A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse

Graziane, Nicholas; Neumann, Peter A.; Dong, Yan

doi:10.3389/fnsyn.2018.00012

Cited by 31 publications

(24 citation statements)

References 82 publications

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“…We previously showed that acute nicotine induces an increase of the LHb neuronal activity in vivo [42] that might be related to its noxious/aversive effect [29,47] and reduced rewarding effect by inhibiting VTA dopaminergic neurons via the rostromedial tegmental neurons [48]. Here we found that 5-HT 2A Rs are overexpressed in the LHb after exposure to acute nicotine and TCB-2 administration induces mainly inhibitory effects on LHb neurons of acute-treated animals.…”

Section: Discussionmentioning

confidence: 50%

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Bombardi

Delicata

Tagliavia

et al. 2020

IJMS

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Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is particularly interesting are the 5-HT2A receptors (5-HT2ARs) and the lateral habenula (LHb), a central area in nicotine addiction that we showed to be under a strong 5-HT2AR-modulation. Single-cell extracellular recording of LHb neurons was used to study the 5-HT2AR function by intravenously administrating the potent agonist TCB-2. Acute nicotine (2 mg/kg, intraperitoneal, i.p.) and chronic nicotine (6 mg/kg/day for 14 days) differently affected both the 5-HT2AR-immuno reactive (IR) neuron number and the 5-HT2AR immunostaining area in the different brain areas studied. After acute nicotine, TCB-2 cumulative doses (5–640 µg/kg, intravenous, i.v.) bidirectionally affected the activity of 74% of LHb recorded neurons. After chronic nicotine treatment, TCB-2 was only capable of decreasing the LHb firing rate. The expression of 5-HT2AR under acute and chronic nicotine exposure was studied in the LHb and in other brain areas involved in nicotine effects in rats by using immunohistochemistry. These data reveal that acute and chronic nicotine differentially affect the 5-HT2AR function in different brain areas and this might be relevant in nicotine addiction and its treatment.

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Section: Discussionmentioning

confidence: 50%

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Bombardi

Delicata

Tagliavia

et al. 2020

IJMS

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“…Genes harboring genetic loci that were associated with major depressive disorder in the largest genetic study to date were not enriched in the medial or lateral habenula ( Wray et al, 2018 ). This enrichment for depressive symptoms and the central role of the habenula in the hedonic neurocircuit motivated an analysis of genes that were differentially expressed in a study of well-being ( Graziane et al, 2018 ). Genes that were up-regulated in the blood of people with low levels of hedonic well-being were enriched in both divisions of the adult habenula (33 genes, p < 0.0005, AUROC > 0.67, specificity rank < 7, Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

Foll

French

2018

Front. Neurosci.

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Due to size and accessibility, most information about the habenula is derived from rodent studies. To better understand the molecular signature of the habenula we characterized the genes that have high expression in the habenula. We compared anatomical expression profiles of three normal adult human brains and four fetal brains. We used gene set enrichment analyses to determine if genes annotated to specific molecular functions, cellular components, and biological processes are enriched in the habenula. We also tested gene sets related to depression and addiction to determine if they uniquely involve the habenula. As expected, we observed high habenular expression of GPR151, nicotinic cholinergic receptors, and cilia-associated genes (medial division). Genes identified in genetic studies of smoking and associated with nicotine response were enriched in the habenula. Genes associated with major depressive disorder did not have enriched expression in the habenula but genes negatively correlated with hedonic well-being were, providing a link to anhedonia. We observed enrichment of genes associated with diseases that are comorbid with addictions (hematopoiesis, thrombosis, liver cirrhosis, pneumonia, and pulmonary fibrosis) and depression (rheumatoid arthritis, multiple sclerosis, and kidney disease). These inflammatory diseases mark a neuroimmune signature that is supported by genes associated with mast cells, acute inflammatory response, and leukocyte migration. We also found enrichment of cytochrome p450 genes suggesting the habenula is uniquely sensitive to endogenous and xenobiotic compounds. Our results suggest the habenula receives negative reward signals from immune and drug processing molecules. This is consistent with the habenular role in the “anti-reward” system and suggests it may be a key bridge between autoimmune disorders, drug use, and psychiatric diseases.

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“…For example, following repeated exposure to morphine, there are increases in norepinephrine-induced modulation of the extended amygdala (Aston-Jones et al, 1999 ; Delfs et al, 2000 ; Smith and Aston-Jones, 2008 ), activation of the amygdalar corticotrophin-releasing factor (CRF) system (Heinrichs et al, 1995 ; Maj et al, 2003 ), norepinephrine release in the extended amygdala (Fuentealba et al, 2000 ; Aston-Jones and Harris, 2004 ), and decreases in dopamine transmission (Diana et al, 1995 ). Also, following repeated exposure to cocaine, the lateral habenula, a brain region whose increased activity is correlated with aversive states (Graziane et al, 2018 ), has increased activation 15 min after repeated cocaine administration (Jhou et al, 2013 ), with evidence suggesting that this increase in cocaine-induced lateral habenula activation lasts until abstinence day 2 in rodents with a history of cocaine self-administration (Neumann et al, 2014 ). Additionally, lateral habenula neuronal firing is increased in vivo during ethanol-induced conditioned taste aversion (Tandon et al, 2017 ).…”

Section: Neurobiology Of Drug-induced Cpp: Focus On Opioid Cppmentioning

confidence: 99%

Drug-Induced Conditioned Place Preference and Its Practical Use in Substance Use Disorder Research

McKendrick

Graziane

2020

Front. Behav. Neurosci.

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142

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The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.

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A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse

Cited by 31 publications

References 82 publications

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

Drug-Induced Conditioned Place Preference and Its Practical Use in Substance Use Disorder Research

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