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

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 degrees C water), or administration of the alpha-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL11108 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective beta-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the alpha-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the alpha-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 beta-ARs. The beta-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the beta-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 beta-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate. Neuropsychopharmacology (2010) 35, 2165-21/8; doi:10.1038/npp.2010.86; published online / July 2010