Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure.
Orexin is a key neurotransmitter of central arousal and reward circuits in the CNS. Two receptors respond to orexin signaling, Orexin 1 Receptor (OX1R) and Orexin 2 Receptor (OX2R) with partially overlapping brain distributions. Genetic and pharmacological studies suggest orexin receptor antagonists could provide therapeutic benefit for insomnia and other disorders in which sleep/wake cycles are disrupted. Preclinical data has also emerged showing that the orexin system is involved in the behavioral and neurological effects of drugs of abuse (Aston-Jones et al., 2009; Harris et al., 2005). Here we report sleep promoting effects of a recently described small molecule dual orexin receptor OX1R and OX2R antagonist. This dual orexin receptor antagonist (DORA) also inhibits the ability of subchronic amphetamine to produce behavioral sensitization measured 10 days following pre-treatment. Transcriptional profiling of isolated reward and arousal circuits from brains of behaviorally sensitized animals showed that the DORA blocked the significant alteration of gene expression levels in response to amphetamine exposure, particularly those associated with synaptic plasticity in the VTA. Further, DORA attenuates the ability of nicotine to induce reinstatement of extinguished responding for a reinforcer, demonstrating selectivity of the effect to reward pathways and not to food intake. In summary, these data demonstrate efficacy of a dual orexin receptor antagonist for promotion of sleep and suggest that pharmacological inhibition of the orexin system may play a role in both prevention of drug-induced plasticity and drug-relapse.
Winrow
Christopher J
CJ
Depression and Circadian Disorders Department, Merck Research Laboratories, West Point, PA, USA.
Tanis
Keith Q
KQ
Reiss
Duane R
DR
Rigby
Alison M
AM
Uslaner
Jason M
JM
Uebele
Victor N
VN
Doran
Scott M
SM
Fox
Steven V
SV
Garson
Susan L
SL
Gotter
Anthony L
AL
Levine
David M
DM
Roecker
Anthony J
AJ
Coleman
Paul J
PJ
Koblan
Kenneth S
KS
Renger
John J
JJ
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009842:Oligopeptides / Q000494:pharmacology*; D064446:Orexin Receptors; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012890:Sleep / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D017557:Ventral Tegmental Area / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism
D001562:Benzimidazoles; D000697:Central Nervous System Stimulants; C578627:Hcrtr1 protein, rat; C547281:N-biphenyl-2-yl-1-(((1-methyl-1H-benzimidazol-2-yl)sulfanyl)acetyl)prolinamide; D018722:Nicotinic Agonists; D009842:Oligopeptides; D064446:Orexin Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D009538:Nicotine; D011392:Proline; D000661:Amphetamine; C056291:prolinamide