Supranormal Stimulation of D1Dopamine Receptors in the Rodent Prefrontal Cortex Impairs Spatial Working Memory Performance

Justin Zahrt, Jane R. Taylor, Rex G. Mathew, Amy F. T. Arnsten
1997 Journal of Neuroscience  
Although previous research has emphasized the beneficial effects of dopamine (DA) on functions of the prefrontal cortex (PFC), recent studies of animals exposed to mild stress indicate that excessive DA receptor stimulation may be detrimental to the spatial working memory functions of the PFC (Arnsten and Goldman- Rakic, 1990; Murphy et al., 1994 Murphy et al., , 1996a Murphy et al., ,b, 1997. In particular, these studies have suggested that supranormal stimulation of D 1 receptors may
more » ... e to the detrimental actions of DA in the PFC (Murphy et al., , 1996a . The current study directly tested this hypothesis by examining the effects of infusing a full D 1 receptor agonist, SKF 81297, into the PFC of rats performing a spatial working memory task, delayed alternation. SKF 81297 produced a dose-related impairment in delayed-alternation performance. The impairment was reversed by pretreatment with a D 1 receptor antagonist, SCH 23390, consistent with drug actions at D 1 receptors. SCH 23390 by itself had no effect on performance, although slightly higher doses impaired performance (Murphy et al., , 1996a . There was a significant relationship between infusion location and drug efficacy; animals with cannulae anterior to the PFC were not impaired by SKF 81297 infusions. Taken together, these results demonstrate that supranormal D 1 receptor stimulation in the PFC is sufficient to impair PFC working memory function. These cognitive data are consistent with recent electrophysiological studies of D 1 receptor mechanisms affecting the PFC (Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996) . Increased D 1 receptor stimulation during stress may serve to take the PFC "off-line" to allow posterior cortical and subcortical structures to regulate behavior, but may contribute to the vulnerability of the PFC in many neuropsychiatric disorders. For many years it has been appreciated that dopamine (DA) has a powerf ul beneficial influence on the spatial working memory functions of the prefrontal cortex (PFC) in monkeys (Brozoski et al., 1979) and rats (Simon, 1981; Bubser and Schmidt, 1990) . Later studies identified the importance of D 1 DA receptor mechanisms in this response. Inf usions of the D 1 receptor antagonists SCH 23390 or SCH 39166 into the PFC of monkeys (Sawaguchi and Goldman-Rakic, 1991) or rats (Seamans et al., 1995) produced a delay-related impairment in spatial working memory performance, whereas comparable inf usions of D 2 DA receptor antagonists were without effect. A similar pattern of response was observed after systemic administration of the D 1 receptor antagonist SCH 23390 in young adult monkeys , indicating that the impairments after intracortical infusions were not simply the result of local anesthetic actions but rather drug actions at D 1 receptors. The importance of D 1 receptor mechanisms has been corroborated by electrophysiological studies of PFC pyramidal cells in monkeys (Sawaguchi et al., 1988; Sawaguchi and Kubota, 1996) and rats (Yang and Seamans, 1996) . This basic research has had a major impact on theories of PFC dysfunction in schizophrenia and other disorders that may involve altered DA transmission (Daniel et al., 1991; Davis et al., 1991; Grace, 1993) . Although there is a body of work upholding the beneficial influence of D 1 receptor mechanisms in the PFC, more recent studies suggest an inverted "U" relationship whereby excessive as well as insufficient D 1 DA receptor stimulation impairs PFC cognitive function (Arnsten and Goldmanstudies in rodents have shown that mild stressors preferentially increase DA turnover in the PFC compared with other DA terminal fields (Thierry et al., 1976; for review, see Deutch and Roth, 1990). Mild stress exposure in monkeys or rats produced working memory deficits that could be blocked by agents that prevent the rise in DA turnover in rodents (Arnsten and Goldman-Rakic, 1986; Murphy et al., 1996b) or that block DA receptors (i.e., haloperidol, SCH 23390, or clozapine; Arnsten and Goldman- Rakic, 1990; Murphy et al., 1994 Murphy et al., , 1996a Murphy et al., , 1997. Cognitive impairment in rodents correlated with increased DA turnover in the PFC (Murphy et al., , 1996a , consistent with a hyperdopaminergic mechanism. The efficacy of the selective D 1 receptor antagonist SCH 23390 in this paradigm suggests that excessive D 1 DA receptor stimulation may underlie the PFC deficits induced by stress. Consistent with this hypothesis, systemic administration of D 1 receptor agonists (dihydrexidine, SKF 81297, and A 77636) to aged monkeys produces inverted Ushaped dose-response curves, with higher doses impairing delayed-response performance through a D 1 receptor mechanism Cai and Arnsten, 1997) . Although these studies suggest that excessive DA D 1 receptor stimulation impairs PFC cognitive function, the results are not conclusive. For example, studies of D 1 agonists in monkeys (Arnsten et al., 1994; Cai and Arnsten, 1997) used systemic adminis-
doi:10.1523/jneurosci.17-21-08528.1997 pmid:9334425 fatcat:uiis3mlbszdsxglq65a4dsbuw4