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

Neuropsychopharmacology. 2010 Oct;35(11):2165-78. doi: 10.1038/npp.2010.86. Epub 2010 Jul 7.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic Antagonists / pharmacology
  • Animals
  • Behavior, Addictive / physiopathology
  • Behavior, Addictive / psychology
  • Cocaine / administration & dosage*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Norepinephrine / physiology*
  • Receptors, Adrenergic, beta-2 / physiology*
  • Stress, Psychological / physiopathology
  • Stress, Psychological / psychology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Adrenergic Antagonists
  • Receptors, Adrenergic, beta-2
  • Cocaine
  • Norepinephrine