Behavioural Brain Research 156 (2005) 191–199 Research report The role of dopamine in cognitive sequence learning: evidence from Parkinson’s disease Daphna Shohamy a,* , Catherine E. Myers b , Steven Grossman a , Jacob Sage c , Mark A. Gluck a a Center for Molecular and Behavioral Neuroscience, Rutgers University, 197 University Avenue, Newark, NJ, USA b Departmentof Psychology, Rutgers University, Newark, NJ, USA c Robert Wood Johnson University Hospital, New Brunswick, NJ, USA Received 14 August 2003; received in revised form 17 May 2004; accepted 19 May 2004 Available online 28 July 2004 Abstract Electrophysiological and computational studies suggest that nigro-striatal dopamine may play an important role in learning about sequences of environmentally important stimuli, particularly when this learning is based upon step-by-step associations between stimuli, such as in second-order conditioning. If so, one would predict that disruption of the midbrain dopamine system — such as occurs in Parkinson’s disease — may lead to deficits on tasks that rely upon such learning processes. This hypothesis was tested using a “chaining” task, in which each additional link in a sequence of stimuli leading to reward is trained step-by-step, until a full sequence is learned. We further examined how medication (L-dopa) affects this type of learning. As predicted, we found that Parkinson’s patients tested ‘off’ L-dopa performed as well as controls during the first phase of this task, when required to learn a simple stimulus–response association, but were impaired at learning the full sequence of stimuli. In contrast, we found that Parkinson’s patients tested ‘on’ L-dopa performed better than those tested ‘off’, and no worse than controls, on all phases of the task. These findings suggest that the loss of dopamine that occurs in Parkinson’s disease can lead to specific learning impairments that are predicted by electrophysiological and computational studies, and that enhancing dopamine levels with L-dopa alleviates this deficit. This last result raises questions regarding the mechanisms by which midbrain dopamine modulates learning in Parkinson’s disease, and how L-dopa affects these processes. © 2004 Elsevier B.V. All rights reserved. Keywords: Dopamine; Reward; Parkinson’s disease; Memory; Cognition 1. Introduction In Parkinson’s disease (PD), patients suffer from a severe loss of dopamine in the substantia nigra pars compacta (SNc), leading to disrupted basal ganglia function and to a loss of motor control [1]. Recent evidence suggests that PD is also associated with learning and memory deficits, implicating the basal ganglia and the midbrain dopamine system in specific aspects of learning and memory function [40,33,24]. * Corresponding author. Department of Psychology, Stanford University, Jordan Hall, Bldg. 420, Stanford, California 94305, USA. Tel.: +1-650-724-9515; fax: +1-973-353-1272. E-mail address: shohamy@psych.stanford.edu (D. Shohamy). The learning and memory deficits in PD are generally characterized as deficits in procedural or habit learning [6,39,24,13]. For example, patients with PD are impaired on visuomotor sequence learning [35,21], verbal serial reaction [52], conditional association tasks [14,54,27], and probabilis- tic classification learning [24] — all tasks which are thought to rely upon procedural learning. However, a precise under- standing of the learning and memory deficits in PD remains elusive. In addition, there is currently no clear understanding of how the procedural deficits in PD relate to the underlying neuropathology of the disease. Some insight into the neural bases of learning and mem- ory deficits in PD may come from examining response pat- terns of SNc dopamine neurons during learning. A series of 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2004.05.023