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Article ; Online: Structural Integrity in the Sustained Antidepressant Effect of Ketamine.

Belujon, Pauline

The international journal of neuropsychopharmacology

2017 Volume 20, Issue 4, Page(s) 359–361

Language	English
Publishing date	2017-04-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1440129-0
ISSN	1469-5111 ; 1461-1457
ISSN (online)	1469-5111
ISSN	1461-1457
DOI	10.1093/ijnp/pyw117
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Article ; Online: The amygdala-ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine.

Salin, Adélie / Dugast, Emilie / Lardeux, Virginie / Solinas, Marcello / Belujon, Pauline

British journal of pharmacology

2023 Volume 180, Issue 14, Page(s) 1819–1831

Abstract: Background and purpose: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behaviour. ... ...

Abstract	Background and purpose: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]-ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. Experimental approach: In a model of cocaine self-administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA-VP pathway using a pharmacological approach. Key results: We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short-term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. Conclusion and implications: Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA-VP pathway in cocaine-induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence.
MeSH term(s)	Rats ; Animals ; Cocaine/pharmacology ; Ventral Tegmental Area/metabolism ; Rats, Sprague-Dawley ; Basal Forebrain/metabolism ; Dopamine/metabolism ; Dopaminergic Neurons/metabolism ; Amygdala/metabolism
Chemical Substances	Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2023-02-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16034
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Article ; Online: Protracted Abstinence From Extended Cocaine Self-Administration Is Associated With Hypodopaminergic Activity in the VTA but Not in the SNc.

Salin, Adélie / Lardeux, Virginie / Solinas, Marcello / Belujon, Pauline

The international journal of neuropsychopharmacology

2020 Volume 24, Issue 6, Page(s) 499–504

Abstract: The chronic relapsing nature of cocaine addiction suggests that chronic cocaine exposure produces persistent neuroadaptations that may be temporally and regionally dynamic in brain areas such as the dopaminergic (DA) system. We have previously shown ... ...

Abstract	The chronic relapsing nature of cocaine addiction suggests that chronic cocaine exposure produces persistent neuroadaptations that may be temporally and regionally dynamic in brain areas such as the dopaminergic (DA) system. We have previously shown altered metabolism of DA-target structures, the ventral and dorsal striatum, between early and late abstinence. However, specific changes within the midbrain DA system were not investigated. Here, we investigated potential time- and region-specific changes of activity in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) in rats that had extended or limited access to cocaine and later underwent a period of abstinence. We found that DA activity is decreased only in the VTA in rats with extended access to cocaine, with no changes in SNc DA activity. These changes in VTA DA activity may participate in the negative emotional state and the incubation of drug seeking that occur during abstinence from cocaine.
MeSH term(s)	Animals ; Behavior, Animal/physiology ; Cocaine/administration & dosage ; Cocaine-Related Disorders/metabolism ; Dopamine/metabolism ; Dopamine Uptake Inhibitors/administration & dosage ; Male ; Pars Compacta/metabolism ; Rats ; Rats, Sprague-Dawley ; Self Administration ; Ventral Tegmental Area/metabolism
Chemical Substances	Dopamine Uptake Inhibitors ; Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2020-10-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440129-0
ISSN	1469-5111 ; 1461-1457
ISSN (online)	1469-5111
ISSN	1461-1457
DOI	10.1093/ijnp/pyaa096
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Article ; Online: Dopamine System Dysregulation in Major Depressive Disorders.

Belujon, Pauline / Grace, Anthony A

The international journal of neuropsychopharmacology

2017 Volume 20, Issue 12, Page(s) 1036–1046

Abstract: Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, ... ...

Abstract	Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, including the ventral subiculum of the hippocampus and the basolateral amygdala. Whereas basic and clinical studies demonstrate deficits of the dopaminergic system in depression, the origin of these deficits likely lies in dysregulation of its regulatory afferent circuits. This review explores the current information regarding the afferent modulation of the dopaminergic system and its relevance to major depressive disorder, as well as some of the system-level effects of novel antidepressants such as agomelatine and ketamine.
MeSH term(s)	Animals ; Brain/metabolism ; Depressive Disorder, Major/metabolism ; Depressive Disorder, Major/pathology ; Dopamine/metabolism ; Humans
Chemical Substances	Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2017-10-03
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440129-0
ISSN	1469-5111 ; 1461-1457
ISSN (online)	1469-5111
ISSN	1461-1457
DOI	10.1093/ijnp/pyx056
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Article ; Online: Regulation of dopamine system responsivity and its adaptive and pathological response to stress.

