology ; Dopamine/metabolism ; Dopamine Antagonists/pharmacology ; Drug-Seeking Behavior/drug effects ; Drug-Seeking Behavior/physiology ; Electroshock ; Ethanol/administration & dosage ; Extinction, Psychological/drug effects ; Extinction, Psychological/physiology ; Feeding Behavior/drug effects ; Feeding Behavior/physiology ; Genetic Predisposition to Disease ; Male ; Nucleus Accumbens/drug effects ; Nucleus Accumbens/metabolism ; Punishment ; Rats ; Receptors, Dopamine D1/antagonists & inhibitors ; Receptors, Dopamine D1/metabolism ; Self Administration
Chemical Substances	Benzazepines ; Central Nervous System Depressants ; Dopamine Antagonists ; Receptors, Dopamine D1 ; SCH 23390 ; Ethanol (3K9958V90M) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2015-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	230159-3
ISSN	1939-0084 ; 0735-7044
ISSN (online)	1939-0084
ISSN	0735-7044
DOI	10.1037/bne0000050
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Article ; Online: Punishment of alcohol-reinforced responding in alcohol preferring P rats reveals a bimodal population: Implications for models of compulsive drug seeking.

Marchant, Nathan J / Campbell, Erin J / Kaganovsky, Konstantin

Progress in neuro-psychopharmacology & biological psychiatry

2017 Volume 87, Issue Pt A, Page(s) 68–77

Abstract: Individual variations in animal behaviour can be used to describe relationships between different constructs, as well as the underlying neurobiological mechanisms responsible for such variation. In humans, variation in the expression of certain traits ... ...

Abstract	Individual variations in animal behaviour can be used to describe relationships between different constructs, as well as the underlying neurobiological mechanisms responsible for such variation. In humans, variation in the expression of certain traits contributes to the onset of psychopathologies, such as drug addiction. Addiction is characterised by persistent drug use despite negative consequences, but it occurs in only a sub-population of drug users. Compulsive drug use is modelled in laboratory animals by punishing a drug-reinforced operant response. It has been reported that there is individual variability in the response to punishment, and in this report we aim to further define the conditions under which this variation can be observed. We have previously used footshock punishment to suppress alcohol seeking in an animal model of context-induced relapse to alcohol seeking after punishment-imposed abstinence. Here we present a re-examination of the training and punishment data from a large cohort of rats (n=499) collected over several years. We found evidence for a bimodal distribution in the response to punishment in alcohol preferring P rats. We only observed this population split when rats received constant shock intensity for three sessions, but not when increasing shock intensity was used. This observation provides evidence for the existence of two distinct groups of rats, defined by their response to punishment, in an otherwise homogeneous population. The implications of this observation are discussed in reference to prior observations using punishment of other addictive drugs (cocaine and methamphetamine), the potential causes of this phenomenon, and with broader implications for the cause of alcohol and drug addiction in humans.
MeSH term(s)	Animals ; Biophysics ; Central Nervous System Depressants/administration & dosage ; Compulsive Behavior/genetics ; Compulsive Behavior/physiopathology ; Compulsive Behavior/psychology ; Conditioning, Operant/physiology ; Disease Models, Animal ; Drug-Seeking Behavior/physiology ; Electric Stimulation/adverse effects ; Ethanol/administration & dosage ; Extinction, Psychological ; Male ; Punishment ; Rats ; Self Administration
Chemical Substances	Central Nervous System Depressants ; Ethanol (3K9958V90M)
Language	English
Publishing date	2017-07-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	781181-0
ISSN	1878-4216 ; 0278-5846
ISSN (online)	1878-4216
ISSN	0278-5846
DOI	10.1016/j.pnpbp.2017.07.020
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Article: Alcohol Seeking Under Risk of Punishment Is Associated With Activation of Cortical and Subcortical Brain Regions.

