Dysfunction of the prefrontal cortex (PFC) is implicated in many human cognitive disorders. One of these is Attention Deficit Hyperactivity Disorder (ADHD), affecting 3-5% of children in the USA. The alpha-2 adrenergic agonist clonidine has improved attention regulation in these patients, but accompanying sedation and hypotension have seriously limited its clinical usefulness. The discovery of three cloned alpha-2 subtypes in primates (A,B and C) suggests the possibility for dissociation of cognitive enhancing versus sedating actions. Research in aged monkeys supports this possibility: alpha-2 agonists improve the cognitive functions of the PFC, and alpha-2A mechanism for cognitive enhancement.
The aim of the proposed research is to further elucidate receptor mechanisms involved in the cognitive enhancing effects of alpha- 2 agonists in young monkeys. Acute drug effects on cognitive performance and sedation will be characterized using two tasks: one PFC-dependent, spatial delayed response, and one control, visual discrimination. alpha- 2 Agonists (clonidine-alpha-2 non- selective, guanfacine-alpha-2A selective), and selective antagonists (BRL44408: alpha-2A, imiloxan: alpha-2B, MK912: alpha-2C) will be used to examine subtype-related effects. It is hypothesized that PFC cognitive function will be enhanced via an alpha-2A mechanism, while sedative effects will be mediated by alpha-2B receptors, which are primarily in the thalamus. Functional SPECT imaging will address the hypothesis that alpha-2A stimulation increases blood flow preferentially in the PFC. This research may direct development of more selective compounds for effective treatment of cognitive disorders such as ADHD.
