title: Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats.
abstract: Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests that HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA). The role of HCRT in the persistence of compulsive-like cocaine-taking has yet to be fully elucidated.
  
  
  
  Systemic and intra-CeA microinfusions of the HCRT-receptor 1 antagonist, SB-334867, were administered to rats allowed either short (1 hour; ShA) or long (6 hours; LgA) access to cocaine self-administration. Animals were tested for fixed and progressive ratio responding for cocaine and stress-induced reinstatement of drug-seeking. In addition, using electrophysiological techniques on in vitro slices, we investigated gamma-aminobutyric acidergic (GABAergic) neurotransmission in the medial CeA and the sensitivity of GABAergic synapses to modulation of the HCRT system in ShA or LgA rats.
  
  
  
  We found systemic administration of SB-334867 (0, 7.5, 15, 30 mg/kg) dose dependently decreased cocaine intake specifically in LgA rats but not in ShA rats. Microinjections of SB-334867 (20 nmol) bilaterally into the CeA significantly reduced cocaine intake in LgA rats. We also observed a significant attenuation of yohimbine-induced reinstatement of cocaine-seeking after intra-CeA SB-334867 (10 nmol) administration. Finally, electrophysiological data indicated enhanced GABAergic neurotransmission within the medial CeA in LgA rats, which was blocked with SB-334867 (10 μmol/L).
  
  
  
  These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking.
authors: Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland. Electronic address: brooke.schmeichel@nih.gov.
authors: Brooke E
authors: BE
authors: Schmeichel
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.
authors: Melissa A
authors: MA
authors: Herman
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.
authors: Marisa
authors: M
authors: Roberto
authors: Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors: George F
authors: GF
authors: Koob
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage; D066274:Central Amygdaloid Nucleus / Q000187:drug effects* / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists / Q000008:administration & dosage; D064446:Orexin Receptors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration; D013315:Stress, Psychological / Q000503:physiopathology*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; C578627:Hcrtr1 protein, rat; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D005680:gamma-Aminobutyric Acid; D014508:Urea; D003042:Cocaine
keywords: Central amygdala; Cocaine; Drug dependence; Hypocretin/orexin; Intravenous self-administration; Reinstatement