Ligands with varying intrinsic activity and selectivity for the various subtypes of the
serotonin receptor were tested in the rat pup ultrasonic vocalization (USV) model, a putative animal model reflecting anxiety. USV were elicited 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
anxiolytics. 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
buspirone,
ipsapirone and
BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl]butyl]-1,2-benzi-isoth iozol-3-(2H)one-1,1-dioxide. 2HCl). The
5-HT1A receptor antagonists
NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piperazide.2H Cl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)piperazin-1 -yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and only in one of both test conditions. The selective
5-HT1A receptor antagonist
DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazi nyl]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 the negative geotaxis was disturbed. The negative geotaxis was impaired after all
5-HT1A receptor ligands, except
BMY 7378 and (+/-)-WAY 100,135.
Hypothermia coincided with USV-suppression, except for
NAN-190 and (S)-UH-301. The USV-suppressing action of
flesinoxan (3 mg/kg) could be antagonized by
DU 125530, but not its NG effect. However, the
hypothermia induced by
flesinoxan was antagonized by
DU 125530. USV were also suppressed by the
5-HT uptake inhibitors fluvoxamine (both warm and cold plate) and
clomipramine (only warm plate). The
tricyclic antidepressant imipramine only decreased USV on the cold plate, however, in a U-shaped dose-response curve. At the highest dose tested, no decrease was present. The
5-HT uptake stimulant
tianeptine reduced USV under both conditions.
Fluvoxamine had no side effects,
clomipramine induced hypothermia and
tianeptine clearly had
sedative properties. The 5-HT1B/2C receptor agonist
TFMPP (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 conditions 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. Clearly, subtypes of the
5-HT receptor affect rat pup USV differentially.