According to Arnsten [53
], relatively high doses of alpha-2 agonists appear to have beneficial effects on cognitive function, although these effects may be eroded by emerging sedative and hypotensive effects. However, Arnsten et al
] and Arnsten and Leslie [54
] have shown that the ability of alpha-2 agonists to improve PFC function without side effects was found to correspond with selectivity for the alpha-2A receptor site. A comparison between the three NA alpha-2 receptors guanfacine, clonidine and BHT showed guanfacine had better selectivity than clonidine, which is more selective than BHT 920. Thus open trials [55
] have shown beneficial effects of guanfacine, including improved performance on the Continuous Performance Task [58
]. Arnsten suggests that NA-alpha-1 and NA-alpha-2 receptors may have opposing effects in the PFC, and that alpha-2 mechanisms may predominate when basal NA release is moderate, as in normal attentive wakening, and alpha-1 mechanisms may predominate under conditions of stress with higher levels of NA release. Thus alpha-2 agonists such as guanfacine may protect PFC cognitive function during stress by preventing excessive NA or DA release in the PFC [53
Easton et al
. utilised phMRI BOLD (magnetic resonance imaging) contrast to image the blood oxygenation level dependant response in rat brain regions following administration of guanfacine [59
]. They postulated that activation of alpha-2 receptors in the dorsolateral PFC by an agonist such as guanfacine might facilitate PFC neuronal activity and in turn exert an inhibitory influence on other cortical areas (such as premotor and motor areas) and/or subcortical structures (such as the striatum) that are involved in the control of locomotion. Time-course analyses of saline vs guanfacine effects were carried out, using both fixed and random effect analyses. Random effect analysis showed that guanfacine produced positive BOLD responses in frontal areas, including the frontal association and secondary motor cortex and prelimbic region of the PFC. This is consistent with single-photon emission computed tomography (SPECT) evidence, which shows improved cognitive performance and increased rCBF (cerebral blood flow) values in the dorsolateral PFC following guanfacine administration to young adult rhesus monkeys, and with human positron emission tomography (PET) data showing increased regional cerebral blood flow in frontal lobes following guanfacine administration. Positive BOLD changes also occurred in the dentate gyrus and CA1.
Guanfacine produced widespread negative BOLD effects in the caudate, putamen, nucleus accumbens and entorhinal cortex, suggesting decreased dopaminergic neuronal function in this area.
Easton et al
. interpreted their data as suggesting that guanfacine acts on the prefrontal cortex (probably post-synaptically at alpha- 2 receptors) to increase cognitive and associated functions, known to be dysfunctional in ADHD sufferers, and also helps in the regulation of locomotor activity via inhibitory control of subcortical brain regions, particularly the caudate putamen and nucleus accumbens [59
]. Thus guanfacine appeared to have the ability to 'turn down' striatal activity, possibly of benefit in the treatment of motoric hyperactivity. The investigators also demonstrated an intense positive BOLD effect in the lateral hypothalamic area, which is strongly associated with feeding behaviour, perhaps a basis of appetite or gastrointestinal side effects [60
According to Easton et al
. the alpha-2A adrenergic receptor subtype appears to be the site of action of the beneficial clinical effects of alpha-2A agonists on the prefrontal cortex (PFC) [59
]. While these receptors are localized both pre- and post- synaptically, some lines of evidence are thought to suggest that their site of action is post-synaptic in the PFC [62
]. Thus, guanfacine has been shown to dose-dependently prevent deficits of spatial working memory, suggesting a role in cognitive deficits associated with NMDA receptor hypofunction [63
]. Application of the D1
receptor agonist SKF81297 has been shown to cause a prominent increase of steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons, and up-regulation of NMDA receptor activity by dopamine D1
receptors suggests reciprocal interactions between D1
and NMDA receptors [65
Arnsten et al
. suggest that stimulants act to enhance the release of and/or inhibit the reuptake of both DA and NE (norepinephrine) [54
]. Arnsten and Dudley [66
] have shown that the PFC-enhancing effects of methylphenidate are prevented by blockade of either NE alpha-2 or DAD1 receptors, suggesting that stimulants facilitate endogenous stimulation of D1
and alpha-2A receptors in the PFC. It is thought to increase delay-related firing and strengthens the functional connectivity of microcircuits in the PFC. In children, Scahill et al
. found that immediate release guanfacine was rated significantly better than placebo by teacher-rated ADHD (37% vs 8%) and subjects performed significantly better on a Continuous Performance Test [67
Arnsten et al
. also suggest that as with DA, moderate levels of NE are critical for proper PFC function [54
]. They suggest that the majority of alpha-2 receptors are localised postsynaptically to NE terminals, and that blockade of alpha-2 receptors in the PFC of monkeys erodes delay-related cell-firing and recreates all the symptoms of ADHD, with poor impulse control, impaired working memory with underlying distractibility.
