Neurogenetics and Clinical Evidence for the Putative Activation of the Brain Reward Circuitry by a Neuroadaptagen: Proposing an Addiction Candidate Gene Panel Map

AbstractThe neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the “reward mountain”). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.Author summaryTo succeed in the struggle for survival and reproductive success, animals must make wise choices about which goals to pursue and how much to pay to attain them. How does the brain make such decisions and adjust behaviour accordingly? An animal model that has long served to address this question entails delivery of rewarding brain stimulation. When the probe is positioned appropriately in the brain, rats will work indefatigably to trigger such stimulation. Dopamine neurons play a crucial role in this phenomenon. The dominant model of the brain circuitry responsible for the reward-seeking behavior treats these cells as a gateway through which the reward-generating brain signals must pass. Here, we challenge this idea on the basis of an experiment in which the dopamine neurons were activated selectively and directly. Mathematical modeling of the results argues for a new view of the structure of brain reward circuitry. On this view, the pathway(s) in which the dopamine neurons are embedded is one of a set of parallel channels that process reward signals in the brain. To achieve a full understanding of how goals are evaluated, selected and pursued, the full set of channels must be identified and investigated.

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Role of the dorsal diencephalic conduction system in the brain reward circuitry

Behavioural Brain Research ◽

10.1016/j.bbr.2015.10.038 ◽

2016 ◽

Vol 296 ◽

pp. 431-441 ◽

Cited By ~ 8

Author(s):

Marc Fakhoury ◽

Pierre-Paul Rompré ◽

Sandra M. Boye

Keyword(s):

Conduction System ◽

Reward Circuitry ◽

Brain Reward ◽

The Brain

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Anhedonia and the Brain Reward Circuitry in Depression

Current Behavioral Neuroscience Reports ◽

10.1007/s40473-015-0044-3 ◽

2015 ◽

Vol 2 (3) ◽

pp. 146-153 ◽

Cited By ~ 88

Author(s):

Mitra Heshmati ◽

Scott J. Russo

Keyword(s):

Reward Circuitry ◽

Brain Reward ◽

The Brain

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Erratum: The brain reward circuitry in mood disorders

Nature Reviews Neuroscience ◽

10.1038/nrn3589 ◽

2013 ◽

Vol 14 (10) ◽

pp. 736-736 ◽

Cited By ~ 3

Author(s):

Scott J. Russo ◽

Eric J. Nestler

Keyword(s):

Mood Disorders ◽

Reward Circuitry ◽

Brain Reward ◽

The Brain

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Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

NeuroImage ◽

10.1016/j.neuroimage.2012.03.050 ◽

2012 ◽

Vol 61 (4) ◽

pp. 884-888 ◽

Cited By ~ 36

Author(s):

M.E. Haahr ◽

P.M. Rasmussen ◽

K. Madsen ◽

L. Marner ◽

C. Ratner ◽

...

Keyword(s):

Reward Circuitry ◽

Brain Reward ◽

The Brain

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Learning of food preferences: mechanisms and implications for obesity & metabolic diseases

International Journal of Obesity ◽

10.1038/s41366-021-00894-3 ◽

2021 ◽

Author(s):

Hans-Rudolf Berthoud ◽

Christopher D. Morrison ◽

Karen Ackroff ◽

Anthony Sclafani

Keyword(s):

Metabolic Diseases ◽

Food Preferences ◽

Reward System ◽

Nutrient Sensing ◽

Vagal Afferents ◽

Dietary Knowledge ◽

Ongoing Work ◽

Brain Reward ◽

The Brain ◽

Vagal Function

AbstractOmnivores, including rodents and humans, compose their diets from a wide variety of potential foods. Beyond the guidance of a few basic orosensory biases such as attraction to sweet and avoidance of bitter, they have limited innate dietary knowledge and must learn to prefer foods based on their flavors and postoral effects. This review focuses on postoral nutrient sensing and signaling as an essential part of the reward system that shapes preferences for the associated flavors of foods. We discuss the extensive array of sensors in the gastrointestinal system and the vagal pathways conveying information about ingested nutrients to the brain. Earlier studies of vagal contributions were limited by nonselective methods that could not easily distinguish the contributions of subsets of vagal afferents. Recent advances in technique have generated substantial new details on sugar- and fat-responsive signaling pathways. We explain methods for conditioning flavor preferences and their use in evaluating gut–brain communication. The SGLT1 intestinal sugar sensor is important in sugar conditioning; the critical sensors for fat are less certain, though GPR40 and 120 fatty acid sensors have been implicated. Ongoing work points to particular vagal pathways to brain reward areas. An implication for obesity treatment is that bariatric surgery may alter vagal function.

