DECREASED PRESYNAPTIC SENSITIVITY TO ADENOSINE AFTER COCAINE WITHDRAWAL

The nucleus accumbens (NAc) is a site mediating the rewarding properti es of drugs of abuse, such as cocaine, amphetamine, opiates, nicotine, and alcohol (Wise and Bozarth, 1987; Koob, 1992; Samson and Harris, 1 992; Woolverton and Johnson, 1992; Self and Nestler, 1995; Pontieri et at., 1996), Acute cocaine has been shown to decrease excitatory synap tic transmission mediated by the cortical afferents to the NAc (Nicola et al., 1996), but the effects of long-term cocaine treatment and wit hdrawal have not been explored. Here, we report that longterm (1 week) withdrawal from chronic cocaine reduced the potency of adenosine to p resynaptically inhibit glutamate (Glu) release by activating adenosine Al receptors. Adenosine Al receptors were not desensitized, because t he potency of the metabolically stable adenosine analog N-6-cyclopenty ladenosine was unchanged after chronic cocaine withdrawal. When adenos ine transporters were blocked, the potency of adenosine to inhibit Glu release from naive and cocaine withdrawn NAc slices was similar. Thes e results suggest that one of the long-term consequences of cocaine wi thdrawal is an augmented uptake of adenosine, This long-lasting change expressed at the presynaptic excitatory inputs to the medium spiny ou tput neurons in the NAc may help identify new therapeutic targets for the treatment of drug abuse.