Hentges Shane T, Low Malcolm J, Williams John T
Vollum Institute, Oregon Health and Science University, Portland, Oregon 97329, USA.
J Neurosci. 2005 Oct 19;25(42):9746-51. doi: 10.1523/JNEUROSCI.2769-05.2005.
Endocannabinoid release from a single neuron has been shown to cause presynaptic inhibition of transmitter release at many different sites. Here, we demonstrate that hypothalamic proopiomelanocortin (POMC) neurons release endocannabinoids continuously under basal conditions, unlike other release sites at which endocannabinoid production must be stimulated. The basal endocannabinoid release selectively inhibited GABA release onto POMC neurons, although exogenous administration of cannabinoid agonists also inhibited glutamate release. The CB1 cannabinoid receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] blocked endocannabinoid-mediated inhibition of GABA release without affecting excitatory synaptic currents, whereas the CB1 receptor agonist WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] inhibited both inhibitory and excitatory synaptic currents in POMC neurons. These data demonstrate that endogenously released cannabinoids and exogenously applied CB1 receptor agonists can have markedly different effects on synaptic inputs. Furthermore, the data suggest a novel form of endocannabinoid-mediated retrograde inhibition, whereby the regulation of a subset of inputs requires either the removal of tonic presynaptic inhibition caused by endocannabinoids or the engagement of a mechanism that actively inhibits endocannabinoid production.
已表明，单个神经元释放内源性大麻素可在许多不同位点引起递质释放的突触前抑制。在此，我们证明，下丘脑阿片促黑素皮质素原（POMC）神经元在基础条件下持续释放内源性大麻素，这与其他需要刺激才能产生内源性大麻素的释放位点不同。基础内源性大麻素释放选择性抑制了向POMC神经元释放的γ-氨基丁酸（GABA），尽管外源性给予大麻素激动剂也抑制了谷氨酸的释放。CB1大麻素受体拮抗剂AM 251 [N-（哌啶-1-基）-5-（4-碘苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺]阻断了内源性大麻素介导的GABA释放抑制，而不影响兴奋性突触电流，而CB1受体激动剂WIN 55,212-2 [R-（+）-（2,3-二氢-5-甲基-3-[(4-吗啉基)甲基]吡咯并[1,2,3-de]-1,4-苯并恶嗪-6-基）（1-萘基）甲酮单甲磺酸盐]抑制了POMC神经元中的抑制性和兴奋性突触电流。这些数据表明，内源性释放的大麻素和外源性应用的CB1受体激动剂对突触输入可能有明显不同的作用。此外，数据提示了一种新型的内源性大麻素介导的逆行抑制形式，即对一部分输入的调节需要消除由内源性大麻素引起的紧张性突触前抑制，或者需要启动一种主动抑制内源性大麻素产生的机制。
