Ultrasonic vocalizations in rat pups, effects of serotonergic ligands

Ligands with varying intrinsic activity and selectivity for the various sub types of the serotonin receptor were tested in the rat pup ultrasonic vocal ization (USV) model, a putative animal model reflecting anxiety. USV were e licited by isolating rat pups from their mother and littermates by placing them on a warm (37 degrees C) or a cold (18 degrees C) plate. Concurrently, the negative geotaxic (NG) response and rectal temperature were determined to assess the potentially sedative and hypothermic effects of putative anx iolytics, USV were reduced at low doses and in both temperature conditions by the full 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT (8-hydroxy-2- (di-n-propylamino) tetralin.HBr) and the partial 5-HT1A receptor agonists b uspirone, ipsapirone and BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl] butyl]-1,2-benzi-isothiozol-3-(2H)one-1,1-dioxide. 2HCl). The 5-HT1A recept or antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piper azide.2HCl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)pi perazin-1-yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-h ydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and o nly in one of both test conditions, The selective 5-HT1A receptor antagonis t DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2- benzisothiazol-3(2H)-one-1,1, dioxide, monomesylate), did not influence USV at the cold plate up to high doses, although concomitantly th e negative geotaxis was disturbed. The negative geotaxis was impaired after all 5-HT1A receptor ligands, except BMY 7378 and (+/-)-WAY 100,135. Hypoth ermia coincided with USV-suppression, except for NAN-190 and (S)-UH-301. Th e USV-suppressing action of flesinoxan (3 mg/kg) could be antagonized by DU 125530, but not its NG effect. However, the hypothermia induced by flesino xan was antagonized by DU 125530. USV were also suppressed by the 5-HT uptake inhibitors fluvoxamine (both wa rm and cold plate) and clomipramine (only warm plate). The tricyclic antide pressant imipramine only decreased USV on the cold plate, however, in a U-s haped dose-response curve. At the highest dose tested, no decrease was pres ent. The 5-HT uptake stimulant tianeptine reduced USV under both conditions . Fluvoxamine had no side effects, clomipramine induced hypothermia and tia neptine clearly had sedative properties. The 5-HT1B/2C receptor agonist TFM PP (trifluorometaphenylpiperazine) stimulated USV at a low dose at the cold plate and suppressed USV at a high dose under both conditions. The 5-HT2A/ 2C receptor antagonist ketanserine enhanced USV at low doses under both con ditions and had no effect at a higher dose. Concurrently heavy sedation and hypothermia occurred. The 5-HT3 receptor agonist phenylbiguanide and the 5 -HT3 receptor antagonist ondansetron had no effect in this paradigm. Clearl y, subtypes of the 5-HT receptor affect rat pup USV differentially. (C) 199 8 Elsevier Science Ltd. All rights reserved.