In studies on aged and brain-lesioned rats the chronic administration of the ACTH(4–9) analog Org2766 has been demonstrated to improve the behavioral performance. Those results suggest that maintenance of hippocampal functioning in senescence and facilitation of functional recovery after brain damage are not due to facilitated reinnervation of denervated structures as suggested in previous studies concerning regeneration of the PNS. Alternative explanations may refer to either the neuroprotective properties of the peptide as demonstrated when chronic treatment immediately follows the damage, or a peptide-induced general change in attention that indirectly may contribute to functional recovery. The behavioral effects after acute treatment with ACTH-like peptides have been previously associated with sustained attention by enhanced neuronal excitability of limbic structures. Now, a hypothesis accounting for both neuroprotection and enhanced attention is forwarded by supposing that the peptide exerts its influence by modulation of NMDA receptor activation. Therefore, the acute effects and interactions between the peptide and the NMDA receptor antagonist AP5 (D,L-2-amino-5-phosphonopentanoic acid), and the peptide and NMDA were studied in a water maze and an open field. Impaired water maze performance induced by an acute intracerebroventricular administration of AP5 was counteracted by the ACTH(4–9) analog Org2766, whereas the peptide alone did not affect spatial orientation. NMDA induced extreme locomotor activity at the periphery of the open field. Interestingly, the ACTH(4–9) analog strongly suppressed NMDA-induced enhanced locomotor activity and normalized the pattern of exploratory behavior.