Hypocretins Regulate the Anxiogenic-Like Effects of Nicotine and Induce Reinstatement of Nicotine-Seeking Behavior

Abstract

Emerging evidence suggests that the hypocretinergic system is involved in addictive behavior. In this study, we investigated the role of these hypothalamic neuropeptides in anxiety-like responses of nicotine and stress-induced reinstatement of nicotine-seeking behavior. Acute nicotine (0.8 mg/kg, s.c.) induced anxiogenic-like effects in the elevated plus-maze and activated the paraventricular nucleus of the hypothalamus (PVN) as revealed by c-Fos expression. Pretreatment with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 or preprohypocretin gene deletion blocked both nicotine effects. In the PVN, SB334867 also prevented the activation of corticotrophin releasing factor (CRF) and arginine-vasopressin (AVP) neurons, which expressed Hcrtr-1. In addition, an increase of the percentage of c-Fos-positive hypocretin cells in the perifornical and dorsomedial hypothalamic (PFA/DMH) areas was found after nicotine (0.8 mg/kg, s.c.) administration. Intracerebroventricular infusion of hypocretin-1 (Hcrt-1) (0.75 nmol/1 l) or footshock stress reinstated a previously extinguished nicotine-seeking behavior. The effects of Hcrt-1 were blocked by SB334867, but not by the CRF1 receptor antagonist antalarmin. Moreover, SB334867 did not block CRF-dependent footshock-induced reinstatement of nicotine-seeking while antalarmin was effective in preventing this nicotine motivational response. Therefore, the Hcrt system interacts with CRF and AVP neurons in the PVN and modulates the anxiogenic-like effects of nicotine whereas Hcrt and CRF play a different role in the reinstatement of nicotineseeking. Indeed, Hcrt-1 reinstates nicotine-seeking through a mechanism independent of CRF activation whereas CRF mediates the reinstatement induced by stress.

Narcolepsy with Cataplexy Associated with Nocturnal Compulsive Behaviors: A Case-Control Study

“…Our results are in line with to recent findings pinpointing the paradoxical anxiolytic effect of nicotine in an experimental animal model of NC. 44 Although SRED and NS were not reciprocally associated in our NC sample, the overlap of abnormal EDI-2 traits in NC with SRED and with NS may suggest a common underlying mechanism for these behaviors. Surprisingly, RLS was not associated with nocturnal compulsive eating/smoking, which differs from prior reports in idiopathic RLS.…”

Nicotinic Regulation of Energy Homeostasis

“…Nicotine-elicited Fos induction in the PVH was blocked by systemic administration of orexin receptor antagonists. The functional consequence of orexin-mediated PVH activation upon nicotine withdrawal is the expression of withdrawal somatic signs, since these signs can be partially blocked by intra-PVH infusion of orexin antagonists (Plaza-Zabala, Martín-García, de Lecea, Maldonado, & Berrendero, 2010). LH GABAergic transmission is thought to elicit decreases in food intake (Stanley, Urstadt, Charles, & Kee, 2011).…”

Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions

“…In this review, we have recommended some guidelines that may serve to facilitate the identification of already approved drugs for repurposing as smoking-cessation agents. Specifically, three key characteristics of already approved molecules are particularly attractive when considering which may be suitable for clinical assessment: Those molecules that are known to be safe in human with minimal toxicity issues and favorable safety and tolerability profiles; those that modulate the activity of targets expressed in brain circuits known to control the reinforcing properties of nicotine, such as the mesoaccumbens dopamine system, the habenulo-interpeduncular system, and the insular cortex; and finally, those molecules that modulate the activity of targets for Levin et al, 2010) SB-334867 Hypocretin-1 (orexin-1) receptor antagonist (Hollander et al, 2008;Lesage, Perry, Kotz, Shelley, & Corrigall, 2010;Plaza-Zabala et al, 2010) Various substituted heteroaromatic compounds hCYP-2A6 inhibitors (Cashman et al, 2012) VDM11 Anandamide transport inhibitor (Gamaleddin, Guranda, Goldberg, & Le Foll, 2011) which there is evidence to support a role in tobacco dependence, for example, human genetics evidence or anecdotal reports of decreases in smoking behavior.…”