Brooke E Schmeichel1, Melissa A Herman2, Marisa Roberto2, George F Koob3. 1. Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland. Electronic address: brooke.schmeichel@nih.gov. 2. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California. 3. 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.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking.
BACKGROUND: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. METHODS: 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. RESULTS: 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). CONCLUSIONS: These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking.
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