The Effects of Dopamine D1 Receptor Blockade in the Prelimbic–Infralimbic Areas on Behavioral Flexibility

There is accumulating evidence that separate prefrontal cortex regions influence distinct cognitive functions (Kolb et al. 1974; Eichenbaum et al. 1983; Seamans et al. 1995; Delatour and Gisquet-Verrier 1996, 1999, 2000; Goldman-Rakic 1996; Kesner et al. 1996; Petrides 1996; Bussey et al. 1997; DeCoteau et al. 1997; Ragozzino et al. 1998, 1999b; Gisquet-Verrier et al. 2000; Kesner 2000; Ragozzino and Kesner 2001). Experiments in nonhuman primates have shown that different prefrontal cortex areas contribute to separate forms of cognitive flexibility (Dias et al. 1996, 1997). Lesions of the lateral prefrontal cortex produce a selective impairment in extra-dimensional shifts for a visual-cue discrimination task (e.g., learning to make a choice based on shape, then learning to make a choice based on lines). However, lateral prefrontal cortex lesions do not impair reversal learning (e.g., learning to always choose a red object but not a blue object, then learning to choose the opposite colored object). Conversely, lesions of the orbital prefrontal cortex impair reversal learning but not extra-dimensional shifts (Dias et al. 1996, 1997). Taken together, the evidence suggests that the lateral prefrontal cortex and orbital prefrontal cortex regions differentially contribute to cognitive flexibility based on the type of task demands. The findings from several studies in rodents suggest that the medial prefrontal cortex plays a critical role in behavioral flexibility (deBruin et al. 1994; Aggleton et al. 1995; Granon and Poucet 1995; Bussey et al. 1997; Joel et al. 1997; Ragozzino et al. 1999a,b; Birrell and Brown 2000; Delatour and Gisquet-Verrier 2000; Dias and Aggleton 2000). Recently, a series of experiments found that temporary inactivation or lesions of the prelimbic–infralimbic areas impairs extra-dimensional shifts in discrimination tasks that require the use of different attribute information (Ragozzino et al. 1999a,b; Birrell and Brown 2000). In contrast, prelimbic–infralimbic inactivation or lesions do not impair acquisition or reversal learning of different two-choice discriminations (Ragozzino et al. 1999a,b; Birrell and Brown 2000; Chudasama et al. 2001), suggesting that these prefrontal cortex subregions are selectively involved in behavioral flexibility requiring shifts between different attributes or dimensions. At present it is unclear what neurochemical mechanisms within the prelimbic–infralimbic subregions enable behavioral flexibility. One neurotransmitter in these prefrontal cortex areas that may contribute to behavioral flexibility is dopamine. The prelimbic–infralimbic areas receive a dopaminergic input from the ventral tegmental area where dopamine neurons synapse on both pyramidal cells and interneurons (Descarries et al. 1987; Van Eden et al. 1987; Carr and Sesack 2000). Voltammetric recordings of dopamine from the prelimbic and infralimbic subregions indicate that dopamine release reliably increases or decreases when reinforcement contingencies are unexpectedly changed in the rat (Richardson and Gratton 1998). In vivo microdialysis studies have revealed that dopamine overflow increases when rats are exposed to novel conditions (Feenstra et al. 1995; Wilkinson et al. 1998). Furthermore, 6-OHDA lesions of the medial prefrontal cortex, including the prelimbic, infralimbic, and medial orbital areas, do not impair acquisition of fear conditioning but do impair extinction of fear conditioning (Morrow et al. 1999). Moreover, dopamine modifies certain forms of synaptic plasticity in the medial prefrontal cortex that may underlie learning and other cognitive functions (i.e., behavioral flexibility; Otani et al. 1998). These studies using a variety of approaches suggest that the dopamine signal may be a key component in modulating activity in the prelimbic–infralimbic areas to facilitate behavioral flexibility. The dopamine D1 receptor in the prefrontal cortex, in particular, may be critical for mediating dopamine effects on cognitive functioning. Blockade of dopamine D1 receptors in the primate dorsolateral prefrontal cortex, in a dose-dependent manner, may enhance or reduce delay period unit activity during a working-memory task (Williams and Goldman-Rakic 1995). In a comparable fashion, previous investigations have shown that either blockade or superfluous stimulation of dopamine D1 receptors in the prelimbic area impairs working memory (Zahrt et al. 1997; Seamans et al. 1998). This raises the possibility that an optimal level of dopamine D1 receptor activation in prelimbic–infralimbic areas may be important for cognitive functioning (Williams and Goldman-Rakic 1995). To test whether dopamine D1 receptors are critical for behavioral flexibility, our experiments examined the effects of SCH23390, a dopamine D1 antagonist, injected into the prelimbic–infralimbic areas on the acquisition and shift between response and visual-cue discrimination tests.