title: The CB1 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.
authors.affiliation: Department of Biology, Psychiatry CEDD, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, Verona, Italy. david.m.sokal@gsk.com
authors.forename: David M
authors.initials: DM
authors.lastname: Sokal
authors.forename: Camilla
authors.initials: C
authors.lastname: Benetti
authors.forename: Elena
authors.initials: E
authors.lastname: Girlanda
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D018891:Dentate Gyrus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005246:Feedback / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D019580:Perforant Pathway / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D000077285:Rimonabant; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D063385:Cannabinoid Receptor Modulators; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018079:Receptors, GABA; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077285:Rimonabant