Noradrenergic influences on prefrontal cortical cognitive function: opposing actions at postjunctional alpha 1 versus alpha 2-adrenergic receptors.
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Biomedical subjects
Publications and source records attributed to J C Steere.
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Administration of either low or high doses of the alpha-2A adrenergic agonist guanfacine (GFC) to aged monkeys has been shown to improve performance of the delayed-response task, a task linked to the dorsolateral prefrontal cortex (dlPFC). Monkeys treated with higher guanfacine doses also appeared less disinhibited, suggesting enhanced ventromedial-orbital PFC (vmPFC) function. To test this hypothesis, the current study examined the effects of low versus high doses of GFC on reversal of a visual object discrimination task, a task particularly sensitive to vmPFC lesions. The results of this study showed that high (0.1 mg/kg) but not low (0.00001-0.001 mg/kg) doses of GFC significantly improved reversal performance in aged monkeys. These results may be relevant to GFC's calming effects in attention deficit hyperactivity disorder.
This article aims to review research in nonhuman primates demonstrating that norepinephrine can enhance the cognitive functioning of the prefrontal cortex through actions at alpha 2 A-adrenergic receptors postjunctional to noradrenergic terminals. As prefrontal cortex cognitive deficits are prominent in several psychiatric disorders, including attention-deficit hyperactivity disorder, these basic findings may have relevance for the development of novel pharmacotherapies.
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The D2 dopamine (DA) receptor agonist, quinpirole, was characterized in young adult monkeys, young reserpine-treated monkeys and aged monkeys to assess the contribution of DA to age-related loss of prefrontal cortical (PFC) cognitive function. Monkeys were tested on a delayed response memory task that depends on the PFC, and a fine motor task that taps the functions of the motor cortex. In young adult monkeys, low quinpirole doses impaired performance of the PFC and fine motor tasks, while higher doses improved memory performance and induced dyskinesias and "hallucinatory-like" behaviors. The pattern of the quinpirole response in reserpine-treated monkeys suggested that the impairments in delayed response and fine motor performance resulted from drug actions at D2 autoreceptors, while the improvement in delayed response performance, dyskinesias and "hallucinatory-like" behaviors resulted from actions at postsynaptic receptors. In aged monkeys, low doses of quinpirole continued to impair fine motor performance, but lost their ability to impair delayed response performance. The magnitude of cognitive improvement and the incidence of "hallucinatory-like" behaviors were also reduced in the aged animals, suggesting some loss of postsynaptic D2 receptor function. The pattern of results is consistent with the greater loss of DA from the PFC than from motor areas in aged monkey brain (Goldman-Rakic and Brown, 1981; Wenk et al., 1989), and indicates that DA depletion contributes significantly to age-related cognitive decline.