Role of astrocytes in rewarding effects of drugs of abuse

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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.