FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, restores the regional cerebral blood flow response abolished by scopolamine but not by HA-966: a positron emission tomography study with unanesthetized rhesus monkeys.
The interactions of FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, with cholinergic and glutamatergic neuronal systems were evaluated with respect to its effects on the regional cerebral blood flow (rCBF) response to vibrotactile stimulation in unanesthetized rhesus monkeys with [15O]H2O and high resolution positron emission tomography (PET). Under a saline condition, the vibrotactile stimulation given on the right forepaw induced a significant increase in the rCBF response in the contralateral somatosensory cortex of the monkey brain. Systemic administration of scopolamine (50 microg/kg, i.v.), a muscarinic cholinergic receptor antagonist, completely abolished the rCBF response to the stimulation, and the abolishment lasted, at least, up to 4 h after scopolamine injection. The scopolamine-induced abolishment of rCBF response was restored by the administration of FK960 at relatively wide dosing range from 1 to 1000 microg/kg (i.v. ), and the recovery by FK960 on the rCBF response lasted for 1 h following the administration of FK960 at doses of 100 and 1000 microg/kg. On the other hand, the rCBF response abolished by 1000 microg/kg of (+)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), an antagonist of the glycine modulatory site on the N-methyl-d-aspartate (NMDA) receptors, was not restored by FK960 (1000 microg/kg, i.v.). These findings suggest that FK960 reverses the abolished rCBF response to somatosensory stimulation via enhancement of cholinergic neurotransmission but not via the glutamatergic one.
Tsukada
H
H
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka 434-8601, Japan.
Yamazaki
S
S
Noda
A
A
Inoue
T
T
Matsuoka
N
N
Kakiuchi
T
T
Nishiyama
S
S
Nishimura
S
S
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D008253:Macaca mulatta; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D018727:Muscarinic Antagonists / Q000633:toxicity*; D018697:Nootropic Agents / Q000627:therapeutic use*; D010812:Physical Stimulation; D010879:Piperazines / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000633:toxicity; D012601:Scopolamine / Q000037:antagonists & inhibitors; D014055:Tomography, Emission-Computed; D014110:Touch / Q000502:physiology; D014732:Vibration
D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; C102991:N-(4-acetyl-1-piperazinyl) -4-fluorobenzamide monohydrate; D018697:Nootropic Agents; D010879:Piperazines; D011760:Pyrrolidinones; D012601:Scopolamine; C001369:1-hydroxy-3-amino-2-pyrrolidone