Steffensen Scott C, Stobbs Sarah H, Colago Eric E O, Lee Rong-Sheng, Koob George F, Gallegos Roger A, Henriksen Steven J
Department of Psychology (1050 SWKT), Brigham Young University, Provo, UT 84602, USA.
Exp Neurol. 2006 Nov;202(1):139-51. doi: 10.1016/j.expneurol.2006.05.023. Epub 2006 Jun 30.
Opiate activation of mu-opioid receptors (muORs) in the ventral tegmental area (VTA) modulates gamma-aminobutyric acid (GABA) neurotransmission within the mesocorticolimbic dopamine (DA) reward system. We combined in vivo extracellular electrophysiological recordings in anesthetized and freely behaving rats with intracellular Neurobiotin filling and immunocytochemistry to characterize the effects of opiates on VTA GABA neurons, evaluate their discharge activity during opiate self-administration, and identify the cellular sites for opiate activation. We identified a subpopulation of VTA GABA neurons that was characterized by location, spike discharge profile, activation by microelectrophoretic DA, and response to internal capsule (IC) stimulation. Systemic administration of heroin or microelectrophoretic application of the selective muOR agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) reduced VTA GABA neuron firing rate (heroin IC(50) = 0.35 mg/kg) and was blocked by the muOR antagonist naloxone. Heroin also reduced IC-evoked post-stimulus spike discharges, a manifestation of gap-junction-mediated electrical coupling between VTA GABA neurons. The baseline firing rate of VTA GABA neurons significantly increased (239%) following the acquisition of heroin self-administration behavior and transiently increased during each response for heroin (105%), but decreased (49%) following heroin, similar to non-contingent heroin. Electrophysiologically characterized VTA GABA neurons were filled with Neurobiotin and labeled dendrites contained plasmalemmal muOR immunoreactivity. Dually labeled muOR dendrites contained dendrodendritic appositions characteristic of gap junctions. These findings indicate that inhibition of this population of GABAergic neurons by opiates acting on dendritic muORs has implications for modulation of electrical coupling between VTA GABA neurons and dopamine (DA) neurotransmission in the VTA and terminal field regions.
腹侧被盖区(VTA)中μ-阿片受体(muORs)的阿片类激活调节中脑皮质边缘多巴胺(DA)奖赏系统内的γ-氨基丁酸(GABA)神经传递。我们将麻醉和自由活动大鼠体内的细胞外电生理记录与细胞内Neurobiotin填充和免疫细胞化学相结合,以表征阿片类药物对VTA GABA能神经元的影响,评估其在阿片类自我给药过程中的放电活动,并确定阿片类激活的细胞位点。我们鉴定出了一群VTA GABA能神经元,其特征在于位置、放电峰形、微电泳DA激活以及对内囊(IC)刺激的反应。全身注射海洛因或微电泳应用选择性muOR激动剂[D-Ala2,N-Me-Phe4,Gly-ol]-脑啡肽(DAMGO)可降低VTA GABA能神经元的放电频率(海洛因IC(50)=0.35mg/kg),并被muOR拮抗剂纳洛酮阻断。海洛因还减少了IC诱发的刺激后放电峰,这是VTA GABA能神经元之间缝隙连接介导的电耦合的一种表现。在获得海洛因自我给药行为后,VTA GABA能神经元的基线放电频率显著增加(239%),并且在每次对海洛因的反应期间短暂增加(105%),但在注射海洛因后降低(49%),类似于非条件性海洛因。经电生理特征鉴定的VTA GABA能神经元用Neurobiotin填充,标记树突含有质膜muOR免疫反应性。双重标记的muOR树突含有缝隙连接特有的树突-树突并置。这些发现表明,作用于树突muOR的阿片类药物对这群GABA能神经元的抑制作用,对调节VTA GABA能神经元之间的电耦合以及VTA和终末场区域的多巴胺(DA)神经传递具有重要意义。