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Article ; Online: Ventral pallidal regulation of motivated behaviors and reinforcement.

Soares-Cunha, Carina / Heinsbroek, Jasper A

2023 Volume 17, Page(s) 1086053

Abstract: The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central ... ...

Abstract	The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central node of the ventral basal ganglia, and recent studies have revealed complex VP cellular heterogeneity and cell- and circuit-specific regulation of reward, aversion, motivation, and drug-seeking behaviors. Although the VP is canonically considered a relay and output structure for this circuit, emerging data indicate that the VP is a central hub in an extensive network for reward processing and the regulation of motivation that extends beyond classically defined basal ganglia borders. VP neurons respond temporally faster and show more advanced reward coding and prediction error processing than neurons in the upstream nucleus accumbens, and regulate the activity of the ventral mesencephalon dopamine system. This review will summarize recent findings in the literature and provide an update on the complex cellular heterogeneity and cell- and circuit-specific regulation of motivated behaviors and reinforcement by the VP with a specific focus on mood and substance use disorders. In addition, we will discuss mechanisms by which stress and drug exposure alter the functioning of the VP and produce susceptibility to neuropsychiatric disorders. Lastly, we will outline unanswered questions and identify future directions for studies necessary to further clarify the central role of VP neurons in the regulation of motivated behaviors.
MeSH term(s)	Animals ; Basal Forebrain ; Motivation ; Reward ; Neurons/physiology ; Nucleus Accumbens/physiology
Language	English
Publishing date	2023-02-02
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2452968-0
ISSN	1662-5110 ; 1662-5110
ISSN (online)	1662-5110
ISSN	1662-5110
DOI	10.3389/fncir.2023.1086053
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Article ; Online: Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction.

Heinsbroek, Jasper A / De Vries, Taco J / Peters, Jamie

Cold Spring Harbor perspectives in medicine

2021 Volume 11, Issue 3

Abstract: Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become ... ...

Abstract	Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which glutamate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expression, extinction, and reinstatement of opioid seeking over the course of opioid addiction.
MeSH term(s)	Animals ; Brain/drug effects ; Dopamine/metabolism ; Glutamic Acid/metabolism ; Humans ; Memory/drug effects ; Morphine/adverse effects ; Opioid-Related Disorders/metabolism ; Opioid-Related Disorders/pathology ; Opioid-Related Disorders/physiopathology ; Reward ; Signal Transduction/drug effects ; Synaptic Transmission/drug effects
Chemical Substances	Glutamic Acid (3KX376GY7L) ; Morphine (76I7G6D29C) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2021-03-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a039602
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Article ; Online: Cocaine shifts dopamine D2 receptor sensitivity to gate conditioned behaviors.

Gong, Sheng / Fayette, Nicholas / Heinsbroek, Jasper A / Ford, Christopher P

Neuron

2022 Volume 110, Issue 7, Page(s) 1272

Language	English
Publishing date	2022-04-07
Publishing country	United States
Document type	Published Erratum
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2022.03.005
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model.

Heinsbroek, Jasper A / Giannotti, Giuseppe / Bonilla, Joel / Olson, David E / Peters, Jamie

Psychedelic medicine (New Rochelle, N.Y.)

2023 Volume 1, Issue 2, Page(s) 111–119

Abstract: Background: The potential use of psychedelic drugs as therapeutics for neuropsychiatric disorders has been limited by their hallucinogenic properties. To overcome this limitation, we developed and characterized tabernanthalog (TBG), a novel analogue of ... ...

Abstract	Background: The potential use of psychedelic drugs as therapeutics for neuropsychiatric disorders has been limited by their hallucinogenic properties. To overcome this limitation, we developed and characterized tabernanthalog (TBG), a novel analogue of the indole alkaloids ibogaine and 5-methoxy- Methodology: Here we employed a polydrug model of heroin and alcohol couse to screen the therapeutic efficacy of TBG on metrics of both opioid and alcohol seeking. We first exposed rats to alcohol (or control sucrose-fade solution) in the home-cage (HC), using a two-bottle binge protocol, over a period of 1 month. Rats were then split into two groups that underwent self-administration training for either intravenous heroin or oral alcohol, so that we could assess the impact of HC alcohol exposure on the self-administration of each substance separately. Thereafter, rats began self-administering both heroin and alcohol in the same sessions. Finally, we tested the effects of TBG on break points for heroin and alcohol in a progressive ratio test, where the number of lever presses required to obtain a single reward increased exponentially. Results and conclusion: TBG effectively reduced motivation for heroin and alcohol in this test, indicating its efficacy is preserved in animals with a history of heroin and alcohol polydrug use.
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article
ISSN	2831-4433
ISSN (online)	2831-4433
DOI	10.1089/psymed.2023.0009
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Article ; Online: Corrigendum: Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction.

Heinsbroek, Jasper A / De Vries, Taco J / Peters, Jamie

Cold Spring Harbor perspectives in medicine

2020 Volume 10, Issue 6

Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Journal Article ; Published Erratum
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a040410
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Article ; Online: Cocaine shifts dopamine D2 receptor sensitivity to gate conditioned behaviors.

Gong, Sheng / Fayette, Nicholas / Heinsbroek, Jasper A / Ford, Christopher P

Neuron

2021 Volume 109, Issue 21, Page(s) 3421–3435.e5

Abstract: Cocaine addiction is a chronic, relapsing disorder characterized by maladaptation in the brain mesolimbic and nigrostriatal dopamine system. Although changes in the properties of D2-receptor-expressing medium spiny neurons (D2-MSNs) and connected ... ...

