The Effects of an Alpha-2 Adrenergic Agonist, Guanfacine, on rCBF in Human Cortex in Normal Controls and Subjects with Focal Epilepsy

Abstract

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 ...

Guanfacine produces differential effects in frontal cortex compared with striatum: assessed by phMRI BOLD contrast

“…Clonidine is known to have effects on feeding behaviour in rats (Sanger 1983;Tsujii and Bray 1992), and guanfacine is known to decrease food intake (Gazzola 1995). The positive BOLD responses produced by guanfacine in frontal areas are consistent with single-photon emission computed tomography (SPECT) evidence showing improved cognitive performance and increased rCBF values in the dorsolateral PFC following guanfacine administration to young adult rhesus monkeys (Avery et al 2000) and with human positron emission tomography (PET) data showing increased rCBF in frontal lobes following guanfacine administration (Swartz et al 2000). Immunohistochemistry using antibodies to the alpha-2A adrenoreceptor shows that the majority of these receptors are located post-synaptically to noradrenaline neurones in the PFC (Aoki et al 1994), and so cognitive enhancement by guanfacine may be a consequence of this effect (Avery et al 2000).…”

Dissociated mean and functional connectivity BOLD signals in visual cortex during eyes closed and fixation

“…Moreover, augmentation of cholinergic transmission sharpens the spatial spread of visually evoked BOLD responses in early retinotopic visual cortex (Silver et al 2008). Conversely, increased noradrenergic activity through stimulation of brain stem nuclei (Goadsby and Duckworth 1989), nonspecific amplification of aminergic transmission (Devous et al 2001), and use of selective noradrenergic agonists (Swartz et al 2000) is followed by decreases of CBF in both primary and extrastriate visual regions.…”

Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

“…Behavioral pharmacological studies in rodents, monkeys, and humans have demonstrated that systemically or locally administered clonidine or guanfacine could improve PFC cognitive performances (Arnsten, 1997;Arnsten et al, 1996;Arnsten and Li, 2005). Brain imaging studies have shown that systemically administered guanfacine enhances regional cerebral blood flow in the PFC in both monkeys and humans (Avery et al, 2000;Swartz et al, 2000). Most recently, Arnsten and colleague have elaborated a model explaining the beneficial effect of a 2A -AR stimulation on PFC working memory .…”