CB1 receptor‐mediated signaling underlies the hippocampal synaptic,learning, and memory deficits following treatment with JWH‐081, a new component of spice/K2 preparations

Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as “Spice” or “K2” to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of “Spice/K2”, including JWH‐081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH‐081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of JWH‐081 on pCaMKIV, pCREB, and pERK1/2 signaling events followed by long‐term potentiation (LTP), hippocampal‐dependent learning and memory tasks using CB1 receptor wild‐type (WT) and knockout (KO) mice. Acute administration of JWH‐081 impaired CaMKIV phosphorylation in a dose‐dependent manner, whereas inhibition of CREB phosphorylation in CB1 receptor WT mice was observed only at higher dose of JWH‐081 (1.25 mg/kg). JWH‐081 at higher dose impaired CaMKIV and CREB phosphorylation in a time‐dependent manner in CB1 receptor WT mice but not in KO mice and failed to alter ERK1/2 phosphorylation. In addition, SR treated or CB1 receptor KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio compared with vehicle or WT littermates. In hippocampal slices, JWH‐081 impaired LTP in CB1 receptor WT but not in KO littermates. Furthermore, JWH‐081 at higher dose impaired object recognition, spontaneous alternation and spatial memory on the Y‐maze in CB1 receptor WT mice but not in KO mice. Collectively our findings suggest that deleterious effects of JWH‐081 on hippocampal function involves CB1 receptor mediated impairments in CaMKIV and CREB phosphorylation, LTP, learning and memory in mice. © 2013 Wiley Periodicals, Inc.