title: Corticotropin-releasing factor (CRF) and α 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats.
abstract: Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2 mg/kg s.c.) displayed an increased ASR when tested 4 h after heroin treatment. A similar increase in ASR was found in rats 10-20 h into withdrawal from extended access (12 h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the α 2 adrenergic receptor agonist clonidine (10 μg/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20 mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and α 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25 mg/kg s.c.)-potentiated startle and clonidine on CRF (2 μg i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and α 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Paula E
authors.initials: PE
authors.lastname: Park
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.forename: Scott
authors.initials: S
authors.lastname: Edwards
authors.forename: Gery
authors.initials: G
authors.lastname: Schulteis
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D000161:Acoustic Stimulation; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D003932:Heroin / Q000009:adverse effects*; D008297:Male; D009294:Narcotics / Q000009:adverse effects*; D009638:Norepinephrine / Q000378:metabolism; D011571:Psychoacoustics; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; C528552:N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5-a)pyrimidin-7-amine; D009294:Narcotics; D011743:Pyrimidines; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D003932:Heroin; D003346:Corticotropin-Releasing Hormone; D003000:Clonidine; D009638:Norepinephrine