AbstractWe previously reported that administration of the synthetic cannabinoid agonist WIN 55,212‐2 causes an increase in norepinephrine (NE) efflux in the frontal cortex (FC). The present study examined the expression levels of α2‐ and β1‐adrenergic receptors (ARs) as well as the norepinephrine transporter (NET) in the FC of rats following exposure to WIN 55,212‐2. Rats received systemic injection of WIN 55,212‐2 (3 mg/kg) acutely or for 7 days. Another group of rats received repeated WIN 55,212‐2 treatment followed by a period of abstinence. Control rats received vehicle injections. Rats were euthanized 30 min after the last WIN 55,212‐2 injection, the FC was microdissected, and protein extracts were probed for α2‐AR, β1‐AR, and NET. Results showed that β1‐AR expression was significantly decreased following repeated WIN 55,212‐2 treatment but significantly increased following a period of abstinence. α2‐AR expression showed no significant change in all groups examined. NET expression was significantly decreased following acute WIN 55,212‐2 treatment, with no changes following chronic administration or a period of abstinence. Alterations in NET may arise from modulation of cannabinoid receptors (CB1) that are localized to noradrenergic axon terminals as we demonstrate colocalization of CB1 receptor and NET in the same cortical axonal processes. The present findings support significant alterations in adrenergic receptor and NET expression in the FC after WIN 55,212 exposure that may underlie the reported changes in attention, cognition, and anxiety commonly observed after cannabinoid exposure. © 2009 Wiley‐Liss, Inc.