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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH011303-03
Application #
2519692
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1997-09-01
Project End
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520