Available online at www.sciencedirect.com Behavioural Brain Research 188 (2008) 227–232 Research report Dopamine tone increases similarly during predictable and unpredictable administration of rewarding brain stimulation at short inter-train intervals Giovanni Hernandez, Heshmat Rajabi, Jane Stewart, Andreas Arvanitogiannis, Peter Shizgal ∗ Center for Studies in Behavioral Neurobiology, Concordia University, Montr´ eal, Qu´ ebec H4B 1R6, Canada Received 29 August 2007; received in revised form 10 October 2007; accepted 29 October 2007 Available online 7 November 2007 Abstract Unpredicted rewards, but not predicted ones, trigger strong phasic changes in the firing rates of midbrain dopamine (DA). In contrast, neurochem- ical measurements of DA tone have failed to reveal an influence of reward predictability. However, the subjects of the neurochemical experiments were asked to predict reward onset over longer intervals (12 s, on average) than the subjects of the electrophysiological studies (typically, 2 s). Thus, the contrasting effects of reward predictability could reflect the difference in the duration of the interval separating the predictor from the reward rather than a difference in the influence of reward predictability on phasic and tonic DA signaling. This hypothesis was tested in rats receiving trains of rewarding electrical brain stimulation with either a predictable or unpredictable onset. The mean inter-train interval was 1.5s, a value close to the 2-s CS–US interval that has been used in electrophysiological studies demonstrating the dependence of phasic DA responses on reward predictability. Despite the shortened inter-train interval, the time courses of the observed stimulation-induced elevations in DA levels were very similar, regardless of whether train onset was predictable. This finding is consistent with the idea that tonic DA signaling is insensitive to the predictability of rewards. © 2007 Elsevier B.V. All rights reserved. Keywords: In-vivo microdialysis; Dopamine; Self-stimulation; Fixed-time schedule; Variable-time schedule; Phasic; Tonic 1. Introduction Dopamine (DA) signaling has been implicated in mul- tiple psychological processes, but general agreement about the exact nature of the dopaminergic contribution has yet to be achieved. An influential hypothesis about the function of DA signaling treats the phasic firing of DA neurons as a reward-prediction error that drives associative learning by pro- viding a weight-changing “teaching signal” [7,17,25]. Data from classical-conditioning experiments are consistent with this view: midbrain DA neurons fire upon receipt of an unpredicted reward but not upon receipt of a reward preceded by a reliable reward- predicting cue [17,24,25]. Phasic release of DA has been monitored in rats working for rewarding electrical brain stimulation. Garris et al. [11] showed that rats would not learn to self-administer electrical stimulation ∗ Corresponding author at: Center for Studies in Behavioral Neurobiology, Concordia University, Room SP-244, 7141 Sherbrooke Street West, Montreal, Quebec H4B 1R6, Canada. Tel.: +1 514 848 2424x2191; fax: +1 514 848 2817. E-mail address: peter.shizgal@concordia.ca (P. Shizgal). unless the stimulation electrode was able to trigger phasic release of DA in the nucleus accumbens (NAc) terminal field. How- ever, once the task was acquired, phasic release of DA was only seen at the beginning of the testing session and was no longer observable after a few minutes. If the DA neurons were trans- synaptically activated by the stimulation [2,3,27,28], then these observations are consistent with the prediction-error model. This model predicts that phasic DA release would be necessary to establish the contingency between lever pressing and delivery of the rewarding stimulation; as the rats learned the contingency, both the reward-prediction error and phasic DA release would decline. (This would not be the case if the DA fibers were directly activated [17].) Recent results suggest that reward predictability plays a very different role in the control of DA tone than in the control of pha- sic bursting [13,29]. Hernandez et al. [13] showed that DA tone in the NAc, estimated by means of in-vivo microdialysis, remained elevated throughout a long period of experimenter-administered, rewarding brain stimulation; similar DA levels were attained regardless of whether the delivery of the stimulation trains was predictable (one stimulation train every 12 s) or unpredictable 0166-4328/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2007.10.035