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In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing

Translational Psychiatry ◽

10.1038/s41398-021-01241-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Juan Kou ◽

Chunmei Lan ◽

Yingying Zhang ◽

Qianqian Wang ◽

Feng Zhou ◽

...

Keyword(s):

Brain Function ◽

Intranasal Administration ◽

Emotional Cues ◽

Beneficial Effects ◽

Social Processing ◽

Concentration Changes ◽

Brain Reward ◽

Male Subjects ◽

The Brain ◽

Potential Therapeutic Intervention

AbstractIntranasal oxytocin exerts wide-ranging effects on socioemotional behavior and is proposed as a potential therapeutic intervention in psychiatric disorders. However, following intranasal administration, oxytocin could penetrate directly into the brain or influence its activity via increased peripheral concentrations crossing the blood–brain barrier or influencing vagal projections. In the current randomized, placebo-controlled, pharmaco-imaging clinical trial we investigated effects of 24IU oral (lingual) oxytocin spray, restricting it to peripherally mediated blood-borne and vagal effects, on responses to face emotions in 80 male subjects and compared them with 138 subjects treated intranasally with 24IU. Oral, but not intranasal oxytocin administration increased both arousal ratings for faces and associated brain reward responses, the latter being partially mediated by blood concentration changes. Furthermore, while oral oxytocin increased amygdala and arousal responses to face emotions, after intranasal administration they were decreased. Thus, oxytocin can produce markedly contrasting motivational effects in relation to socioemotional cues when it influences brain function via different routes. These findings have important implications for future therapeutic use since administering oxytocin orally may be both easier and have potentially stronger beneficial effects by enhancing responses to emotional cues and increasing their associated reward.

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Synergistic Effect of Several Neurotransmitters in PFC-NAc-VTA Neural Circuit for the Anti-Depression Effect of Shuganheweitang in a Chronic Unpredictable Mild Stress Model

Natural Product Communications ◽

10.1177/1934578x211002415 ◽

2021 ◽

Vol 16 (3) ◽

pp. 1934578X2110024

Author(s):

Xin Chen ◽

Yuanchun Ma ◽

Xiongjun Mou ◽

Hao Liu ◽

Hao Ming ◽

...

Keyword(s):

Animal Behavior ◽

Neural Circuit ◽

Concentration Level ◽

Brain Regions ◽

Mild Stress ◽

Depression Effect ◽

Monoamine Neurotransmitters ◽

Reward Circuitry ◽

High Doses ◽

The Brain

Depression, a major worldwide mental disorder, leads to massive disability and can result in death. The PFC-NAc-VTA neuro circuit is related to emotional, neurovegetative, and cognitive functions, which emerge as a circuit-level framework for understanding reward deficits in depression. Neurotransmitters, which are widely distributed in different brain regions, are important detected targets for the evaluation of depression. Shuganheweitang (SGHWT) is a popular prescription in clinical therapy for depression. In order to investigate its possible pharmacodynamics and anti-depressive mechanism, the complex plant material was separated into different fractions. These in low and high doses, along with low and high doses of SGHWT were tested in animal behavior tests. The low and high doses of SGHWT were more effective than the various fractions, which indicate the importance of synergistic function in traditional Chinese medicine. Furthermore, amino acid (GABA, Glu) and monoamine neurotransmitters (DA, 5-HT, NA, 5-HIAA) in the PFC-NAc-VTA neuro circuit were investigated by UPLC-MS/MS. The level trend of DA and 5-HT were consistent in the PFC-NAc-VTA neuro circuit, whereas 5-HIAA was decreased in the PFC, Glu was decreased in the PFC and VTA, and NA and GABA were decreased in the NAc. The results indicate that the pathogenesis of depression is associated with dysfunction of the PFC-NAc-VTA neural circuit, mainly through the neural projection effects of neurotransmitters associated with various brain regions in the neural circuit. PCA and OPLS-DA score plots demonstrated the similarities of individuals within each group and the differences among the groups. In this study, SGHWT could regulate the concentration level of different neurotransmitters in the PFC-NAc-VTA neuro circuit to improve the depression, which benefitted from the recognition of the brain reward circuitry in mood disorders.

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