Hoffman A F, Lupica C R
Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Neurosci. 2000 Apr 1;20(7):2470-9. doi: 10.1523/JNEUROSCI.20-07-02470.2000.
The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons 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 (EC(50) of 138 nM). This effect was blocked by the CB1 receptor antagonist SR141716A (1 microM) but not by the opioid antagonist naloxone. In contrast, evoked GABA(B)-mediated IPSCs were insensitive to the CB agonist. WIN 55,212-2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmium also eliminated the effect of WIN 55,212-2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212-2. The presynaptic effect of WIN 55,212-2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212-2 on evoked IPSCs. 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.
大麻素（CB）受体在海马体中定位到γ-氨基丁酸能（GABAergic）中间神经元，这表明大麻素可能调节GABA能功能，从而介导大麻对空间记忆和感觉加工的一些破坏作用。为了研究CB受体调节海马体中GABA能神经传递的可能机制，对大鼠脑片的CA1锥体神经元进行了全细胞电压钳记录。CB受体激动剂WIN 55,212-2以浓度依赖的方式降低了刺激诱发的GABA(A)受体介导的抑制性突触后电流（IPSCs）（半数有效浓度（EC(50)）为138 nM）。这种作用被CB1受体拮抗剂SR141716A（1 μM）阻断，但未被阿片受体拮抗剂纳洛酮阻断。相反，诱发的GABA(B)介导的IPSCs对CB激动剂不敏感。WIN 55,212-2还降低了自发的、动作电位依赖性IPSCs（sIPSCs）的频率，而在钠通道被河豚毒素（TTX）阻断时测量的动作电位非依赖性微小IPSCs（mIPSCs）未发生改变。镉对电压依赖性钙通道（VDCCs）的阻断也消除了WIN 55,212-2对sIPSCs的作用。细胞外钾升高使抑制性终末去极化，导致mIPSCs频率大幅增加，而镉和WIN 55,212-2均能抑制这种增加。还使用钾通道阻滞剂钡和4-氨基吡啶研究了WIN 55,212-2的突触前效应。这两种药物均未显著改变WIN 55,212-2对诱发的IPSCs的作用。总之，这些数据表明，突触前CB1受体通过抑制位于抑制性神经终末的VDCCs，减少CA1锥体神经元的GABA(A)介导而非GABA(B)介导的突触抑制。