Abstract	Cocaine addiction is a chronic, relapsing disorder characterized by maladaptation in the brain mesolimbic and nigrostriatal dopamine system. Although changes in the properties of D2-receptor-expressing medium spiny neurons (D2-MSNs) and connected striatal circuits following cocaine treatment are known, the contributions of altered D2-receptor (D2R) function in mediating the rewarding properties of cocaine remain unclear. Here, we describe how a 7-day exposure to cocaine alters dopamine signaling by selectively reducing the sensitivity, but not the expression, of nucleus accumbens D2-MSN D2Rs via an alteration in the relative expression and coupling of G protein subunits. This cocaine-induced reduction of D2R sensitivity facilitated the development of the rewarding effects of cocaine as blocking the reduction in G protein expression was sufficient to prevent cocaine-induced behavioral adaptations. These findings identify an initial maladaptive change in sensitivity by which mesolimbic dopamine signals are encoded by D2Rs following cocaine exposure.
MeSH term(s)	Animals ; Cocaine/pharmacology ; Cocaine-Related Disorders ; Mice ; Mice, Transgenic ; Nucleus Accumbens/metabolism ; Receptors, Dopamine D1/metabolism ; Receptors, Dopamine D2/metabolism
Chemical Substances	Receptors, Dopamine D1 ; Receptors, Dopamine D2 ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2021-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2021.08.012
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking.

Giannotti, Giuseppe / Mottarlini, Francesca / Heinsbroek, Jasper A / Mandel, Mitchel R / James, Morgan H / Peters, Jamie

Translational psychiatry

2022 Volume 12, Issue 1, Page(s) 432

Abstract: As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating ...

Abstract	As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats-heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.
MeSH term(s)	Analgesics, Opioid ; Animals ; Cues ; Heroin ; Intracellular Signaling Peptides and Proteins ; Neuropeptides ; Orexin Receptor Antagonists/pharmacology ; Orexins ; Oxytocin/pharmacology ; Rats ; Receptors, Oxytocin
Chemical Substances	Analgesics, Opioid ; Intracellular Signaling Peptides and Proteins ; Neuropeptides ; Orexin Receptor Antagonists ; Orexins ; Receptors, Oxytocin ; Oxytocin (50-56-6) ; Heroin (70D95007SX)
Language	English
Publishing date	2022-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-022-02161-z
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Article ; Online: Circuit selectivity in drug versus natural reward seeking behaviors.

Nall, Rusty W / Heinsbroek, Jasper A / Nentwig, Todd B / Kalivas, Peter W / Bobadilla, Ana-Clara

Journal of neurochemistry

2021 Volume 157, Issue 5, Page(s) 1450–1472

Abstract: Substance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where ... ...

Abstract	Substance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry is selectively necessary for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate the necessity of brain regions in drug- versus natural reward-associated behaviors.
MeSH term(s)	Animals ; Brain/drug effects ; Brain/physiology ; Drug-Seeking Behavior ; Humans ; Nerve Net/physiology ; Neural Pathways/drug effects ; Neural Pathways/physiology ; Nucleus Accumbens/physiology ; Reward ; Substance-Related Disorders/psychology
Language	English
Publishing date	2021-02-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15297
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Article ; Online: A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse.

Heinsbroek, Jasper A / Furbish, Amelia B / Peters, Jamie

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2018 Volume 43, Issue 7, Page(s) 1492–1497

Abstract: Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the ... ...

Abstract	Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.
MeSH term(s)	3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology ; Animals ; Cocaine/pharmacology ; Cocaine-Related Disorders/drug therapy ; Cocaine-Related Disorders/prevention & control ; Conditioning, Operant/drug effects ; Cues ; Drug-Seeking Behavior/drug effects ; Extinction, Psychological/drug effects ; Imidazoles/administration & dosage ; Imidazoles/pharmacology ; Infusions, Intraventricular ; Lithium Chloride/pharmacology ; Male ; Pyridines/administration & dosage ; Pyridines/pharmacology ; Rats ; Receptors, Opioid, kappa/agonists ; Recurrence ; Self Administration ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
Chemical Substances	Imidazoles ; Pyridines ; Receptors, Opioid, kappa ; 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer (67198-13-4) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Lithium Chloride (G4962QA067) ; Cocaine (I5Y540LHVR) ; SB 203580 (OU13V1EYWQ)
Language	English
Publishing date	2018-02-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-017-0006-4
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Article ; Online: Cocaine and sucrose rewards recruit different seeking ensembles in the nucleus accumbens core.

Bobadilla, Ana-Clara / Dereschewitz, Eric / Vaccaro, Lucio / Heinsbroek, Jasper A / Scofield, Michael D / Kalivas, Peter W

Molecular psychiatry

2020 Volume 25, Issue 12, Page(s) 3150–3163

Abstract: Poorly regulated reward seeking is a central feature of substance use disorder. Recent research shows that rewarding drug-related experiences induce synchronous activation of a discrete number of neurons in the nucleus accumbens that are causally linked ... ...

Abstract	Poorly regulated reward seeking is a central feature of substance use disorder. Recent research shows that rewarding drug-related experiences induce synchronous activation of a discrete number of neurons in the nucleus accumbens that are causally linked to reward-related contexts. Here we comprehensively characterize the specific ensemble of neurons built through experience that are linked to seeking behavior. We additionally address the question of whether or not addictive drugs usurp the neuronal networks recruited by natural rewards by evaluating cocaine- and sucrose-associated ensembles within the same mouse. We used Fos
MeSH term(s)	Animals ; Cocaine ; Cues ; Drug-Seeking Behavior ; Extinction, Psychological ; Mice ; Nucleus Accumbens ; Rats ; Rats, Sprague-Dawley ; Reward ; Self Administration ; Sucrose
Chemical Substances	Sucrose (57-50-1) ; Cocaine (I5Y540LHVR)
Keywords	covid19
Language	English
Publishing date	2020-09-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-020-00888-z
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