Belujon, Pauline / Grace, Anthony A

Proceedings. Biological sciences

2015 Volume 282, Issue 1805

Abstract: Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the ...

Abstract	Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood. The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system. This review explores the current knowledge of afferent modulation of the stress/DA circuitry, and presents recent data focusing on the effect of stress on the DA system and its relevance to psychiatric disorders.
MeSH term(s)	Afferent Pathways/physiology ; Dopamine/metabolism ; Humans ; Hypothalamo-Hypophyseal System/physiology ; Stress, Psychological
Chemical Substances	Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2015-04-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	209242-6
ISSN	1471-2954 ; 0080-4649 ; 0962-8452 ; 0950-1193
ISSN (online)	1471-2954
ISSN	0080-4649 ; 0962-8452 ; 0950-1193
DOI	10.1098/rspb.2014.2516
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Article ; Online: Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity.

Belujon, Pauline / Grace, Anthony A

Biological psychiatry

2014 Volume 76, Issue 12, Page(s) 927–936

Abstract: Background: One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic ... ...

Abstract	Background: One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear. Methods: Wistar-Kyoto rats were exposed to inescapable, uncontrollable footshocks. To evaluate learned helplessness behavior, we used an active avoidance task in a shuttle box equipped with an electrical grid floor. After helplessness assessment, we performed in vivo electrophysiological recordings first from ventral tegmental area dopaminergic (DA) neurons and second from accumbens neurons responsive to fimbria stimulation. Ketamine was injected and tested on helpless behavior and electrophysiological recordings. Results: We show that ketamine is able to restore the integrity of a network by acting on the DA system and restoring synaptic dysfunction observed in stress-induced depression. We show that part of the antidepressant effect of ketamine is via the DA system. Indeed, injection of ketamine restores a decreased dopamine neuron population activity, as well as synaptic plasticity (long-term potentiation) in the hippocampus-accumbens pathway, via, in part, activation of D1 receptors. Conclusions: This work provides a unique systems perspective on the mechanisms of ketamine on a disrupted limbic system.
MeSH term(s)	Action Potentials/drug effects ; Animals ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Benzazepines/pharmacology ; Brain/pathology ; Depression/drug therapy ; Depression/etiology ; Depression/pathology ; Disease Models, Animal ; Dopamine Agonists/pharmacology ; Dopaminergic Neurons/drug effects ; Dopaminergic Neurons/physiology ; Electroshock/adverse effects ; Helplessness, Learned ; Ketamine/pharmacology ; Ketamine/therapeutic use ; Long-Term Potentiation/drug effects ; Long-Term Potentiation/physiology ; Male ; Neural Pathways/drug effects ; Rats ; Rats, Inbred WKY ; Reaction Time/drug effects ; Time Factors
Chemical Substances	Antidepressive Agents ; Benzazepines ; Dopamine Agonists ; SCH 23390 ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2014-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2014.04.014
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Article ; Online: L-dopa treatment duration versus Parkinson's disease progression: the dorsal-ventral divide.

Belujon, Pauline / Grace, Anthony A

Movement disorders : official journal of the Movement Disorder Society

2013 Volume 28, Issue 2, Page(s) 120–121

MeSH term(s)	Antiparkinson Agents/adverse effects ; Basal Ganglia/physiopathology ; Dopamine Agents/adverse effects ; Female ; Humans ; Male ; Parkinson Disease/drug therapy ; Parkinson Disease/physiopathology
Chemical Substances	Antiparkinson Agents ; Dopamine Agents
Language	English
Publishing date	2013-02-07
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.25334
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Article ; Online: Prevention of relapse to methamphetamine self-administration by environmental enrichment: involvement of glucocorticoid receptors.

Nicolas, Céline / Hofford, Rebecca S / Dugast, Emilie / Lardeux, Virginie / Belujon, Pauline / Solinas, Marcello / Bardo, Michael T / Thiriet, Nathalie

Psychopharmacology

2021 Volume 239, Issue 4, Page(s) 1009–1018

Abstract: Rationale: In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE's actions on the stress system.: Objectives: This study investigated ... ...

