S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine.
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 alpha2-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.
Millan
M J
MJ
Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France. mark.millan@fr.netgrs.com
Dekeyne
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Papp
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La Rochelle
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CD
MacSweeny
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Peglion
J L
JL
Brocco
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D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D002997:Clomipramine / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D000077593:Reboxetine; D012110:Reserpine / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters; D000069470:Venlafaxine Hydrochloride; D010133:p-Chloroamphetamine / Q000494:pharmacology
D014150:Antipsychotic Agents; D002352:Carrier Proteins; D015283:Citalopram; D002997:Clomipramine; D003511:Cyclohexanols; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000077593:Reboxetine; D012110:Reserpine; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D000069470:Venlafaxine Hydrochloride; D010133:p-Chloroamphetamine; C432168:1-(1-dimethylaminomethyl-5-methoxybenzocyclobutan-1-yl)cyclohexanol; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat