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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Compulsivity, impulsivity, and the DSM-5 process.CNS Spectr. 2014; 19: 62-68
- Drug intake is sufficient, but conditioning is not necessary for the emergence of compulsive cocaine seeking after extended self-administration.Neuropsychopharmacology. 2012; 37: 1612-1619
- Compulsive drug seeking by rats under punishment: Effects of drug taking history.Psychopharmacology (Berl). 2007; 194: 127-137
- Neurobiological evidence for hedonic allostasis associated with escalating cocaine use.Nat Neurosci. 2002; 5: 625-626
- Effects of dose and session duration on cocaine self-administration in rats.J Pharmacol Exp Ther. 2007; 320: 1134-1143
- Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats.Psychopharmacology. 2008; 195: 591-603
- Transition from moderate to excessive drug intake: change in hedonic set point.Science. 1998; 282: 298-300
- A role for brain stress systems in addiction.Neuron. 2008; 59: 11-34
- Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats.Psychopharmacology (Berl). 2004; 175: 26-36
- Excessive cocaine use results from decreased phasic dopamine signaling in the striatum.Nat Neurosci. 2014; 17: 704-709
- The dark side of emotion: The addiction perspective.Eur J Pharmacol. 2015; 753: 73-87
- Orexin, stress, and anxiety/panic states.Prog Brain Res. 2012; 198: 133-161
- Multiple roles for orexin/hypocretin in addiction.Prog Brain Res. 2012; 198: 79-121
- Neurons containing hypocretin (orexin) project to multiple neuronal systems.J Neurosci. 1998; 18: 9996-10015
- Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress.J Comp Neurol. 2003; 464: 220-237
- Orexinergic innervation of the extended amygdala and basal ganglia in the rat.Brain Struct Funct. 2012; 217: 233-256
- Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking.Eur J Neurosci. 2009; 30: 493-503
- The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system.Eur J Neurosci. 2010; 31: 336-348
- Orexin-1 receptor mediation of cocaine seeking in male and female rats.J Pharmacol Exp Ther. 2012; 340: 801-809
- Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.Proc Natl Acad Sci U S A. 2005; 102: 19168-19173
- Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin.Brain Res. 2010; 1314: 145-161
- A role for lateral hypothalamic orexin neurons in reward seeking.Nature. 2005; 437: 556-559
- A key role for orexin in panic anxiety.Nat Med. 2010; 16: 111-115
- Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior.Brain Res. 2005; 1044: 116-121
- Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers.J Neurosci. 2009; 29: 11215-11225
- Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: Pharmacological and behavioral genetics evidence.Front Behav Neurosci. 2012; 6: 47
- Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction.Biol Psychiatry. 2013; 74: 520-528
- A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence.Sci Transl Med. 2012; 4: 146ra110
- Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats.Addict Biol. 2012; 17: 300-308
- Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: Alcohol and CRF effects.Neuropharmacology. 2013; 67: 337-348
- Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep.Behav Brain Res. 2015; 291: 377-384
- Modulation of respiratory activity by hypocretin-1 (orexin A) in situ and in vitro.Adv Exp Med Biol. 2010; 669: 109-113
- Hypocretin-1 (orexin A) prevents the effects of hypoxia/hypercapnia and enhances the GABAergic pathway from the lateral paragigantocellular nucleus to cardiac vagal neurons in the nucleus ambiguus.Neuroscience. 2011; 175: 18-23
- DMSO as a vehicle for central injections: tests with feeding elicited by norepinephrine injected into the paraventricular nucleus.Pharmacol Biochem Behav. 2002; 71: 277-282
- Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats.Psychopharmacology (Berl). 2010; 208: 211-222
- Addiction as a stress surfeit disorder.Neuropharmacology 76(Pt B). 2014; : 370-382
- Negative reinforcement in drug addiction: The darkness within.Curr Opin Neurobiol. 2013; 23: 559-563
- The mechanisms and functions of spontaneous neurotransmitter release.Nat Rev Neurosci. 2015; 16: 5-16
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
Access this article on ScienceDirectLinked Article
- 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.
- Full-Text
- Preview
