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It is well recognized that drugs of abuse lead to plastic changes in synapses and that these long-term modifications have the potential to underlie adaptive changes of the brain that lead to substance abuse. However the variety of molecular mechanisms involved in these responses are not completely defined. We are just beginning to understand some of the roles of glial cells that are associated with synapses. At many synapses an astrocyte process is associated with pre- and postsynaptic neuron processes leading to the naming of this synaptic structure as the Tripartite Synapse. Therefore, these glial cells are positioned so that they influence synaptic transmission and thus could potentially regulate the actions of some drugs of abuse. In mammalian systems there are correlations between long-term structural changes in astrocytes and responses to drugs of abuse. However, whether such changes in glia impact brain function and subsequent behaviors associated with addiction is poorly understood. Studies using Drosophila show important roles of fly glia in mediating responses to cocaine pointing to the potential for the involvement of mammalian glia in the brain's responses to this as well as other drugs. In agreement with this possibility three receptor systems known to be important in substance abuse, mGluR5, GABA(B) and CB-1 receptors, are all expressed by astrocytes and the activation of these glial receptors is now known to impact neuronal excitability and synaptic transmission. Given our new knowledge about the presence of reciprocal signaling between astrocytes and synapses we are now at a time when it becomes appropriate to determine how glial cells respond to drugs of abuse and whether they contribute to the changes in brain function underlying substance abuse.