Abstract	Rationale: In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE's actions on the stress system. Objectives: This study investigated whether exposure to EE during abstinence reduces methamphetamine seeking after extended self-administration. In addition, we investigated whether these effects are associated with alterations in the levels of glucocorticoid receptors (GR) in the brain and whether administration of GR antagonists blocks methamphetamine relapse. Methods: We allowed rats to self-administer methamphetamine for twenty 14-h sessions. After 3 weeks of abstinence either in standard (SE) or EE conditions, we measured methamphetamine seeking in a single 3-h session. Then, we used western blot techniques to measure GR levels in several brain areas. Finally, in an independent group of rats, after methamphetamine self-administration and abstinence in SE, we administered the GR antagonist mifepristone, and we investigated methamphetamine seeking. Results: Exposure to EE reduced methamphetamine seeking and reversed methamphetamine-induced increases in GR levels in the ventral and dorsal hippocampus. In addition, EE decreased GR levels in the amygdala in drug-naive animals, but this effect was prevented by previous exposure to methamphetamine. Administration of mifepristone significantly decreased methamphetamine seeking. Conclusions: The anti-craving effects of EE are paralleled by restoration of methamphetamine-induced dysregulation of GR in the hippocampus. These results provide support for the hypothesis that the effect of EE on methamphetamine relapse is at least in part mediated by EE's action on the brain stress system.
MeSH term(s)	Animals ; Drug-Seeking Behavior ; Methamphetamine/pharmacology ; Mifepristone/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; Recurrence ; Self Administration
Chemical Substances	Receptors, Glucocorticoid ; Mifepristone (320T6RNW1F) ; Methamphetamine (44RAL3456C)
Language	English
Publishing date	2021-03-25
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/s00213-021-05770-6
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Article ; Online: Reorganization of striatal inhibitory microcircuits leads to pathological synchrony in the Basal Ganglia.

Belujon, Pauline / Grace, Anthony A

Neuron

2011 Volume 71, Issue 5, Page(s) 766–768

Abstract: Neural synchronization plays an important role in information flow in the nervous system under healthy and pathological conditions. In this issue of Neuron, Gittis et al. show that reorganization of striatal microcircuits promotes synchronous activity ... ...

Abstract	Neural synchronization plays an important role in information flow in the nervous system under healthy and pathological conditions. In this issue of Neuron, Gittis et al. show that reorganization of striatal microcircuits promotes synchronous activity and may underlie the pathological network oscillations at the root of motor symptoms described in Parkinson's disease.
Language	English
Publishing date	2011-09-06
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2011.08.012
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Article ; Online: Dopamine and addiction: what have we learned from 40 years of research.

Solinas, Marcello / Belujon, Pauline / Fernagut, Pierre Olivier / Jaber, Mohamed / Thiriet, Nathalie

Journal of neural transmission (Vienna, Austria : 1996)

2018 Volume 126, Issue 4, Page(s) 481–516

Abstract: Among the neurotransmitters involved in addiction, dopamine (DA) is clearly the best known. The critical role of DA in addiction is supported by converging evidence that has been accumulated in the last 40 years. In the present review, first we describe ... ...

Abstract	Among the neurotransmitters involved in addiction, dopamine (DA) is clearly the best known. The critical role of DA in addiction is supported by converging evidence that has been accumulated in the last 40 years. In the present review, first we describe the dopaminergic system in terms of connectivity, functioning and involvement in reward processes. Second, we describe the functional, structural, and molecular changes induced by drugs within the DA system in terms of neuronal activity, synaptic plasticity and transcriptional and molecular adaptations. Third, we describe how genetic mouse models have helped characterizing the role of DA in addiction. Fourth, we describe the involvement of the DA system in the vulnerability to addiction and the interesting case of addiction DA replacement therapy in Parkinson's disease. Finally, we describe how the DA system has been targeted to treat patients suffering from addiction and the result obtained in clinical settings and we discuss how these different lines of evidence have been instrumental in shaping our understanding of the physiopathology of drug addiction.
MeSH term(s)	Animals ; Behavior, Addictive/metabolism ; Behavior, Addictive/physiopathology ; Dopamine/metabolism ; Humans ; Substance-Related Disorders/metabolism ; Substance-Related Disorders/physiopathology
Chemical Substances	Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2018-12-19
Publishing country	Austria
Document type	Journal Article ; Review
ZDB-ID	184163-4
ISSN	1435-1463 ; 0300-9564
ISSN (online)	1435-1463
ISSN	0300-9564
DOI	10.1007/s00702-018-1957-2
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