Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats
Overview
Affiliations
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.
Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation.
Mohammadkhani A, Mitchell C, James M, Borgland S, Dayas C Br J Pharmacol. 2024; 181(22):4430-4449.
PMID: 39317446 PMC: 11458361. DOI: 10.1111/bph.17325.
The anxiogenic drug yohimbine is a reinforcer in male and female rats.
Renda B, Leri F Neuropsychopharmacology. 2024; 50(2):432-443.
PMID: 39289489 PMC: 11631961. DOI: 10.1038/s41386-024-01985-1.
Bolik K, Hellmann J, Maschauer S, Neu E, Einsiedel J, Riss P EJNMMI Res. 2024; 14(1):80.
PMID: 39231867 PMC: 11374953. DOI: 10.1186/s13550-024-01141-2.
The Role of Orexin Receptor Antagonists in Inhibiting Drug Addiction: A Review Article.
Esmaili-Shahzade-Ali-Akbari P, Ghaderi A, Sadeghi A, Nejat F, Mehramiz A Addict Health. 2024; 16(2):130-139.
PMID: 39051042 PMC: 11264478. DOI: 10.34172/ahj.2024.1491.
Kohler R, Zhornitsky S, Potenza M, Yip S, Worhunsky P, Angarita G Am J Drug Alcohol Abuse. 2024; 50(3):345-356.
PMID: 38551365 PMC: 11305926. DOI: 10.1080/00952990.2024.2318585.