The effects of low dose MK-801 administration on NMDA_R dependent executive functions in pigeons

An avian analogue of human fronto-executive dysfunction was used to study the long-term effects of a repeated low dose of MK-801. MK-801 is known to selectively antagonize the excitatory N-methyl-d-aspartate receptors (NMDA_R) and indirectly impair inhibitory related processes (GABA-_AR). First, eight pigeons were divided into two groups, receiving either 0.15mg/kg MK-801 or saline (i.p.) 1-hour prior to each session. Thirty 90-min sessions of a Differential Reinforcement of Low Rate of Response (DRL-10s) schedule were run over 3-months. Both overall number of responses and efficiency were unaffected by treatment, establishing a sub-threshold motoric dose. Then, another eight pigeons, treated identically, were given an operant visual discrimination task. Results demonstrated impairment of the fronto-striatal function of both excitatory and inhibitory processes in the MK-801 group during the entire 3-months. A 30-session treatment cross-over showed that the Saline-to-MK-801 group was unaffected, whereas the MK-801-to-Saline group exhibited rapid recovery of inhibitory control, however excitatory control did not fully recover. Together, these results suggested that the NMDA_R system is involved in the acquisition of excitatory learning, but only in the expression of inhibitory learning. Our findings were discussed in terms of the value of avian models in translational research. Furthermore, our results were examined within the context of the NIH Research Domain of Criteria initiative and the role of NMDA_R disruption, which underlie executive dysfunction in various neuropsychiatric disorders. Finally, our findings suggested that the potential long-term effects of the clinical and recreational use of NMDA_R antagonists require further study.