Corticotropin-Releasing Factor Within the Central Nucleus of the Amygdala and the Nucleus Accumbens Shell Mediates the Negative Affective State of Nicotine Withdrawal in Rats

Marcinkiewcz, Catherine A.; Prado, Melissa; Isaac, Shani; Marshall, Alex; Rylkova, Daria; Bruijnzeel, Adrie W.

doi:10.1038/npp.2008.231

Cited by 81 publications

(68 citation statements)

References 68 publications

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“…The decreased CRF immunodensity in the CeA is in accordance with previous reports showing increased CRF release 27 and reduction of negative emotional states after blockade of CRF 1 receptors in the CeA 34 . The lack of increased CRF mRNA in the CeA suggests that the VTA and CeA CRF neurons may be upregulated at different time points.…”

Section: Discussionsupporting

confidence: 92%

VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation

et al. 2014

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SUMMARY Dopaminergic neurons in the ventral tegmental area (VTA) are well known for their role in mediating the positive reinforcing effects of drugs of abuse. Here, we identify in rodents and humans a population of VTA dopamine neurons co-expressing corticotropin releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates CRF mRNA in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors, and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of CRF mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal, and limited the escalation of nicotine intake. These results link the brain reward and stress systems within the same brain region in signaling the negative motivational effects of nicotine withdrawal.

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Section: Discussionsupporting

confidence: 92%

VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation

et al. 2014

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“…Normalized levels of CRF-R1 and CRF-R2 during withdrawal may be important, given that these receptors are necessary for the expression of the behavioral effects of nicotine withdrawal. 35,36 Future studies are warranted to examine posttranslational changes in neuropeptide receptor levels during withdrawal and the mechanisms by which these changes occur following chronic nicotine exposure.…”

Section: Discussionmentioning

confidence: 99%

Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner

Torres

Pipkin

Ferree

et al. 2015

Nicotine & Tobacco Research

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IntroductionTobacco use is the number one cause of preventable deaths in the United States. 1 Of particular concern is the high rate of tobacco use among women, who are more susceptible to the negative health consequences of long-term smoking than men. 2 As a result, tobacco use is believed to be a major contributing factor to health disparities in women. In spite of the magnitude of the problem, surprisingly little is known about the underlying biological factors that promote tobacco relapse in females.Much work has suggested that stress promotes tobacco use in women. For example, women report more negative mood states, such as depression, anxiety, and intense craving during smoking abstinence than men. [3][4][5] Women also use more tobacco products and display lower quit rates relative to men. 6 Furthermore, women report that they maintain tobacco use to relieve intense withdrawal symptoms that emerge during abstinence, and they claim more often than men that the anxiety-reducing effects of cigarettes are the main reason for smoking. [7][8][9] Preclinical studies have shown that the behavioral and biological consequences of nicotine withdrawal are greater in female versus AbstractIntroduction: Previous work led to our hypothesis that sex differences produced by nicotine withdrawal are modulated by stress and dopamine systems in the nucleus accumbens (NAcc). We investigated our hypothesis by studying intact females to determine whether the mechanisms that promote withdrawal are ovarian-hormone mediated. Methods: Female rats were ovariectomized (OVX) or received sham surgery (intact) on postnatal day (PND 45-46). On PND 60, they received sham surgery (controls) or were prepared with nicotine pumps. Fourteen days later, half of the rats had their pumps removed (nicotine withdrawal) and the other half received sham surgery (nicotine exposure). Twenty-four hours later, the rats were tested for anxiety-like behavior using the elevated plus maze and light/dark transfer procedures. The NAcc was then dissected for analysis of several genes related to stress (CRF, UCN, CRF-R1, CRF-R2, CRF-BP, and Arrb2) or receptors for dopamine (Drd1 and Drd2) and estradiol (Esr2). Results: During withdrawal, intact females displayed an increase in anxiety-like behavior in both tests and CRF, UCN, and Drd1 gene expression. During nicotine exposure, intact females displayed a decrease in CRF-R1, CRF-R2, Drd3, and Esr2 gene expression and an increase in CRF-BP. This pattern of results was absent in OVX females. Conclusions: Nicotine withdrawal produced an increase in anxiety-like behavior and stress-associated genes in intact females that is distinct from changes produced by nicotine exposure. The latter effects were absent in OVX females, suggesting that stress produced by withdrawal is ovarianhormone mediated. These findings have important implications towards understanding tobacco use liability among females.

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“…Chronic cocaine use as well as abuse of other substances, including alcohol and nicotine all reflect up-regulation of CRF and NE feed-forward circuitry (Smith & Aston-Jones, 2008) (Marcinkiewcz et al, 2009), as well as elevated noradrenergic transporter binding in the hypothalamus, brainstem, hippocampus, midbrain and limbic forebrain regions and a desensitization of the alpha2-adrenoceptors in the prefrontal cortex (PFC) (Baumann, Milchanowski, & Rothman, 2004; Beveridge, Smith, Nader, & Porrino, 2005; Goldstein & Volkow, 2002; Porrino, Lyons, Smith, Daunais, & Nader, 2004). In addition, anxiety involves up-regulated extra-hypothalamic CRF and NE circuits involving the amygdala, bed nucleus of the stria terminalis (BNST) and down-regulated medial prefrontal circuits, which in turn, result in changes in stress-related pathways involving the hypothalamic paraventricular nucleus and locus coeruleus to construct a powerful ‘feed forward’ loop that contributes to increased anxiety and stress responses (Dunn & Berridge, 1990; Dunn & Swiergiel, 2008a; Dunn et al, 2004; Koob, 2009a) (Kushner, Abrams, & Borchardt, 2000).…”

Section: The Role Of Anxiety Symptomatology In Compulsive Cocaine-seementioning

confidence: 99%

The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

Fox

Sinha

2014

Advances in Pharmacology

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The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence.

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Corticotropin-Releasing Factor Within the Central Nucleus of the Amygdala and the Nucleus Accumbens Shell Mediates the Negative Affective State of Nicotine Withdrawal in Rats

Cited by 81 publications

References 68 publications

VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation

VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation

Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner

The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

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