Vol. 302, Issue 3, 1201-1211, September 2002

Acute Cocaine Differentially Alters Accumbens and Striatal Dopamine Clearance in Low and High Cocaine Locomotor Responders: Behavioral and Electrochemical Recordings in Freely Moving Rats

Jilla Sabeti, Greg A. Gerhardt and Nancy R. Zahniser

Departments of Pharmacology (J.S., N.R.Z.) and Neuroscience Program (N.R.Z.), University of Colorado Health Sciences Center, Denver, Colorado, and Departments of Anatomy & Neurobiology and Neurology (G.A.G), University of Kentucky Chandler Medical Center, Lexington, Kentucky

Behavioral responses of rodents to cocaine are characterized by marked individual variability. Here, outbred male Sprague-Dawley rats were profiled based on concomitant recording of behavioral and electrochemical responses. Rats were categorized as either low or high cocaine responders (LCRs or HCRs, respectively) based on their differential locomotor responsiveness to an acute, low-dose injection of cocaine (10 mg/kg i.p.). LCRs and HCRs also differed in other cocaine-induced behaviors. The role of the dopamine transporter (DAT) in mediating the behavioral differences in cocaine responsiveness in LCRs and HCRs was investigated by high-speed chronoamperometric recording of exogenous dopamine (DA) clearance signals in nucleus accumbens (NAc) and dorsal striatum (dSTR). Higher volumes of DA were required in NAc of HCRs, than of LCRs, to produce equivalent peak DA signal amplitude (A_max) responses. In HCRs, systemic cocaine administration evoked an immediate and prolonged 2-fold augmentation in A_max in both brain regions, coincident with locomotor activation. The cocaine-induced decrease in the efficiency of DA clearance (k) in NAc of HCRs was more immediate and prolonged than in dSTR, where the transient decrease coincided with maximal stereotypic behavior. In contrast, in LCRs, A_max was not altered by cocaine, and decay rate constant (k) was transiently attenuated only in dSTR. Correlation analyses of individual responses revealed that cocaine-induced changes in DA clearance signal parameters accounted for 20 to 40% of the variation in behavioral responsiveness to cocaine. Overall, our findings emphasize the importance of characterizing individual responses to understand more fully the range of functional consequences resulting from DAT inhibition.