Margolis Elyssa B, Hjelmstad Gregory O, Fujita Wakako, Fields Howard L
Department of Neurology, The Wheeler Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94143, and
Department of Neurology, The Wheeler Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94143, and.
J Neurosci. 2014 Oct 29;34(44):14707-16. doi: 10.1523/JNEUROSCI.2144-14.2014.
The ventral tegmental area (VTA) is required for the rewarding and motivational actions of opioids and activation of dopamine neurons has been implicated in these effects. The canonical model posits that opioid activation of VTA dopamine neurons is indirect, through inhibition of GABAergic inputs. However, VTA dopamine neurons also express postsynaptic μ-opioid peptide (MOP) receptors. We report here that in Sprague Dawley rat, the MOP receptor-selective agonist DAMGO (0.5-3 μM) depolarized or increased the firing rate of 87 of 451 VTA neurons (including 22 of 110 dopamine neurons). This DAMGO excitation occurs in the presence of GABAA receptor blockade and its EC50 value is two orders of magnitude lower than for presynaptic inhibition of GABA release on to VTA neurons. Consistent with a postsynaptic channel opening, excitations were accompanied by a decrease in input resistance. Excitations were blocked by CdCl2 (100 μM, n = 5) and ω-agatoxin-IVA (100 nM, n = 3), nonselective and Cav2.1 Ca(2+) channel blockers, respectively. DAMGO also produced a postsynaptic inhibition in 233 of 451 VTA neurons, including 45 of 110 dopamine neurons. The mean reversal potential of the inhibitory current was -78 ± 7 mV and inhibitions were blocked by the K(+) channel blocker BaCl2 (100 μM, n = 7). Blockade of either excitation or inhibition unmasked the opposite effect, suggesting that MOP receptors activate concurrent postsynaptic excitatory and inhibitory processes in most VTA neurons. These results provide a novel direct mechanism for MOP receptor control of VTA dopamine neurons.
腹侧被盖区（VTA）是阿片类药物产生奖赏和动机行为所必需的，多巴胺能神经元的激活与这些效应有关。经典模型认为，VTA多巴胺能神经元的阿片类激活是间接的，通过抑制GABA能输入实现。然而，VTA多巴胺能神经元也表达突触后μ-阿片肽（MOP）受体。我们在此报告，在斯普拉格-道利大鼠中，MOP受体选择性激动剂DAMGO（0.5 - 3 μM）使451个VTA神经元中的87个去极化或提高了其放电频率（包括110个多巴胺能神经元中的22个）。这种DAMGO激发在GABAA受体阻断的情况下发生，其半数有效浓度（EC50）值比VTA神经元上GABA释放的突触前抑制低两个数量级。与突触后通道开放一致，激发伴随着输入电阻的降低。激发被CdCl2（100 μM，n = 5）和ω-芋螺毒素-IVA（100 nM，n = 3）分别阻断，它们分别是非选择性和Cav2.1钙通道阻滞剂。DAMGO还在451个VTA神经元中的233个中产生了突触后抑制，包括110个多巴胺能神经元中的45个。抑制性电流的平均反转电位为-78 ± 7 mV，抑制作用被钾通道阻滞剂BaCl2（100 μM，n = 7）阻断。阻断激发或抑制会揭示出相反的效应，这表明MOP受体在大多数VTA神经元中激活了同时存在的突触后兴奋和抑制过程。这些结果为MOP受体对VTA多巴胺能神经元的控制提供了一种新的直接机制。
