title: Involvement of noradrenergic neurotransmission in the stress- but not cocaine-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: role for β-2 adrenergic receptors.
abstract: The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20-25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate.
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA. john.mantsch@marquette.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Mantsch
authors.forename: Andy
authors.initials: A
authors.lastname: Weyer
authors.forename: Oliver
authors.initials: O
authors.lastname: Vranjkovic
authors.forename: Chad E
authors.initials: CE
authors.lastname: Beyer
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.forename: Holly
authors.initials: H
authors.lastname: Caretta
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology / Q000523:psychology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018674:Adrenergic Antagonists; D018343:Receptors, Adrenergic, beta-2; D003042:Cocaine; D009638:Norepinephrine