European Journal of Neuroscience, Vol. 10, pp. 1113–1120, 1998 © European Neuroscience Association The relation between dopamine oxidation currents in the nucleus accumbens and conditioned increases in motor activity in rats following repeated administration of d-amphetamine or cocaine Patricia Di Ciano, Charles D. Blaha and Anthony G. Phillips University of British Columbia, Department of Psychology, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada Keywords: chronoamperometry, conditioning, intravenous, psychostimulants, rat Abstract Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the nucleus accumbens associated with unconditioned and conditioned increases in motor activity in rats, following the intravenous administration of either d-amphetamine (0.63 mg/kg) or cocaine (3 mg/kg), or the presentation of a conditioned stimulus paired repeatedly with one of these psychostimulants. Each drug was administered daily for 7 days, either in the home cage or an environment in which a compound stimulus (light offset, odour) was presented. Rats in control groups received saline instead of drug in the distinctive test environment. On day 7 of training, significant increases in unconditioned motor activity were observed in the 30 min session following infusions of either d-amphetamine or cocaine. Associated dopamine oxidation currents in the nucleus accumbens increased immediately following administration of either drug and remained significantly elevated above baseline during the entire 30 min recording period. On the test day, presentation of the conditioned stimulus with vehicle infusions, in the distinct environment, was accompanied by an increase in dopamine oxidation currents and a conditioned increase in motor activity, only in the groups in which these stimuli had been paired with d-amphetamine or cocaine. Neither the magnitude or duration of the conditioned motor activity matched the corresponding change in extracellular dopamine efflux in the nucleus accumbens. Accordingly, it is argued that the increase in dopamine concentration serves as a neurochemical correlate of the unconditioned and conditioned stimuli. The change in motor activity constitutes the unconditioned and conditioned responses that are subserved by the neural systems activated by the initial rise in extracellullar dopamine. Introduction It has been hypothesized that conditioned stimuli previously paired with psychostimulants, such as d-amphetamine or cocaine, acquire the ability to prime drug-seeking behaviours in humans (Ehrman et al., 1992; Avants et al., 1995) by activating the same neurochemical systems as the psychostimulants themselves (Stewart et al., 1984). In this analysis, it is important to specify that it is the pharmacological effect of the drug, such as increased extracellular concentrations of monoamines, including dopamine (DA), not simply administration of the drug itself, which serves as the unconditioned stimulus (Eikelboom & Stewart, 1982; Stewart et al., 1984; Ramsay & Woods, 1997). Thus, conditioned stimuli serve to enhance DA transmission through stimulus–stimulus associations which subsequently activate neural systems controlling specific motor responses. In this regard, adminis- tration of psychostimulants produce increases in motor behaviour such as sniffing, rearing, grooming, nose pokes, and horizontal and vertical motion (Pickens & Crowder, 1967; Pickens & Dougherty, 1971; Bridger, 1981), of which only a subset, including nose pokes and sniffing, were shown to be conditioned behaviours (Martin- Iversen & Fawcett, 1996). Correspondence: Anthony G. Phillips, University of British Columbia, Department of Psychology, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada. Received 13 June 1997, revised 26 September 1997, accepted 17 November 1997 In vivo neurochemical evidence (Di Chiara & Imperato, 1988; Kalivas & Duffy, 1990; Kuczenski & Segal, 1992) indicates that increases in d-amphetamine- or cocaine-elicited motor activity is related to enhancements in DA neurotransmission in the nucleus accumbens (N.Acc.) (for reviews, see: Fishman et al., 1983; Beninger, 1983). However, Kuczenski and colleagues (Kuczenski & Segal, 1989; Kuczenski et al., 1991) note that motor activity levels observed following d-amphetamine administration are approximately threefold lower in magnitude than those observed following cocaine administra- tion, whereas the peak amplitude increase in DA efflux in the N.Acc. with d-amphetamine administration was μ 300% greater than that seen following a cocaine challenge injection (Kuczenski et al., 1991). These authors suggest that, although enhanced DA efflux in the N.Acc. may accompany psychostimulant-induced increases in motor activity, such changes are not the direct determinant of either the magnitude or duration of the motor activity observed. In fact, an increase in DA efflux need only coincide with the initiation of associated motor activity. Similar questions are asked about the role