MSH/ACTH 4-10 and aging effects on delayed response performance in rats.

The present study examines the effect of MSH/ACTH 4-10 on delayed response performance (DRP) in a two choice version of the Hunter paradigm incorporating the Honzik opaque door modification. DRP was measured in male, Long-Evans rats after administration (IP) of various doses of MSH/ACTH 4-10 or control when animals were young (3 months) and aged (30 months) and aged (30 months). Between MSH/ACTH dose response observations animals received a variety of psychoactive agents of various classes prior to DRP assessment. In addition, DRP was assessed once per month, without drug, from ages 10 to 30 months. MSH/ACTH 4-10, at a dose of 95 ug/kg, significantly enhanced retention of a visual stimulus, while larger doses of MSH/ACTH 4-10 impaired delayed response performance in animals when young. Reversal of anticholinergic-induced DRP impairments by physostigmine and MSH/ACTH 4-10, but not strychnine or methylphenidate, suggests that the effect of MSH/ACTH 4-10 on DRP is specific and may be mediated by enhancement of the cholinergic system(s) in the CNS. Animals began to demonstrate significant impairment in DRP, at longer delays, at the age of 23 months. While confounds such as changes in sensory acuity, motor performance and food preference cannot be totally ignored, the assessment of performance at shorter delay periods served as a control for these problems. No significant age-related changes in DRP at shorter periods of delay were found, indicating that perception and motor capabilities played little role in age-related DRP alterations. Trend analysis revealed that animals demonstrate significant linear and quadratic MSH/ACTH 4-10 dose responses which appear as an inverted "U" in the Hunter paradigm when young. As animals age, this dose response becomes a purely positive linear relationship. Thus, the age-induced decrease in acetylcholine (ACh) levels, and hence MSH/ACTH peptide-induced release, may result in the change in MSH/ACTH dose response profiles. These findings may have clinical implications in the treatment of age-induced or Alzheimer's related cognitive pathologies, which are of cholinergic etiology.