Mechanisms of cannabinoid inhibition of GABA(A) synaptic transmission in the hippocampus

The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and the reby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through whic h CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neuron s in rat brain slices. Stimulus-evoked GABA(A) receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212-2 (EC50 of 138 nM). This effect was blocked by the CB1 receptor ant agonist SR141716A (1 mu M) but not by the opioid antagonist naloxone. In co ntrast, evoked GABA(B)-mediated IPSCs were insensitive to the CB agonist. W IN 55,212-2 also reduced the frequency of spontaneous, action potential-dep endent IPSCs (sIPSCs), without altering action potential-independent miniat ure IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodot oxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmi um also eliminated the effect of WIN 55,212-2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large i ncrease in the frequency of mIPSCs that was inhibited by both cadmium and W IN 55,212-2. The presynaptic effect of WIN 55,212-2 was also investigated u sing the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212-2 on evoked IPS Cs. Together, these data suggest that presynaptic CB1 receptors reduce GABA (A)- but not GABA(B)-mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.