Effects of anxiogenic drugs on the emission of 22- and 50-kHz ultrasonic vocalizations in adult rats.

RATIONALE: Adult rat 22-kHz vocalizations are often associated with alarm or distress, whereas a subset of 50-kHz calls is preferentially emitted in response to amphetamine and other rewarding stimuli. Whether any 50-kHz calls reflect anxiety is unknown. OBJECTIVE: To determine the effects of anxiogenic drugs on 50-kHz call rate and call subtype profile, in comparison with D-amphetamine. METHODS: Adult male rats received systemic amphetamine (1 mg/kg) three times several days before testing. Ultrasonic vocalizations were then recorded after acute intraperitoneal injection of amphetamine or one of five anxiogenic drugs: yohimbine (2.5 mg/kg), N-methyl-ß-carboline-3-carboxamide (FG 7142, 5 mg/kg), pentylenetetrazol (PTZ, 20 mg/kg), m-chlorophenylpiperazine (mCPP, 1 mg/kg), caffeine (25 mg/kg), or vehicle. RESULTS: The duration of immobility was increased by FG 7142, PTZ, and mCPP; this measure was unchanged by yohimbine and reduced by the locomotor stimulant drugs amphetamine and caffeine. Conversely, the 50-kHz call rate was reduced by FG 7142, PTZ and mCPP, and increased by caffeine and amphetamine. Overall, the most common 50-kHz call subtypes were flat, trill, step-up, and complex. Consistent with previous reports, amphetamine increased the relative prevalence of trill calls while reducing the relative prevalence of flat calls. Yohimbine and caffeine reduced flat call prevalence, whereas mCPP reduced trill call prevalence. No other shifts in the call profile were observed, and no anxiogenic drug induced 22-kHz calls. CONCLUSION: Anxiogenic drugs, as a class, did not uniformly alter the 50-kHz call rate or subtype profile. Amphetamine-induced effects on 50-kHz call rate and profile do not reflect anxiety.

Effect of Trazodone on the Rat Cerebral Hemodynamics / 대한정신약물학회지

OBJECTIVES: The present study assessed the effect of trazodone on the cerebral hemodynamics of male Sprague-Dawley rats. METHOD: The changes of regional cerebral blood flow(rCBF) and pill arterial diameter were measured by laser-Doppler flowmetry and by a videomicroscopy, respectively. The changes in vascular tone and intracellular free Ca2+ concentration ([Ca2+]i) of isolated basilar artery were simultaneously measured using a small vessel myograph and a cation measurement system, respectively. RESULT: Both the rCBF and the pill arterial diameter were dose-dependently decreased by systemic administration of trazodone(0.3-10 mg/kg, i.v.), but not by topical application of trazodone(10-300 micrometer). Pretreatment with 5-HT(2A/2C) receptor antagonist(ketanserin or ritanserin, 1 mg/kg, i.v., respectively) significantly blocked the changes in rCBF induced by trazodone. m-Chlorophenylpiperazine(mCPP ; 0.1-3 mg/kg, i.v. or 5-500 micrometer topical), a major active metabolite of trazodone, also dose-dependently decreased the rCBF as well as the pial arterial diameter. The mCPP-induced decreases in rCBF were significantly blocked by ketanserin. Pretreatment with itraconazole(1 mg/kg, p.o.), a selective inhibitor of CYP3A4, a subfamily of cytochrome P450, markedly attenuated the trazodone-induced changes in rCBF. In an isolated rat basilar arterial strip loaded with fura-2/AM, mCPP(5-500 micrometer caused a vasoconstriction in association with increases in [Ca2+]i, in a concentration-dependent manner. Pretreatment with 1 micrometerketanserin strongly blocked the effects of mCPP on the vascular tone as well as on the [Ca2+]i, of rat basilar artery. CONCLUSION: These results suggest that trazodone decreases rCBF through stimulation of 5-HT(2A/2C) receptors by its active metabolite, mCPP.

Effect of 5-HT2c Receptor Modulation on the m-Chlorophenlpiperazine-Induced Hypoactivity / 대한정신약물학회지

It was aimed to investigate the effect of 5-HT2C receptor modulation on the rat behavioral responses induced by 1-(m-chlorophenyl) piperazine(mCPP), a major metabolite of trazodone. The animal activities(ambulation, stereotypy and total activity) were measured for 3 hours following mCPP administration, using an animal activity meter which accumulates the frequency of light beam interruption. mCPP(1-10 mg / kg, i.p.) induced dose-dependent decreases in ambulation and stereotypy, consequently leading to hypoactivity. The hypoactivity induced by mCPP(1mg / kg, i.p.) was significantly inhibited by pretreatment with mianserin(1mg / kg, i.p.), an antagonist with high affinity for 5-HT2C receptor, whereas pretreatment with 5-HT2 antagonists, ketanserin and ritanserin(1mg / kg, i.p., respectively) was without effect. Furthermore, long-term pretreatment with imipramine(10mg / kg, i.p., b.i.d. for 2 weeks) markedly attenuated the mCPP-induced hypoactivity. Mianserin and imipramine in the absence of mCPP did not increase the animal activity. Taken together, these results indicate that the mCPP-induced hypoactivity is mediated by 5-HT2C receptor, and that selective 5-HT2C antagonists and down regulation of 5-HT2C receptor might be useful for inhibiting the mCPP-induced hypoactivity.