Interactive effects of AM251 and baclofen on synaptic plasticity in the rat dentate gyrus.

Long-term potentiation (LTP), a form of synaptic plasticity, is considered to be a critical cellular mechanism that underlies learning and memory. Cannabinoid CB and metabotropic GABA receptors display similar pharmacological effects and co-localize in certain brain regions. In this study, we examined the effects of co-administration of the CB and GABA antagonists AM251 and baclofen, respectively, on LTP induction in the rat dentate gyrus (DG). Male Wistar rats were anesthetized with urethane. A stimulating electrode was placed in the lateral perforant path (PP), and a bipolar recording electrode was inserted into the DG until maximal field excitatory postsynaptic potentials (fEPSPs) were observed. LTP was induced in the hippocampal area by high-frequency stimulation (HFS) of the PP. fEPSPs and population spikes (PS) were recorded at 5, 30, and 60min after HFS in order to measure changes in the synaptic responses of DG neurons. Our results showed that HFS coupled with administration of AM251 and baclofen increased both PS amplitude and fEPSP slope. Furthermore, co-administration of AM251 and baclofen elicited greater increases in PS amplitude and fEPSP slope. The results of the present study suggest that CB receptor activation in the hippocampus mainly modifies synapses onto GABAergic interneurons located in the DG. Our results further suggest that, when AM251 and baclofen are administered simultaneously, AM251 can alter GABA release and thereby augment LTP through GABA receptors. These results suggest that functional crosstalk between cannabinoid and GABA receptors regulates hippocampal synaptic plasticity.