There is a growing body of evidence suggesting that the neuromodulator adenosine is involved in drug addiction and withdrawal and that adenosine signaling pathways may offer new targets for therapeutic treatments of addiction. Recent studies have suggested that chronic exposure to drugs of abuse may alter adenosine metabolism in the nucleus accumbens, a brain region critically involved in drug addiction and withdrawal. The present study examined the effects of chronic morphine treatment on the ability of adenosine to inhibit excitatory postsynaptic currents in nucleus accumbens medium spiny neurons. It was found that chronic morphine treatment via subcutaneous implantation of morphine pellets in rats for 1 wk did not alter the level of adenosine-mediated tonic inhibition of nucleus accumbens excitatory synapses. However, chronic morphine treatment did induce a leftward shift in the adenosine dose-response curve, indicating an increase in the sensitivity of synaptic currents to exogenously applied adenosine. This shift was not due to a change in adenosine receptors or their effectors, because chronic morphine treatment had no effect on the dose-response relationship of a nonmetabolized adenosine receptor agonist. When adenosine transport was blocked, the ability of chronic morphine to shift the adenosine dose-response curve was eliminated. These experiments suggest that the increase in the sensitivity of nucleus accumbens synapses to the inhibitory effects of adenosine may be due to a decrease in adenosine transport. The identification of these changes in the adenosine system after chronic drug exposure may help identify new therapeutic strategies aimed at easing withdrawal from opioids.
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