title: The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal.
abstract: Much research has focused on pathways leading to opiate addiction. Pathways opposing addiction are more difficult to study but may be critical in developing interventions to combat drug dependence and withdrawal. Galanin decreases firing of locus coeruleus neurons, an effect hypothesized to decrease signs of opiate withdrawal. The current study addresses whether galanin affects morphine withdrawal signs by using a galanin agonist, galnon, that crosses the blood-brain barrier, and mice genetically engineered to under- or overexpress galanin peptide. Galnon significantly decreased morphine withdrawal signs in C57BL/6 mice. Further, knockout mice lacking galanin showed exacerbated morphine withdrawal signs, suggesting that endogenous galanin normally counteracts opiate withdrawal. Transgenic mice overexpressing galanin in noradrenergic neurons also showed decreased morphine withdrawal signs, suggesting a possible neuroanatomical locus for these effects of galanin. Both c-fos immunoreactivity, a marker of neuronal activity, and phosphorylation of tyrosine hydroxylase at Ser-40, a marker of cAMP levels, are decreased in the locus coeruleus by galnon treatment after morphine withdrawal, suggesting a possible molecular mechanism for the behavioral effects of galanin. These studies suggest that galanin normally acts to counteract opiate withdrawal and that small molecule galanin agonists could be effective in diminishing the physical signs of withdrawal.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
authors.forename: Darlene H
authors.initials: DH
authors.lastname: Brunzell
authors.forename: Jessica
authors.initials: J
authors.lastname: Hawes
authors.forename: Diann R
authors.initials: DR
authors.lastname: Stedman
authors.forename: Tamas
authors.initials: T
authors.lastname: Bartfai
authors.forename: Robert A
authors.initials: RA
authors.lastname: Steiner
authors.forename: David
authors.initials: D
authors.lastname: Wynick
authors.forename: Ulo
authors.initials: U
authors.lastname: Langel
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003374:Coumarins / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005260:Female; D019004:Galanin / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009020:Morphine / Q000633:toxicity*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology
chemical_list: C456547:7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin; D003374:Coumarins; D009020:Morphine; D019004:Galanin; D004299:Dopamine beta-Hydroxylase