This study assessed whether dopamine in the dorsomedial striatum is necessary for flexible adaptation to changes in stimulus–response contingencies. As KW-6002 (Istradefylline), an adenosine A2A antagonist, improves motor deficits resulting from striatal dopamine depletion, we also tested for potential ameliorative effects of KW-6002 on dopamine depletion-induced cognitive deficits. Male Lister hooded rats were presented with two bowls, discriminable by either a textured covering on the outer surface, their scent or the bowl contents (digging media) in which bait was buried. Once they had learned in which bowl food was buried, the stimulus–response contingencies were reversed. In both phases (acquisition and reversal), the criterion for learning was defined a priori as six consecutive correct trials. Following depletion of dopamine in the dorsomedial striatum, acquisition of the discriminations was intact but there was an increase in the number of trials to attain criterion performance in the reversal phases, indicating an impairment in reversal learning. KW-6002 (1 mg/kg bidaily for 10 days) non-specifically increased the number of trials to criterion at all stages of the test and in both controls (sham-operated) and dopamine-depleted rats. Chronic KW-6002 treatment did not improve the reversal deficits in dopamine-depleted rats. These findings suggest that dopamine transmission in the dorsomedial striatum is critical for the flexible shifting of response patterns and the ameliorative effects of KW-6002 following depletion of dopamine in the striatum may be restricted to motor functions without relieving deficits in response-shifting flexibility.
Accumulating evidence suggests that animals with lesions of the dorsolateral striatum are impaired in learning tasks that require formation of stimulus–response associations (Adams et al., 2001, Featherstone and McDonald, 2004a, Featherstone and McDonald, 2004b, Featherstone and McDonald, 2005, Kantak et al., 2001, McDonald and Hong, 2004, McDonald and White, 1993, McDonald and White, 1994, Reading et al., 1991, White, 1989 and White and McDonald, 2002). In contrast to the dorsolateral striatum, the dorsomedial striatum does not appear to play a critical role in the initial formation of stimulus–response associations. Inactivation of the dorsomedial striatum does however impair the ability of animals to flexibly adapt their response patterns when stimulus–response contingencies change (Kirkby, 1969, Kolb, 1977, Pisa and Cyr, 1990, Ragozzino and Choi, 2004 and Ragozzino et al., 2002).
