There are several lines of evidence implying the involvement of the central glutamatergic system in morphine dependence. Extracellular glutamate released from nerve terminals is counterbalanced by glutamate transporters in neurons (EAAC1 and EAAT4) and glial cells (GLT-1 and GLAST), thereby modulating the glutamatergic system and protecting neurons from an excitotoxic action of glutamate. Here we show that a glial glutamate transporter GLT-1 could be involved in physical and psychological morphine dependence. By Northern blot analysis, the expression of glial glutamate transporter GLT-1, but not GLAST, mRNA was decreased in the striatum/nucleus accumbens (NAc) and thalamus of morphine-dependent rats. Subcutaneous administration of a glutamate transporter activator suppressed the development of physical morphine dependence and morphine-induced conditioned place preference. Intracerebroventricular administration of a glutamate transporter inhibitor to morphine-dependent rats facilitated the expression of naloxone-precipitated morphine withdrawal-induced somatic signs and conditioned place aversion. Furthermore, gene transfer techniques using recombinant adenoviruses revealed that GLT-1 in the locus coeruleus and NAc shell plays inhibitory roles in physical and psychological morphine dependence, respectively. These findings may provide evidence that a glial glutamate transporter GLT-1 could be a new target for preventing physical and psychological morphine dependence.
