The selective 5-HT(1A) 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 HT(1A) 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 3micromol/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 (2.63micromol/kg s.c.). Moreover, the ACh levels in the FC increased even after repeated (14days) 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 (3micromol/kg s.c.) or local (100microM) administration. The present data support the hypothesis that cholinergic transmission in cortico-limbic regions can be enhanced via blockade of postsynaptic 5-HT(1A) receptors, which may underlie the proposed cognitive enhancing properties of NAD-299 in models characterized by cholinergic deficit.
Kehr
Jan
J
Department of Neuroscience, Retzius väg 8, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Jan.Kehr@ki.se
Hu
Xiao-Jing
XJ
Yoshitake
Takashi
T
Wang
Fu-Hua
FH
Osborne
Peter
P
Stenfors
Carina
C
Ogren
Sven Ove
SO
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001578:Benzopyrans / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D009388:Neostigmine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014851:Wakefulness
D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D009388:Neostigmine; D018698:Glutamic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000077265:Donepezil; C108607:robalzotan; D000109:Acetylcholine