Orbitofrontal dopaminergic dysfunction causes age-related impairment of reversal learning in rats.

Reversal learning is a domain that involves cognitive flexibility and is defined as the ability to rapidly alter established patterns of behavior when confronted with changing circumstances. This function depends critically on the orbitofrontal cortex (OFC) in the prefrontal cortical (PFC) structure, which is among the most sensitive to the influences of aging, and impaired reversal learning is a common functional disturbance of aged brain. The present study was designed to clarify the precisely neurochemical basis of this impaired learning in rats. For this purpose, we first examined reversal learning in young (3-month-old) and aged (24-month-old) rats using a T-maze discrimination task. The ability of aged rats to learn initially a reward rule for a T-maze discrimination task was almost equal to that of young rats, suggesting that simple discrimination ability was normal in aged rats. However, the ability to learn a reversed rule in a subsequent task was markedly impaired in aged rats. In addition, aged rats had reduced dopaminergic transmission concomitant with attenuated tyrosine hydroxylase (TH) activity in the OFC. Moreover, age-related impairment of reversal learning was improved by an intra-OFC infusion of 30 ng, but not 10 ng, of the D1 receptor agonist SKF 81297. Increasing dose of SKF 81297 to 100 ng also improved the impairment, but this effect was weaker than that of 30 ng, indicating that the SKF 81297 response was an inverted "U" pattern. The maximum SKF 81297 response (30 ng) was abolished by the D1 receptor antagonist SCH 23390. Thus, age-related impairment of reversal learning was due to a D1 receptor-mediated hypodopaminergic mechanism in the OFC. This finding provides direct evidence showing the involvement of OFC dopaminergic dysfunction in the development of cognitive inflexibility during the normal aging process.