Cannabinoid agonist, WIN 55,212-2, increases in vivo paired-pulse facilitation, long-term potentiation, and Arc...

The endogenous cannabinoid system in the hippocampus has the potential to modulate synaptic transmission, including short and long term plasticity, by acting as retrograde messengers. The present study evaluated the effects of WIN 55,212-2, a potent cannabinoid agonist, on paired-pulse facilitation (PPF) and long-term potentiation (LTP) in the dentate gyrus in vivo. WIN 55,212-2 (10  μg/μL; 0.5  μL volume) or vehicle was unilaterally infused into the right dorsal hippocampus of anesthetized rats prior to perforant path stimulation and electrophysiological recordings. Upon completion of physiological recordings, brains were processed for immediate early gene expression (Arc, c-Fos, zif268). WIN 55,212-2 reduced baseline population spike amplitude at high stimulation intensities (500-600 μA), without affecting baseline fEPSP slopes. WIN 55,212-2 also altered fEPSP paired-pulse ratios, suggesting changes in glutamate release probability and GABAergic inhibition. WIN 55,212-2 significantly increased fEPSP slopes following high-frequency stimulation without affecting population spike amplitude, indicating selective enhancement of fEPSPs. Arc expression was significantly elevated in the stimulated dentate gyrus of WIN 55,212-2-treated rats, with no changes in c-Fos or zif268 expression. WIN 55,212-2 may modulate LTP through a combined reduction of glutamate and GABA via feedforward and feedback processes, and may influence baseline and activity-dependent changes via distinct mechanisms. Taken together, these results suggest cannabinoids at high concentration enhance synaptic plasticity mechanisms, which may be important factors driving the effects of cannabinoids on learning and memory.