REDUCED CLEARANCE OF EXOGENOUS DOPAMINE IN RAT NUCLEUS-ACCUMBENS, BUTNOT IN DORSAL STRIATUM, FOLLOWING COCAINE CHALLENGE IN RATS WITHDRAWNFROM REPEATED COCAINE ADMINISTRATION

We investigated whether changes in the dopamine transporter in the nuc leus accumbens or striatum are involved in cocaine-induced behavioral sensitization by using in vivo electrochemistry to monitor the clearan ce of locally applied dopamine in anesthetized rats. Rats were injecte d with cocaine-HCI (1 0 mg/kg i.p.) or saline daily for 7 consecutive days and then withdrawn for 7 days. Pressure ejection of a finite amou nt of dopamine at 5-min intervals from a micropipette adjacent to the electrochemical recording electrode produced transient and reproducibl e dopamine signals. After a challenge injection of cocaine (1 0 mg/kg i.p.), the signals in the nucleus accumbens of cocaine-treated animals became prolonged and the clearance rate of the dopamine decreased, in dicating significant inhibition of the dopamine transporter. In contra st, simultaneous measurements in the dorsal striatum indicated a trans ient increase in both the amplitude of the signals and the clearance r ate of the dopamine. The signals in both brain regions in the saline-t reated animals given the cocaine challenge were similar to those in un treated animals given an acute injection of cocaine (1 0 mg/kg i.p.) o r saline. Behaviorally, not all of the cocaine-treated animals were se nsitized; however, both sensitized and nonsensitized animals displayed similar changes in dopamine clearance rate. Quantitative autoradiogra phy with [H-3]mazindol revealed that the affinity of the dopamine tran sporter for cocaine and the density of binding sites were similar in c ocaine- and saline-treated rats. The decrease in dopamine clearance ra te observed in the nucleus accumbens of the cocaine-treated rats after a challenge injection of cocaine is consistent with increased dopamin ergic transmission, but does not appear to be sufficient in itself for producing behavioral sensitization.