title: Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.
abstract: Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Meriem
authors.initials: M
authors.lastname: Gaval-Cruz
authors.affiliation: Department of Biology, Neurosciences Institute, University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Goertz
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Puttick
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Bowles
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Meyer
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Randy A
authors.initials: RA
authors.lastname: Hall
authors.affiliation: Department of Management Science and Statistics, University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: Daijin
authors.initials: D
authors.lastname: Ko
authors.affiliation: Department of Biology, Neurosciences Institute, University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Paladini
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
mesh_terms: D000818:Animals; D019390:Arrestins / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology; D002864:Chromogranins; D003042:Cocaine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000037:antagonists & inhibitors; D008124:Locomotion / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000819:agonists; D000071557:beta-Arrestins
chemical_list: C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D019390:Arrestins; D001557:Benzenesulfonates; D002864:Chromogranins; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000071557:beta-Arrestins; D019257:Quinpirole; D004299:Dopamine beta-Hydroxylase; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs; D003042:Cocaine; D009638:Norepinephrine
keywords: Cocaine; D2 receptor; dopamine; dopamine β-hydroxylase; mice; norepinephrine