Cannabinoids selectively decrease paired-pulse facilitation of perforant path synaptic potentials in the dentate gyrus in vitro

Perforant path synaptic potentials recorded from the outer molecular layer of the dentate gyrus were tested for paired-pulse potentiation and stimulus sensitivity in the presence and absence of the potent cannabinoid receptor ligand, WIN 55,212-2. Extracellular perforant path synaptic potential amplitudes were increased by 51% in 2 mM Ca2+ medium and 60% in 3 mM Ca2+ medium at a conditioning-test (C-T) interval of 10 ms, decreasing to 10-15% facilitation at an 80 ms C-T interval. Exposure to the potent cannabinoid receptor ligand WIN 55,212-2 produced a marked and dose-dependent reduction in the amplitude of the facilitated perforant path synaptic potentials. Maximum paired-pulse facilitation was reduced to 35% and 25% in 2.0 and 5.0 microM WIN 55,212-2 respectively. The effect was selective for potentials facilitated at C-T intervals of 10-60 ms. Input/output (I/O) curves of perforant path field potentials were shifted to the right in a dose-dependent (2.0 and 5.0 microM) manner by WIN 55,212-2. Significant differences in peak amplitudes of perforant path potentials were obtained at all suprathreshold stimulus intensities. A comparison of WIN 55,212-2 (5 microM) with the GABAB receptor agonist baclofen (200 microM) showed that when both drugs were administered independently each produced similar decreases in perforant path paired-pulse potentiation. However when administered together at these concentrations baclofen and WIN failed to potentiate each other, suggesting nonadditivity due to effects on a common process.(ABSTRACT TRUNCATED AT 250 WORDS)