Repeated administration of cannabinoid receptor agonist and antagonist impairs short and long term plasticity of rat's dentate gyrus in vivo

The effects of cannabinoids (CBs) on synaptic plasticity of hippocampal dentate gyrus neurons have been shown in numerous studies. However, the effect of repeated exposure to cannabinoids on hippocampal function is not fully understood. In this study, using field potential recording, we investigated the effect of repeated administration of the nonselective CB receptor agonist WIN55212-2, and the CB1 receptor antagonist AM251, on both short- and long-term synaptic plasticity in dentate gyrus (DG) of hippocampus. Drugs were administered three times daily for seven consecutive days into lateral ventricle of rats. Short term synaptic plasticity was assessed by measuring paired-pulse index (PPI) in DG neurons after stimulation of perforant pathway. Long-term plasticity was assessed through measurement of both population spike (PS) amplitude and field excitatory postsynaptic potential (fEPSP) slope after high frequency stimulation (HFS) of DG neurons. Repeated administration of WIN55212-2 not only significantly decreased PPI in 20, 30 and 50 ms intervals but also blocked LTP. This effect was reversed by pretreatment of rats with CB1 receptor antagonist AM251. Moreover, AM251 by itself increased PPI in 10 and 20 ms interval stimulations, but had no effect on HFS-induced PS amplitude and fEPSP slope. These results suggest that repeated administration of cannabinoids could impair short term and long term synaptic plasticity that may be due to desensitization of cannabinoid receptors and/or changes in synaptic spine density of hippocampus which leads to alteration in short and long term memories that remains to be elucidated.