Wang et al
. have shown that spatial working memory is maintained by spatially tuned recurrent excitation within networks of prefrontal cortical neurons [68
]. They investigated monkeys performing on an oculomotor spatial delayed response, which required monkeys to make a memory-guided saccade to a visuo-spatial target. Neurons recorded from area 46 of the dorsolateral PFC were isolated and subjected to iontophonetic application of pharmacological agents. Intra-PFC administration of guanfacine was shown to significantly enhance delay-related activity for the 180° location (preferred direction) in 28 out of 35 cases. Studies indicated that suppression of cyclic AMP impaired WM performance.
Wang et al
suggest that cAMP (cyclic AMP) has powerful influences on Hyperpolarisation Activated Cyclic Nucleotide-gated (HCN) channels that pass on h current when opened [68
]. They are localised on distal pyramidal dendrites and according to the authors, are co-expressed with the alpha-2A adrenoreceptor, thus providing a potent substratum for functional integration in the primate PFC. In electrophysiological studies with alpha-2A adrenoreceptor stimulation or cAMP inhibition, HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Exposure to uncontrollable stress via excessive catecholamine release, high levels of D1
receptor stimulation, or by activating cAMP, has been shown to impair working memory. Under these conditions, the PFC is functionally disconnected rendering it "decorticate". The process may be exacerbated in patients with aberrant genes that regulate cAMP signaling e.g. COMT [69
]. This co-localisation of cAMP, HCN channels and D1
excess stimulation effects may help to explain the cross-talk between DA and NE receptors in the PFC discussed below.
Vijayraghavan et al
. showed that dopamine D1
receptor stimulation in PFC produced an 'inverted-U' dose-response, whereby either too little or too much D1
receptor stimulation impaired spatial working memory [69
]. This response has been observed across species, including genetic linkages with human cognitive abilities, PFC activation states and DA synthesis. According to the authors the cellular basis for the inverted U has long been sought, with in vitro intracellular recordings supporting a variety of potential mechanisms. Their study demonstrated that the D1
receptor agonist inverted-U response was observed in PFC neurons of behaving monkeys: low levels of D1
receptor stimulation enhanced spatial tuning by suppressing responses to non-preferred directions, whereas high levels reduced delay-related firing for all directions, eroding tuning. These actions of D1
receptor stimulation were mediated in monkeys and rats by cyclic AMP intracellular signaling. The evidence for an inverted-U at the cellular level in behaving animals promised to bridge in vitro molecular analyses with human cognitive experience.
Arnsten et al
. have described three different subtypes of alpha-2 adrenoreceptors in humans, the alpha-2A alpha-2B and alpha-2C subtypes [54
]. The alpha-2A and alpha-2C subtypes are widely distributed in the brain, including the PFC, the alpha-2B receptor is most concentrated in the thalamus. Guanfacine is thought to be the most selective agonist available for the alpha-2A subtype [70
]. On the other hand the sedating effects of clonidine are thought to involve the thalamus, basal forebrain and other alpha-2B and alpha-2C effects. Atomoxetine, which also has sedating effects in some children, may also have alpha-2B and/or alpha-2C effects [48
A recent study by Chamberlain et al
. suggested that NE is more sensitive in modulating lateral compared to orbital PFC functioning [71
]. They showed that atomoxetine (60 mg single dose) improved response inhibition on a stop- signal task, but had no effect on a task requiring probabilistic learning. On the other hand administration of citalopram (30 mg single dose) impaired probabilistic learning with no effect on response inhibition. The authors concluded that finding that atomoxetine improved response inhibition in healthy volunteers implicated ascending noradrenergic systems in its control, whereas the role of 5-HT in probabilistic learning might operate according to an inverted-U function.