title: Dopamine receptors and the persistent neurovascular dysregulation induced by methamphetamine self-administration in rats.
abstract: Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth self-administration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1α was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans.
authors.affiliation: Center for Compulsive Behavior and Addiction (S.M.K., T.C.N., P.M.C.), Department of Pharmacology (S.M.K., T.C.N., P.M.C.), Department of Psychiatry (T.C.N.), Department of Neurologic Sciences (P.M.C.), and Department of Anatomy and Cell Biology (R.D.R., D.R.S.), Rush University Medical Center, Chicago, Illinois.
authors.forename: Sharanya M
authors.initials: SM
authors.lastname: Kousik
authors.affiliation: Center for Compulsive Behavior and Addiction (S.M.K., T.C.N., P.M.C.), Department of Pharmacology (S.M.K., T.C.N., P.M.C.), Department of Psychiatry (T.C.N.), Department of Neurologic Sciences (P.M.C.), and Department of Anatomy and Cell Biology (R.D.R., D.R.S.), Rush University Medical Center, Chicago, Illinois.
authors.forename: T Celeste
authors.initials: TC
authors.lastname: Napier
authors.affiliation: Center for Compulsive Behavior and Addiction (S.M.K., T.C.N., P.M.C.), Department of Pharmacology (S.M.K., T.C.N., P.M.C.), Department of Psychiatry (T.C.N.), Department of Neurologic Sciences (P.M.C.), and Department of Anatomy and Cell Biology (R.D.R., D.R.S.), Rush University Medical Center, Chicago, Illinois.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Ross
authors.affiliation: Center for Compulsive Behavior and Addiction (S.M.K., T.C.N., P.M.C.), Department of Pharmacology (S.M.K., T.C.N., P.M.C.), Department of Psychiatry (T.C.N.), Department of Neurologic Sciences (P.M.C.), and Department of Anatomy and Cell Biology (R.D.R., D.R.S.), Rush University Medical Center, Chicago, Illinois.
authors.forename: D Rick
authors.initials: DR
authors.lastname: Sumner
authors.affiliation: Center for Compulsive Behavior and Addiction (S.M.K., T.C.N., P.M.C.), Department of Pharmacology (S.M.K., T.C.N., P.M.C.), Department of Psychiatry (T.C.N.), Department of Neurologic Sciences (P.M.C.), and Department of Anatomy and Cell Biology (R.D.R., D.R.S.), Rush University Medical Center, Chicago, Illinois paul_carvey@rush.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Carvey
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism; D012646:Self Administration; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017448:Receptors, Dopamine D2; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D008694:Methamphetamine; D052248:Nitric Oxide Synthase Type I