A large number of studies over the last 14 years show that orexin neurons play an important role in reward processing and drug abuse. Although these studies show that orexin-1 receptor (OxR1) signaling is particularly involved in the motivation for many drugs of abuse, none have linked this system to the persistent, chronically relapsing nature of addiction. Here, we extend studies from the previous terms of this project to tackle this important issue. We recently found that the intermittent access (IntA) cocaine self-administration paradigm produces a strong, multiphenotype addiction-like state as well as increased numbers of orexin-expressing neurons. Importantly we find that the IntA-induced increase in addiction behaviors and orexin expression are persistent (>30d of abstinence). We also find that chronic administration of an OxR1 antagonist during IntA blocks the increased demand that this paradigm normally produces. Here, we propose to more fully characterize the IntA-linked addiction profile and induced-orexin neurons following 30d abstinence. We also will examine the contribution of OxR1 and OxR2 signaling in ventral tegmental area (VTA) and paraventricular thalamus (PVT), two reward-related areas previously linked to orexin function, in persistent addiction behaviors after IntA. Finally, we will test whether the FDA-approved dual orexin receptor antagonist, Belsomra? (suvorexant), is effective in acutely decreasing addiction behaviors, and in preventing the transition from a moderate to a severe addiction profile. Together, the proposed experiments are a natural and important extension of the prior studies in this project and will represent an important step forward in the development of an orexin-based treatment for cocaine addiction.

Public Health Relevance

Cocaine addiction is a chronic condition that remains clinically difficult to treat. The proposed studies will reveal the role of a key brain neuropeptide system in the persistent, chronically relapsing nature of cocaine addiction. These findings will increase our knowledge of brain mechanisms involved in chronic addiction, and test a novel method for treating this disorder using a currently approved medication.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Moore, Holly Marie
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Rbhs-Robert Wood Johnson Medical School
Schools of Medicine
United States
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Kohtz, Amy S; Lin, Belle; Smith, Michael E et al. (2018) Attenuated cocaine-seeking after oxytocin administration in male and female rats. Psychopharmacology (Berl) 235:2051-2063
McGlinchey, Ellen M; Aston-Jones, Gary (2018) Dorsal Hippocampus Drives Context-Induced Cocaine Seeking via Inputs to Lateral Septum. Neuropsychopharmacology 43:987-1000
James, Morgan H; McGlinchey, Ellen M; Vattikonda, Asrita et al. (2018) Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core. Int J Neuropsychopharmacol 21:89-94
Freeman, Linnea R; Aston-Jones, Gary (2018) Activation of medial hypothalamic orexin neurons during a Go/No-Go task. Brain Res :
Campese, Vincent D; Soroeta, Jose M; Vazey, Elena M et al. (2017) Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer. eNeuro 4:
Cox, Brittney M; Bentzley, Brandon S; Regen-Tuero, Helaina et al. (2017) Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand. Biol Psychiatry 81:949-958
Porter-Stransky, Kirsten A; Bentzley, Brandon S; Aston-Jones, Gary (2017) Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addict Biol 22:303-317
Bentzley, Brandon S; Aston-Jones, Gary (2017) Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential. Addict Biol 22:946-957
Bowrey, Hannah E; James, Morgan H; Aston-Jones, Gary (2017) New directions for the treatment of depression: Targeting the photic regulation of arousal and mood (PRAM) pathway. Depress Anxiety 34:588-595
Buchta, William C; Mahler, Stephen V; Harlan, Benjamin et al. (2017) Dopamine terminals from the ventral tegmental area gate intrinsic inhibition in the prefrontal cortex. Physiol Rep 5:

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