title: Species differences in the effects of the κ-opioid receptor antagonist zyklophin.
abstract: We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts.
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, WA, USA; Department of Integrative Physiology & Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sirohi
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA.
authors.forename: Jane V
authors.initials: JV
authors.lastname: Aldrich
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, WA, USA; Department of Integrative Physiology & Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, WA, USA; Graduate Program in Neuroscience, Washington State University, Pullman, WA, USA; Translational Addiction Research Center, Washington State University, Pullman, WA, USA. Electronic address: b_walker@wsu.edu.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Walker
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012646:Self Administration; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000523:psychology
chemical_list: D009292:Narcotic Antagonists; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; C502814:dynorphin A-(1-11)-NH2, Nalpha-benzylTyr(1)-cyclo(Asp(5)-Dap(8))-; D000431:Ethanol; D004399:Dynorphins
keywords: Alcohol dependence and withdrawal; Alcohol self-administration; GTPyS coupling; Kappa-opioid receptor; Zyklophin