The selective 5-HT1A receptor antagonist NAD-299 increases acetylcholine release but not extracellular glutamate levels in the frontal cortex and hippocampus of awake rat

The effects of the HT1A receptor antagonist NAD-299 on extracellular acetylcholine (ACh) and glutamate (Glu) levels in the frontal cortex (FC) and ventral hippocampus (HPC) of the awake rats were investigated by the use of in vivo microdialysis. Systemic administration of NAD-299 (0.3; 1 and 3 µmol/kg s.c.) caused a dose-dependent increase in ACh levels in FC and HPC (peak value of 209% and 221%, respectively) and this effect was comparable to that induced by donepezil (2.63 µmol/kg s.c.). Moreover, the ACh levels in the FC increased even after repeated (14 days) treatment with NAD-299 and when NAD-299 was injected locally into the nucleus basalis magnocellularis or perfused through the microdialysis probe implanted in the cortex. In contrast, NAD-299 failed to alter the extracellular levels of glutamate after systemic (3 µmol/kg s.c.) or local (100 µM) administration. The present data support the hypothesis that cholinergic transmission in cortico-limbic regions can be enhanced via blockade of postsynaptic 5-HT1A receptors, which may underlie the proposed cognitive enhancing properties of NAD-299 in models characterized by cholinergic deficit.