Modulation of PFC Pyramidal Cell Excitability by Clonidine: A Computational Modeling Study

The prefrontal cortex (PFC) is critically involved in cognitive processes underlying working memory (WM), attention, and inhibition of responses to non-relevant stimuli (Fuster, 2000; Goldman-Rakic, 1996). In this context, catecholaminergic inputs have proven to be critical for the regulation of these cognitive processes (Levitt et al., 1984; Lewis et al., 1987; Lewis and Morrison, 1989; Porrino and Goldman-Rakic, 1982). Aston-Jones and Bloom (1981a, b) showed that, in addition to dopamine (DA) the norepinephrine (NE) neurons located in the locus coeruleus (LC) and terminating in the PFC are important in mediating selective and sustained attention and vigilance. Moreover, stimulation of the LC increases the discrimination of incoming external stimuli to the PFC by reducing the background noise, therefore enhancing the cortical signal-to-noise ratio (Aston-Jones et al., 1985; Berridge and Waterhouse, 2003; Foote et al., 1980, 1983; Waterhouse et al., 1980; Robbins, 2000). More recently, several studies have shown that adrenergic agonists, especially specific alpha-2 agonists, are very effective in enhancing WM and attention. Indeed, administration of alpha-2 agonists can ameliorate some of the negative effects on cognition produced by NE depletion due to aging in monkeys (Arnsten and Goldman-Rakic, 1985; Arnsten et al., 1988; Arnsten and Leslie, 1991) and improve performance in WM-related tasks in young monkeys with NE depletion (Arnsten and Goldman-Rakic, 1985; Cai et al., 1993). Moreover, the therapeutic effects of the specific alpha-2 agonists, clonidine and guanfacine in treating disorders related to dysfunction of WM in patients have been proved (Fields et al., 1988; Mair and McEntree 1986, 1988; Hunt et al., 1985, 1990, 1995).