Abstract
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 (Amax) responses. In HCRs, systemic cocaine administration evoked an immediate and prolonged 2-fold augmentation in Amax 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,Amax 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.
Footnotes
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This work was supported by National Institutes of Health Grants DA04216 (N.R.Z.), AG06434 (G.A.G.), and NS39787 (G.A.G), and Research Scientist Development Awards DA00174 (N.R.Z.) and MH01245 (G.A.G). A preliminary report of this work has been presented: Sabeti J, Gerhardt GA, and Zahniser NR (2001) Soc Neurosci Abstr 27: Program no. 443.18.
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DOI: 10.1124/jpet.102.035816
- Abbreviations:
- DA
- dopamine
- DAT
- dopamine transporter
- dSTR
- dorsal striatum
- NAc
- nucleus accumbens
- LCR
- low cocaine responder
- HCR
- high cocaine responder
- Amax
- peak signal amplitude
- k
- decay rate constant
- ANOVA
- analysis of variance
- KS
- Kolmogorov-Smirnov
- Received March 6, 2002.
- Accepted May 15, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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