European Journal of Neuroscience, Vol. 10, pp. 1121–1127, 1998 © European Neuroscience Association Conditioned changes in dopamine oxidation currents in the nucleus accumbens of rats by stimuli paired with self- administration or yoked-administration of d-amphetamine 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, psychostimulants, drug addiction, self-administration. Abstract In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked- or self-administered intravenous injections of the psychostimulant d-amphetamine. Daily conditioning trials began with a non-contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d-amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4–7, and on each trial, intravenous d-amphetamine (0.25 mg/kg per injection) self-administration produced a significant maximal increase in mean dopamine oxidation currents of μ 8 nA above baseline. Dopamine oxidation currents in rats receiving yoked d-amphetamine were μ 5 nA above baseline by the fourth day of drug administration and reached μ 8 nA on the seventh and final day of drug administration. On day 9 the first presentation of the vehicle injection and conditioned stimulus, in combination with illumination of the house lights, induced an immediate increase in nucleus accumbens dopamine oxidation currents in all rats that had previously received d-amphetamine. Subsequent presentations of the conditioned stimulus at 30 min intervals induced further increases in extracellular dopamine oxidation currents in both drug-treated groups. By the end of the 3 h session, both groups had similar maximal conditioned increases in dopamine oxidation currents of μ 6 nA. These data are discussed with relation to the neurochemistry of drug craving. Introduction Drug craving in humans is often elicited by exposure to stimuli paired repeatedly with psychostimulants such as cocaine or d-amphetamine (Ehrman et al., 1992; O’Brien et al., 1993; Kilgus & Pumariega, 1994). These conditioned stimuli (CS) are believed to elicit a subjective state of craving by their ability to activate neurotransmitter systems similar to those associated with the pharmacological activity of the drug itself, thereby initiating the reinstatement of drug use (Stewart et al., 1984). A number of behavioural and neurochemical studies have implicated the mesolimbic dopamine (DA) system, and in particular DA transmission in the nucleus accumbens (N.Acc.), in mediating several aspects of psychostimulant craving (Robinson & Berridge, 1993). Intravenous self-administration of psychostimulant drugs has a high degree of face and construct validity and is therefore an excellent animal model of drug use. This procedure takes advantage of the fact that animals will readily perform an operant response to obtain psychostimulant infusions (Brady, 1991), a behaviour that is believed to be mediated by DA in the N.Acc. (Roberts et al., 1977; Blaha & Phillips, 1996; Gratton, 1996). In this regard, in vivo microdialysis and electrochemical procedures employed to investigate the neurochemical Correspondence: Anthony G. Phillips, University of British Columbia, Department of Psychology, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada. Received 13 June 1997, revised 17 November 1997, accepted 18 November 1997 correlates of stimulant self-administration have demonstrated that extracellular DA levels in the N.Acc. are maintained above a ‘reinforcing’ threshold level over relatively brief (Di Ciano et al., 1995) or long-term bouts of psychostimulant self-administration (Weiss et al., 1992; Wise et al., 1995; Di Ciano et al., 1996). In humans, presentation of stimuli previously paired with psychosti- mulant use produces subjective and physiological indices of craving (Ehrman et al., 1992; O’Brien et al., 1993; Kilgus & Pumariega, 1994). Therefore, a relevant question for the role of DA in drug craving, is whether exposure to a drug-paired CS can elicit an increase in DA neurotransmission in the N.Acc. in a manner similar to that observed during the self-administration of the drug. In this regard, several in vivo electrochemical studies have shown that a single passive presentation of a light stimulus previously paired with self- administered cocaine can elicit a conditioned increase in DA efflux in the N.Acc. Moreover, the pattern and magnitude of the conditioned change in DA efflux over the 4–15 min recording period following presentation of the CS was comparable with changes in DA observed during cocaine administration (Gratton & Wise, 1994; Kiyatkin & Stein, 1996). Although these latter studies provide evidence that the