Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal

Zhao-Shea, Rubing; DeGroot, Steven R.; Liu, Liwang; Vallaster, Markus; Pang, Xiaowu; Su, Qin; Gao, Guangping; Rando, Oliver J.; Martin, Gilles E.; George, Olivier; Gardner, Paul; Tapper, Andrew R.

doi:10.1038/ncomms7770

Cited by 130 publications

(140 citation statements)

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“…It has recently become apparent that dorsal IPN neurons control somatic withdrawal responses (Zhao-Shea et al, 2013), and ventral IPN neurons control affective responses (Zhao-Shea et al, 2015). Moreover, during precipitated withdrawal from chronic nicotine exposure, MHb-derived inputs onto ventral IPN neurons control anxiety responses (Zhao-Shea et al, 2015). In our study, enhanced baseline firing and reduced nicotine-elicited firing in MHbVI neurons chronically exposed to nicotine is likely involved in activation of this affective withdrawal circuit in ventral IPN.…”

Section: Discussionmentioning

confidence: 58%

“…Our recent data describing nAChR subunit expression/localization in the MHb/IPN pathway (Shih et al, 2014) confirm what was previously seen in anatomic studies (Contestabile and Flumerfelt, 1981): MHbVI projects to ventral IPN areas, whereas MHbVL projects more preferentially to dorsal IPN. It has recently become apparent that dorsal IPN neurons control somatic withdrawal responses (Zhao-Shea et al, 2013), and ventral IPN neurons control affective responses (Zhao-Shea et al, 2015). Moreover, during precipitated withdrawal from chronic nicotine exposure, MHb-derived inputs onto ventral IPN neurons control anxiety responses (Zhao-Shea et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the dorsal IPN, which receives projections from the ventrolateral MHb (MHbVL), is a key mediator of the somatic aspect of nicotine withdrawal (ZhaoShea et al, 2013). Further, areas in the ventral IPN, which receive projections preferentially from ventroinferior MHb (MHbVI), appear to more strongly control affective signs of nicotine withdrawal (Zhao-Shea et al, 2015). These recent data point to the need for a more thorough description of the nAChRs in different subnuclei of MHb.…”

Section: Introductionmentioning

confidence: 99%

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Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

2015

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Nicotinic acetylcholine receptors (nAChRs) are the molecular target of nicotine. nAChRs in the medial habenula (MHb) have recently been shown to play a role in nicotine dependence, but it is not clear which nAChR subtypes or MHb neuron types are most important. To identify MHb nAChRs and/or cell types that play a role in nicotine dependence, we studied these receptors and cells with brain slice electrophysiology using both acute and chronic nicotine application. Cells in the ventroinferior (MHbVI) and ventrolateral MHb (MHbVL) subregions expressed functional nAChRs with different pharmacology. Further, application of nicotine to cells in these subregions led to different action potential firing patterns. The latter result was correlated with a differing ability of nicotine to induce nAChR desensitization. Chronic nicotine caused functional upregulation of nAChRs selectively in MHbVI cells, but did not change nAChR function in MHbVL. Importantly, firing responses were also differentially altered in these subregions following chronic nicotine. MHbVI neurons treated chronically with nicotine exhibited enhanced basal pacemaker firing but a blunted nicotine-induced firing response. MHbVL neurons did not change their firing properties in response to chronic nicotine. Together, these results suggest that acute and chronic nicotine differentially affect nAChR function and output of cells in MHb subregions. Because the MHb extensively innervates the interpeduncular nucleus, an area critical for both affective and somatic signs of withdrawal, these results could reflect some of the neurophysiological changes thought to occur in the MHb to the interpeduncular nucleus circuit in human smokers.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

2015

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“…For example, studies have shown that somatic nicotine withdrawal signs are mediated by both central and peripheral nicotinic receptors, while anhedonia and aversion are mediated solely through central nicotinic receptor populations such as the nucleus accumbens (NAc) and habenulo-interpeduncular system (Watkins et al 2000; De Biasi and Dani 2011). Finally, corticotropin-releasing factor-1 (CRF1) receptors in the central nucleus of the amygdala (CeA) and the mesohabenular pathway through the interpeduncular nucleus seem to play an important role in the emergence of anxiety-like behaviors in nicotine-dependent animals (Cohen et al 2015; Zhao-Shea et al 2015). Alternatively, these data may reflect a limitation of the elevated plus maze to detect differences under the conditions examined.…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice

et al. 2015

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Rationale N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. Objectives The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. Methods N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia were measured 18 - 24 hrs after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: Mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.) precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. Results Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine were found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. Conclusions These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence.

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“…In humans, blocking the degradation of ACh can induce depressive symptoms even in individuals with no history of illness (Janowsky et al, 1972;Risch et al, 1981), whereas in mice, blocking ACh breakdown in the hippocampus alone is sufficient to induce depression-and anxiety-like behaviors (Mineur et al, 2013). Finally, activity of the medial habenula-IPN pathway (a region rich in α3β4 nAChRs; Gotti et al, 2006) is also critical for the control of anxiety induced by nicotine withdrawal (Zhao-Shea et al, 2015) and contributes to the aversive properties of self-administered nicotine through nAChRs containing the α5 subunit (Fowler et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

Mineur

Fote

Blakeman

et al. 2015

Neuropsychopharmacol

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Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala (BLA) in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both β2 subunit-containing (β2*) and α7 nAChRs in the effects of nicotine in models of anxiety-and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated downregulation of the β2 or α7 nAChR subunit in the amygdala all induced robust anxiolytic-and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the BLA. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the BLA, and a decrease in signaling through β2 nAChRs alters anxiety-and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.

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Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal

Cited by 130 publications

References 56 publications

Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

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