RT Journal Article
SR Electronic
T1 S33005, a Novel Ligand at Both Serotonin and Norepinephrine Transporters: II. Behavioral Profile in Comparison with Venlafaxine, Reboxetine, Citalopram, and Clomipramine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 581
OP 591
VO 298
IS 2
A1 Mark J. Millan
A1 Anne Dekeyne
A1 Mariusz Papp
A1 Christophe Drieu La Rochelle
A1 Cliona MacSweeny
A1 Jean-Louis Peglion
A1 Mauricette Brocco
YR 2001
UL http://jpet.aspetjournals.org/content/298/2/581.abstract
AB Reflecting its potent inhibition of serotonin (5-HT) reuptake (accompanying paper), S33005 blocked spontaneous tail-flicks induced by parachloroamphetamine in rats. This action was mimicked by the 5-HT reuptake inhibitor, citalopram, and the 5-HT/norepinephrine (NE) reuptake inhibitor, venlafaxine, whereas the preferential NE reuptake inhibitor, reboxetine, was inactive. Consistent with its less potent interaction with NE transporters, higher doses of S33005 attenuated induction of hypothermia by reserpine, an action mimicked by reboxetine and venlafaxine, whereas citalopram was ineffective. In mice, S33005 reduced immobility in forced-swim and tail-suspension procedures. It also inhibited marble-burying behavior and suppressed aggressive behavior between resident and intruder animals. In rats, S33005 generalized to a discriminative stimulus elicited by citalopram and attenuated hypnotic-sedative actions of the α2-adrenoceptor agonist, S18616. For these parameters, S33005 was a more potent agent (median, 1.2 mg/kg, s.c.) than venlafaxine, citalopram, reboxetine, or the tricyclic agent, clomipramine. Even at markedly higher doses (40.0–80.0 mg/kg, s.c.), S33005 little affected motor behavior. S33005 (10.0 mg/kg, s.c.) also increased responses in a learned helplessness paradigm in rats, whereas venlafaxine was ineffective. Finally, in a rat chronic mild-stress model, S33005 dose- (2.5–40.0 mg/kg) and time- (2–5 weeks) dependently enhanced sucrose consumption. Venlafaxine was likewise active in this procedure. In conclusion, in line with its inhibition of 5-HT and (less potently) NE reuptake, S33005 is active in a broad range of models suggestive of antidepressant activity. It exerts its actions more potently than venlafaxine and clomipramine, and its overall profile is distinct from those of citalopram and reboxetine. The American Society for Pharmacology and Experimental Therapeutics