Cocaine and nicotine research illustrates a range of hypocretin mechanisms in addiction.
Hypocretins (also known as orexins) are neuropeptides synthesized in the lateral hypothalamus and perifornical region and projecting widely throughout the brain. They play an important modulatory role in plasticity related to addictive behavior. Hypocretin signaling to the ventral tegmental area (VTA) promotes synaptic plasticity by potentiating glutamatergic inputs to dopamine neurons and is required for the plasticity induced by stimulant drugs like cocaine. Plasticity in the VTA leads to increased output of dopamine neurons and increased release of dopamine in projection areas, which is associated with the development of addiction-related behaviors. Antagonists of hypocretin receptors inhibit some of these behaviors, particularly those with high effort requirements, suggesting a significant role of hypocretin in the motivation to obtain drugs. Furthermore, hypocretin neurons are also targeted by drugs of abuse, such as nicotine. Projections of hypocretin neurons to regions beyond the VTA may also play a significant role in motivation and addiction. Taken together, the hypocretin system may be a prime drug target for treatment of addiction and related disorders.
Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
Corey
C
Baimel
Stephanie L
SL
Borgland
William
W
Corrigall
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology* / Q000633:toxicity; D003042:Cocaine / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology* / Q000633:toxicity; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D009538:Nicotine; D003042:Cocaine