title: Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex.
abstract: Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Schmidt
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Schroeder
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Foster
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Squires
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Brilee M
authors.initials: BM
authors.lastname: Smith
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Pitts
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Epstein
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA. Electronic address: dweinshenker@genetics.emory.edu.
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D005502:Food; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018340:Receptors, Adrenergic, alpha-1; C041226:Terazosin; D003042:Cocaine; D009638:Norepinephrine; D011224:Prazosin
keywords: Alpha-1 adrenergic receptor; Cocaine; Norepinephrine; Prefrontal cortex; Rat; Reinstatement