CRF–CRF
            <sub>1</sub>
            system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats

Self Cite

The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB 1 ) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB 1 receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB 1 receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB 1 receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB 1 receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.

Section: Discussionmentioning

confidence: 96%

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

Blasio

Iemolo

Sabino

et al. 2013

Self Cite

“…CRF antagonists injected intracerebroventricularly or systemically also block the potentiated anxiety-like responses to stressors observed during protracted abstinence from chronic ethanol, and the effects of CRF antagonists have been localized to the CeA (Koob, 2008). Precipitated withdrawal from nicotine produces anxiety-like responses that are also reversed by CRF antagonists (Tucci et al, 2003;George et al, 2007). Thus, acute withdrawal is associated with within-system changes reflected in a decrease in dopaminergic activity in the mesolimbic dopamine system and with between-system recruitment of neurotransmitter systems that convey stress and anxiety-like effects such as CRF and dynorphin.…”

Section: Withdrawal/negative Affect Stagementioning

confidence: 99%

Erratum: Neurocircuitry of Addiction

Koob¹,

Volkow²

2010

Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: 'binge/intoxication', 'withdrawal/negative affect', and 'preoccupation/anticipation' (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

“…The negative affective state of withdrawal and its alleviation by nicotine is one of the primary factors driving nicotine craving in nicotine-dependent subjects. A majority of the studies on nicotine motivation in dependent animals involve antagonist precipitated withdrawal (George et al, 2007;Kenny and Markou, 2001;Laviolette et al, 2008;Watkins et al, 2000). However, a spontaneous withdrawal procedure more closely models human withdrawal.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

Grieder

Sellings

Vargas‐Perez

et al. 2009

The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist a-flupenthixol (a-flu) and in DA D 2 receptor knockout mice. Conversely, a-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D 2 receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals. Neuropsychopharmacology (2010) 35, 943-954;