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.
Keywords
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Article info
Publication history
Published online: June 16, 2016
Accepted:
July 7,
2016
Received in revised form:
June 6,
2016
Received:
February 9,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2016.
ScienceDirect
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- Orexin/Hypocretin, Central Amygdala, and Escalation of Cocaine IntakeBiological PsychiatryVol. 81Issue 7
- PreviewCocaine 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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