Alpha-2 agonist studies
The noradrenergic system is thought to be modulatory in exciting or inhibiting target cells. Moderate levels of NA are thought to act on alpha-2A adrenoreceptors coupled with Gi proteins to inhibit cyclic adenosine monophosphate signaling, whereas higher levels released during stress activate lower-affinity β1 adrenoreceptors.3 According to Arnsten,3 NA is crucial for many PFC functions such as working memory, attention, planning, and behavioral inhibition. A useful study in relation to inverted-U effects was reported by Gamo et al.8 The study examined the effects of both MPH and atomoxetine (ATM) on PFC function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. Monkeys performed a working memory task after administration of a wide range of MPH or ATM doses, and optimal doses were challenged with the alpha-2 adrenoreceptor antagonist, indoxan, or the D1 dopamine receptor antagonist, SCH 23390. Also, in a parallel physiological study, neurons were recorded from the dorsolateral PFC of a monkey performing a working memory task, whereas ATM, SCH 23390, or the alpha-2 antagonist yohimbine was applied to the neurons by iontophoresis. The results indicated that both MPH and ATM generally produced inverted-U dose–response curves, with improvements at moderate doses, but not at higher doses, and that these effects were shown to be blocked by indoxan or SCH 23390, respectively.
Kim et al investigated the relationship between measures of attention (reaction time variability, visual and auditory selective attention tests, Flanker interference task, and an impulsivity task) and polymorphisms in the alpha-2A-adrenergic receptor and the norepinephrine receptor (SLC6A2) in children administered MPH osmotic release oral system (OROS) for 12 weeks.27 The authors pointed out that although the primary mode of action of MPH in ADHD was thought to be blockade of the DAT, evidence from animal studies demonstrated that MPH might also inhibit the NA transporter.28 Kim et al27 found that increasing amounts of an A-allele at the G1287A polymorphism of SLC6A2 was significantly related to greater response time variability at baseline in the sustained and auditory selective tests, whereas the response time variability at baseline increased additively with possession of the T allele at the Dral polymorphism of the alpha-2A-adrenergic receptor gene in the auditory selective task. The investigators found that increasing possession of a G-allele at the Mspi polymorphism of the alpha-2A-adrenergic receptor gene after taking medication was associated with an increased MPH-related change in response time variability in the Flanker task. These results suggested an association between norepinephrine gene variants and response time variability at baseline and after MPH treatment in ADHD children. The authors pointed to growing evidence for central noradrenergic dysregulation in the pathophysiology of ADHD, suggesting that allelic variation in the alpha-2 adrenergic receptor gene located on chromosome 10q24-26 or the norepinephrine transporter gene (SLC6A2) located on chromosome 16q12.2 might confer genetic risk for ADHD. They also suggested that response time variability is a “viable endophenotype” for ADHD and treatment response.
According to Arnsten,3 alpha 2A agonists enhance delay-related cell firing, whereas D1 receptor stimulation suppresses “noise,” so these receptors act synchronously with each other at optimal catecholamine levels. Either excessive or insufficient catecholamine receptor stimulation can markedly impair PFC function.3 The beneficial effects of alpha-2A versus D1 are thought to arise from opposing effects on cyclic adenosine monophosphate signaling, where alpha-2A stimulation inhibits and D1 activates cyclic adenosine monophosphate production. Moderate levels of D1 receptor stimulation are believed to lead to the opening of hyperpolarization-activated cyclic nucleotide-gated channels on spines receiving inputs from neurons with dissimilar spatial properties, reducing delay-related firing to nonpreferred directions, whereas alpha-2A adrenoreceptor stimulation is thought to result in the closure of hyperpolarization-activated cyclic nucleotide-gated channels on spines receiving inputs from neurons with similar spatial properties, possibly increasing firing during delay periods for preferred directions.10 This selective process allows a particular spatial representation in the PFC that is important for working memory, as well as guidance of action. Importantly, the modulation of dopamine/NA functions involved in working memory at cortical levels depend on dopamine/NA synchronicity, as distinct from subcortical motor sequencing modulation by D1/D2 balance. It should be noted that although working memory effects at the PFC differ from subcortical motor effects, both are modulated via dopaminergic mechanisms, although the former modulation also requires noradrenergic effects. These differences may have implications for the phenomenology of stimulant versus noradrenergic therapies, as well as for adverse effect profiles.