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بخشی از مقاله انگلیسیعنوان انگلیسی:Supranormal Stimulation of D1 Dopamine Receptors in the Rodent Prefrontal Cortex Impairs Spatial Working Memory Performance~~en~~

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, 1996a,b, 1997). In particular, these studies have suggested that supranormal stimulation of D1 receptors may contribute to the detrimental actions of DA in the PFC (Murphy et al., 1994, 1996a). The current study directly tested this hypothesis by examining the effects of infusing a full D1 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 D1 receptor antagonist, SCH 23390, consistent with drug actions at D1 receptors. SCH 23390 by itself had no effect on performance, although slightly higher doses impaired performance (Murphy et al., 1994, 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 D1 receptor stimulation in the PFC is sufficient to impair PFC working memory function. These cognitive data are consistent with recent electrophysiological studies of D1 receptor mechanisms affecting the PFC (Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996). Increased D1 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 powerful 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 D1 DA receptor mechanisms in this response. Infusions of the D1 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 infusions of D2 DA receptor antagonists were without effect. A similar pattern of response was observed after systemic administration of the D1 receptor antagonist SCH 23390 in young adult monkeys (Arnsten et al., 1994), indicating that the impairments after intracortical infusions were not simply the result of local anesthetic actions but rather drug actions at D1 receptors. The importance of D1 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 D1 receptor mechanisms in the PFC, more recent studies suggest an inverted “U” relationship whereby excessive as well as insufficient D1 DA receptor stimulation impairs PFC cognitive function (Arnsten and Goldman-Rakic, 1986, 1990; Arnsten et al., 1994; Murphy et al., 1994, 1996a,b, 1997; Williams and Goldman-Rakic, 1995; Verma and Moghaddam, 1996). Biochemical studies 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, 1996a, 1997). Cognitive impairment in rodents correlated with increased DA turnover in the PFC (Murphy et al., 1994, 1996a), consistent with a hyperdopaminergic mechanism. The efficacy of the selective D1 receptor antagonist SCH 23390 in this paradigm suggests that excessive D1 DA receptor stimulation may underlie the PFC deficits induced by stress. Consistent with this hypothesis, systemic administration of D1 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 D1 receptor mechanism (Arnsten et al., 1994; Cai and Arnsten, 1997).

Although these studies suggest that excessive DA D1 receptor stimulation impairs PFC cognitive function, the results are not conclusive. For example, studies of D1 agonists in monkeys (Arnsten et al., 1994; Cai and Arnsten, 1997) used systemic adminis tration, and thus conclusions cannot be drawn regarding actions in the PFC. Stress has widespread effects in the nervous system and, even within the PFC, alters the release of many neurotransmitters (e.g., norepinephrine) in addition to DA (e.g., Goldstein et al., 1996). Thus it is not known whether increased DA receptor stimulation in the PFC is sufficient to produce PFC cognitive deficits. In particular, a role for D1 receptor mechanisms was not supported in a recent study that used the noncompetitive NMDA receptor antagonist ketamine to increase DA release in the PFC in rats (Verma and Moghaddam, 1996). Ketamine induced delayed-alternation deficits that were reversed by D2 , but not D1 , receptor antagonists (Verma and Moghaddam, 1996).

The current study directly tested the hypothesis that supranormal D1 receptor stimulation in the PFC is sufficient to impair the spatial working memory functions of the PFC. These experiments used SKF 81297, a full D1 receptor agonist (activity comparable with DA itself; Andersen and Jansen, 1990). Rats were tested on the delayed-alternation task, the test of spatial working memory most associated with the PFC in rodents (Larsen and Divac, 1978; van Haaren et al., 1985). Experiment 1 examined the effects of intra-PFC infusions of SKF 81297 on delayed-alternation performance. In experiment 2, the role of D1 receptor mechanisms was confirmed by blocking the SKF 81297 response with the D1 receptor antagonist SCH 23390. Finally, the efficacy of the SKF 81297 response was related to anatomical localization of the cannulae and to the delay intervals used during delayedalternation testing.

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