title: Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs.
abstract: The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (N.M.A., S.-H.L., J.B.A.); and Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (T.H.H.) nappel@nih.gov.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Appel
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (N.M.A., S.-H.L., J.B.A.); and Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (T.H.H.).
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Li
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (N.M.A., S.-H.L., J.B.A.); and Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (T.H.H.).
authors.forename: Tyson H
authors.initials: TH
authors.lastname: Holmes
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (N.M.A., S.-H.L., J.B.A.); and Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (T.H.H.).
authors.forename: Jane B
authors.initials: JB
authors.lastname: Acri
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000009:adverse effects* / Q000494:pharmacology; D016739:Behavior, Addictive / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D004285:Dogs; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D010080:Oxazoles / Q000009:adverse effects* / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*
chemical_list: D053961:Azabicyclo Compounds; D018492:Dopamine Antagonists; C000594007:GSK598809; D010080:Oxazoles; D050637:Receptors, Dopamine D3; D003042:Cocaine