Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats



      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.


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      • Orexin/Hypocretin, Central Amygdala, and Escalation of Cocaine Intake
        Biological PsychiatryVol. 81Issue 7
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          Cocaine addiction is characterized by a transition from controlled and episodic drug use to a state of compulsive drug taking. This transition often involves a process of escalated cocaine intake that is associated with repeated and chronic exposure to the drug (1). Nearly 20 years ago, Ahmed and Koob (1) reported that the phenomenon of exaggerated drug use could be recapitulated in laboratory animals by giving rats extended (6-hour) access to cocaine in daily self-administration sessions. This long access (LgA) paradigm results in escalation of drug intake over self-administration days, which is in contrast to animals with restricted access (1 hour/day; short access [ShA]) to cocaine that exhibit relatively stable levels of cocaine consumption.
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