In two experiments including a total of 30 irritable bowel syndrome patients, symptom-mimicking rectal pressure stimuli elicited changes in regional neural activation as measured by positron electron tomography (PET) cerebral blood flow images. Although most stimuli were not rated as painful, rectal pressure increased regional cerebral blood flow (rCBF) in areas commonly associated with somatic pain, including the anterior cingulate, insula, prefrontal cortex, thalamus, and cerebellum. Despite similar stimulus ratings in male and female patients, regional activations were much stronger for males. In both experiments, rectal pressure activated the insula bilaterally in males but not in females. Insula activation was associated most strongly with objective visceral pressure, whereas anterior cingulate activation was associated more with correlated ratings of subjective discomfort. The insula is discussed as a visceral sensory cortex. Several possible reasons for the insula gender effect are proposed.

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Alpha-2 noradrenergic agonists may have wide applicability in the treatment of pre-frontal cortex deficits in primates and behavioral dysfunction in man. We have undertaken this study to determine the effect of an alpha-2 agonist, guanfacine, on regional cerebral blood flow (rCBF) in humans. Three subject groups were evaluated: normal controls, subjects with frontal lobe epilepsy (FLE), and subjects with temporal lobe epilepsy (TLE). All underwent a number of PET scans using 15 O-water, with A growing body of evidence has established that norepinephrine (NE) plays an important role in the performance of cognitive functions in a variety of species (Stein et al. 1975;Oke and Adams 1978;McEntee and Mair 1980;Carli et al. 1983;McGaugh et al. 1984;Leslie et al. 1985). Aged monkeys and young monkeys with either surgical ablations or toxin-induced catecholamine depletion in the prefrontal region (principal sulcus) are unable to perform delayed-response tasks (Bartus et al. 1978;Goldman and Rosvold 1979;Brozoski et al. 1979). Arnsten and colleagues studied rhesus monkeys from 17 to over 30 years in age, and found improved baseline performance on a spatial delayed non-match to sample task following a single dose of the alpha-2 agonist, clonidine (Arnsten and Goldman-Rakic 1985). There were both dose and interval NO . 3 (delay) interactions, with greater effects observed as the delay was lengthened. Yohimbine, an alpha-2-antagonist, blocked the effect while neither beta nor alpha-1 antagonists did. A later study showed that guanfacine, an alpha-2A agonist, was 10-1000 times more potent than clonidine in this effect (Arnsten et al. 1988).The alpha-2A adrenergic receptor subtype appears to be the site of action of the beneficial effects of alpha-2 agonists on prefrontal cortex (PFC) function (reviewed in Arnsten et al. 1996;Arnsten 1998). Alpha-2A receptors are localized both pre-and post-synaptically, but several lines of evidence suggest that the site of action is post-synaptic in PFC (Arnsten and Goldman-Rakic 1985;Cai et al. 1993). Their effects on working memory are more pronounced in animals with cell loss or catecholamine depletion, being found at low concentrations in old or depleted monkeys but only at high concentrations in young intact monkeys (Franowicz and Arnsten 1998;Arnsten and Goldman-Rakic 1985 1990;Cai et al. 1993). Stimulation of the locus coeruleus produces a largely inhibitory effect on cortical neurons, whereas a presynaptic action would be expected to produce disinhibition through reduced NE release (Langer 1974). Iontophoresis of the alpha-2 antagonist, yohimbine in monkey PFC neurons suppresses delay-related cellular activity during working memory tasks (Li and Kubota 1998; Sawaguchi 1998). Systemic clonidine enhances this delay-related activity, and this enhancement is reversed by iontophoresis of yohimbine in PFC.Efficacy has also been found with clonidine in an object working memory paradigm, a function believed to rely on ventral prefrontal regions (Jackson and Buccafusco 1991). High ...

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