Hypocretin and Drug Addiction
Principal Investigator: L de Lecea
Affiliation: Stanford University
Abstract: DESCRIPTION (provided by applicant): The hypocretins, also known as orexins, are excitatory neuropeptides produced in the lateral hypothalamus, which have a key role in the regulation of arousal. Hypocretin deficiency in dogs, mice and humans causes narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Hypocretin-containing neurons project to key structures involved in brain reward, most notably the nucleus accumbens, central amygdala and bed nucleus of stria terminalis. Since stress may represent an overactivation of the body's normal activational system and therefore is linked to the construct of arousal, we hypothesize that hypocretins may mediate at least in part, the activation of stress-induced signals that precipitate addiction and relapse. Under this proposal we will test three hypotheses: 1) that hypocretin neurons activate a "stress-like" response that results in reinstatement of cocaine seeking behavior;2) that hypocretin signaling is important for stress and cue-induced reinstatement of cocaine seeking behavior, and 3) that hypocretin deficient mice are resistant to drug abuse. In a first specific aim, mice with a history of cocaine self-administration and extinction will be infused with hypocretin and tested for reinstatement of cocaine seeking behavior. To determine whether stress signals are involved in hypocretin-induced reinstatement, mice deficient in corticotrophin release factor (CRF) receptor 1 will be tested for reinstatement of cocaine seeking behavior after hypocretinl infusion. Hypocretin-induced reinstatement will be blocked with hypocretin receptor antagonists and (CRF) receptor antagonists. In a second specific aim, the role of endogenous hypocretin on reinstatement will be tested by using a hypocretin receptor antagonist to block stress or cue- induced reinstatement. Accumulated clinical data has shown that hypocretin-deficient narcoleptic patients rarely abuse psychostimulants that are used to treat excessive daytime sleepiness. In specific aim 3, we will further examine whether hypocretin-deficient animals are resistant to stimulant abuse by amphetamine conditioned place preference test and by amphetamine and cocaine self administration. Finally, hypocretin-deficient mice will be tested for stress- and cue- induced reinstatement of cocaine or amphetamine seeking behavior. The results from these experiments will give us important clues about the role of the hypocretinergic system in brain reward and may result in new therapeutic tools to prevent drug craving and relapse.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- Mechanism for Hypocretin-mediated sleep-to-wake transitionsMATTHEW E CARTER
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Proc Natl Acad Sci U S A 109:E2635-44. 2012..This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain...
- Tuning arousal with optogenetic modulation of locus coeruleus neuronsMATTHEW E CARTER
Neurosciences Program, Stanford University, Stanford, California, USA
Nat Neurosci 13:1526-33. 2010..These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders...
- Intraventricular administration of neuropeptide S has reward-like effectsJunran Cao
Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224, USA
Eur J Pharmacol 658:16-21. 2011..Our data suggest that intraventricular NPS injections have reward-like effects in that NPS weakly facilitates seeking and induces positive reinforcement. These effects may depend on intact dopamine and hypocretin systems...
- Optogenetic investigation of neural circuits in vivoMATTHEW E CARTER
Neurosciences Program and Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Trends Mol Med 17:197-206. 2011..Finally, we survey the application of optogenetic tools to studying functional neuroanatomy, behavior and the etiology and treatment of various neurological disorders...
- Optogenetic interrogation of dopaminergic modulation of the multiple phases of reward-seeking behaviorAntoine R Adamantidis
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA
J Neurosci 31:10829-35. 2011..Collectively, these data suggest that activation of dopaminergic neurons facilitates the development of positive reinforcement during reward-seeking and behavioral flexibility...