The CB 1 receptor antagonist, SR141716A, prevents high-frequency stimulation-induced reduction of feedback inhibition in the rat dentate gyrus following perforant path stimulation in vivo

Abstract

Endocannabinoids acting through CB 1 receptors are thought to regulate GABAergic and glutamatergic neurotransmission and may modulate long-term potentiation (LTP). High-frequency stimulation (HFS) of the medial perforant path to induce LTP was studied in the dentate gyrus with or without the selective CB 1 receptor antagonist, SR141716A in isoflurane-anaesthetised rats. HFS significantly increased the slope of the field excitatory post-synaptic potential (fEPSP) and the amplitude of the population spike (PS; P < 0.001 in each case; n = 6). Following administration of SR141716A, HFS no longer increased fEPSP slope, whereas PS amplitude potentiation remained significant ( P < 0.0001; n = 6). Paired-stimuli revealed that HFS significantly reduced inhibition observed at intervals of 10 ms ( P < 0.01; n = 6), and produced a leftward shift of the interval–inhibition curve ( P < 0.05; n = 6). Following administration of SR141716A, HFS no longer reduced inhibition at the 10 ms interval, but a leftward shift in the interval–inhibition curve was still observed ( P < 0.05, n = 6). These results indicate that LTP in the dentate gyrus reduces local circuit inhibition, consistent with a reduction of GABA release and/or duration of the post-synaptic GABA-receptor mediated response. Selective effects of SR141716A on the degree, but not the timecourse, of paired-pulse inhibition suggest that the reduction in GABA release following LTP induction is due to CB 1 activation. Results also suggest that CB 1 receptors contribute to HFS-induced potentiation of the fEPSP, but not to the mechanism underlying potentiation of PS amplitude. We suggest that CB 1 activation during HFS of the medial perforant path increases glutamate release from perforant path synapses, but inhibits release of GABA from local circuit interneurons.