Role of astrocytes in rewarding effects of drugs of abuse

众所周知，长期暴露于精神兴奋剂诱导神经元可塑性。近年来，越来越多的证据表明星形胶质细胞可能积极参与突触可塑性。在这项研究中，我发现，在体外处理皮质神经元/胶质细胞与甲基苯丙胺（METH）或吗啡（MRP）的共培养物通过蛋白激酶C（PKC）引起星形胶质细胞的激活。纯化的星形胶质细胞被METH显著激活，而MRP没有这种作用。METH，而不是MRP，引起了长期持续的星形胶质细胞激活皮质神经元/神经胶质细胞共培养。METH处理增强了皮层神经元对谷氨酸的Ca^<2+>反应。我在这里表明，神经胶质调节剂propentofylline（PPF）显着减少了星形胶质细胞的激活诱导滥用药物，如甲基苯丙胺和MRP。PPF治疗也抑制了METH和MRP诱导的奖励效应。另一方面，核内的神经元（N. Acc.）给予星形胶质细胞条件培养液（ACM）可加重METH和MRP诱导的奖赏效应。此外，用从METH处理的星形胶质细胞收集的ACM（METH-ACM）进行的N.Acc.内处理显著且显著地增强了METH的奖励效应。我还发现一些趋化因子，如单核细胞趋化蛋白-5和可溶性肿瘤坏死因子受体-1，在METH-ACM中被鉴定。这些结果表明，通过PKC或星形胶质细胞相关的可溶性因子的刺激，星形胶质细胞的激活可以放大METH和MRP的奖励效应的发展。本研究提供了直接的证据，星形胶质细胞可能，至少部分，有助于精神兴奋剂和阿片类药物诱导的奖励效应的发展。

It is well known that long-term exposure to psychostimulants induces neuronal plasticity. Recently, accumulating evidence suggests that astrocytes may actively participate in synaptic plasticity. In this study, I found that in vitro treatment with cortical neuron/glia co-cultures with either methamphetamine (METH) or morphine (MRP) caused the activation of astrocytes via protein kinase C (PKC). Purified astrocytes were markedly activated by METH, whereas MRP had no such effect. METH, but not MRP, caused a long-lasting astrocytic activation in cortical neuron/glia co-cultures. Treatment with METH enhanced the Ca^<2+> responses to glutamate in cortical neurons. I show here that a glial modulator propentofylline (PPF) dramatically diminished the activation of astrocytes induced by drugs of abuse, such as METH and MRP. Treatment with PPF also suppressed both METH-and MRP-induced rewarding effects. On the other hand, intra-nucleus accumbens (N.Acc.) administration of astrocyte-conditioned medium (ACM) aggravated the development of rewarding effects induced by METH and MRP. Moreover, intra-N.Acc. treatment with ACM collected from METH-treated astrocytes (METH-ACM) significantly and dramatically enhanced the rewarding effect of METH. I also found that some chemokines, such as monocyte chemoattractant protein-5 and soluble tumor necrosis factor receptor-1, were identified in METH-ACM. These findings suggest that astrocytic activation through the stimulation of PKC or astrocyte-related soluble factors could amplify the development of rewarding effect of METH and MRP. The present study provides direct evidence that astrocytes may, at least in part, contribute to the development of rewarding effects induced by psychostimulants and opioids.