McDonald, Allison J / Alonso-Lozares, Isis / Rauh, Vasco / van Mourik, Yvar / Schetters, Dustin / De Vries, Taco J / Marchant, Nathan J

Frontiers in behavioral neuroscience

2021 Volume 15, Page(s) 739681

Abstract: In humans, stimuli associated with alcohol availability can provoke relapse during abstinence. In this study, we investigated the role of discriminative stimuli (DS) in the control of alcohol seeking in two types of behavioral tests. The first test ... ...

Abstract	In humans, stimuli associated with alcohol availability can provoke relapse during abstinence. In this study, we investigated the role of discriminative stimuli (DS) in the control of alcohol seeking in two types of behavioral tests. The first test examined the ability of an alcohol-associated DS to promote alcohol seeking (relapse) after punishment-imposed abstinence in the presence of a different DS. Following this, we tested whether the differentially associated DS can promote and suppress alcohol self-administration in a within-session discrimination task. During the within-session discrimination task, we also tested the rate of alcohol self-administration when two DS are presented in a compound. We first trained Long-Evans male rats (
Language	English
Publishing date	2021-10-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2021.739681
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Article ; Online: Role of anterior insula cortex in context-induced relapse of nicotine-seeking.

Ghareh, Hussein / Alonso-Lozares, Isis / Schetters, Dustin / Herman, Rae J / Heistek, Tim S / Van Mourik, Yvar / Jean-Richard-Dit-Bressel, Philip / Zernig, Gerald / Mansvelder, Huibert D / De Vries, Taco J / Marchant, Nathan J

eLife

2022 Volume 11

Abstract: Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce ... ...

Abstract	Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence.
MeSH term(s)	Animals ; Extinction, Psychological/physiology ; Female ; Male ; Nicotine/adverse effects ; Punishment ; Rats ; Recurrence ; Self Administration
Chemical Substances	Nicotine (6M3C89ZY6R)
Language	English
Publishing date	2022-05-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.75609
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Article ; Online: Context-induced relapse after extinction versus punishment: similarities and differences.

Marchant, Nathan J / Campbell, Erin J / Pelloux, Yann / Bossert, Jennifer M / Shaham, Yavin

Psychopharmacology

2018 Volume 236, Issue 1, Page(s) 439–448

Abstract: Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of ... ...

Abstract	Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction in a different context (B) and reinstate (or relapse to) drug seeking after exposure to the original drug-associated context (A). In a more recent version of the model introduced in 2013, the experimental conditions in context A are identical to those used in the classical model, but drug-reinforced responding in context B is suppressed by probabilistic punishment. The punishment-based ABA renewal model is proposed to resemble abstinence in humans, which is often initiated by the desire to avoid the negative consequences of drug use. The goal of our review is to discuss similarities and differences in mechanisms that play a role in suppression of drug seeking in context B and context-induced relapse to drug seeking in context A in the two models. We first describe psychological mechanisms that mediate extinction and punishment of drug-reinforced responding in context B. We then summarize recent findings on brain mechanisms of context-induced relapse of drug seeking after extinction, or punishment-imposed abstinence. These findings demonstrate both similarities and differences in brain mechanisms underlying relapse in the two variations of the ABA renewal model. We conclude by briefly discussing clinical implications of the preclinical studies.
MeSH term(s)	Animals ; Association Learning/physiology ; Brain/physiopathology ; Brain Mapping ; Conditioning, Classical/physiology ; Craving/physiology ; Disease Models, Animal ; Drug-Seeking Behavior/physiology ; Extinction, Psychological/physiology ; Humans ; Punishment/psychology ; Rats ; Recurrence ; Reinforcement (Psychology) ; Self Administration/psychology ; Substance-Related Disorders/physiopathology ; Substance-Related Disorders/psychology
Language	English
Publishing date	2018-05-24
Publishing country	Germany
Document type	Comparative Study ; Journal Article ; Review
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-018-4929-1
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