Comparison of single vs. multiple administrations of the AMPA receptors modulator S 18986 in the object recognition task in rats.
The present study aimed at defining the best scheme of administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-positive modulator (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986) [once daily (o.d.) administration of 1 mg/kg for 3 days vs. three times daily (t.i.d.) administration of 0.3 mg/kg for 3 days] to get an optimal procognitive activity in the object recognition task in rats. Memory performance [Recognition Index (RI)] of rats was significantly improved 1 h (RI = 41%, P < 0.01) and 3 h (RI = 46%, P < 0.001) following oral administration of S 18986 (1 mg/kg, o.d.) when compared with animals receiving the vehicle (RI = 6%). When the interval between administration and testing was increased to 6 h and 9 h, no statistically significant improvement in memory performance was observed (RI = 42% for 6 h and RI = 18% for 9 h vs. 20% for the vehicle group). When S 18986 was administered at 0.3 mg/kg t.i.d., no statistically significant improvement in memory performance was observed (RI = 36%). These findings show a long-lasting efficacy of the AMPA receptor allosteric modulator in the object recognition task despite a short half-life in plasma and in brain (approximately 1 h). Accordingly, multiple administrations of S 18986 are not required to obtain a maximal efficacy in this paradigm, because a o.d. schedule of administration leads to a powerful procognitive activity.
Bertaina-Anglade
V
V
Preclinical Pharmacology Department, Biotrial, 35000 Rennes, France. valerie.bertaina@biotrial.com
la Rochelle
C Drieu
CD
Muñoz
C
C
Morain
P
P
Bernard
K
K
D000494:Allosteric Regulation; D000818:Animals; D001581:Benzothiadiazines / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects*; D013997:Time Factors
D001581:Benzothiadiazines; D018697:Nootropic Agents; D018091:Receptors, AMPA; C414205:S18986-1