Boulay Denis, Ho-Van Sophie, Bergis Olivier, Avenet Patrick, Griebel Guy
Sanofi Research & Development, Exploratory Unit, Chilly-Mazarin, France.
Behav Pharmacol. 2013 Oct;24(7):543-51. doi: 10.1097/FBP.0b013e3283654044.
The objective of the present study was to examine the idea that the decrease in 50-kHz ultrasonic vocalizations elicited by tickling in juvenile rats following the administration of the psychotomimetic drug phencyclidine (PCP) may represent a valid model of the negative symptoms of schizophrenia. Fifty-kilohertz calls in rodents have been suggested to represent an archaic model of human laughter. Our results showed that daily tickling sessions produced a gradual increase in 50-kHz vocalizations, an effect that reached statistical significance from day 3. Administration of PCP (1 mg/kg, intraperitoneally) attenuated the 50-kHz calls induced by 4 consecutive days of tickling. The ability of several clinically effective or potential antipsychotics to reverse the effects of PCP was investigated. The 5-HT1A receptor partial agonist, buspirone (0.3 and 1 mg/kg, intraperitoneally), the dual D2/5-HT1A receptor ligand, SSR181507 (0.5-0.75 mg/kg, intraperitoneally), but not the atypical antipsychotic, aripiprazole (0.1-1 mg/kg, intraperitoneally), the 5-HT2A receptor antagonist, eplivanserin (0.3-3 mg/kg, intraperitoneally), and the GlyT1 inhibitor, SSR103800 (0.3-3 mg/kg, intraperitoneally) significantly attenuated the effects of PCP on 50-kHz calls. Importantly, in animals not treated with PCP, none of the drugs affected 50-kHz calls elicited by a first handling-tickling session, indicating that the action of buspirone and SSR181507 cannot be explained by an intrinsic effect. To investigate further the specificity of these drug effects, we tested the anxiolytic and antidepressant agents, diazepam (0.1-1 mg/kg, intraperitoneally) and fluoxetine (1-10 mg/kg, intraperitoneally), respectively, in this procedure. Neither drug affected tickling-induced 50-kHz calls in naive or PCP-treated rats. In conclusion, the results of the present study confirm that 50-kHz calls elicited by several tickling sessions in rats can be reduced by acute administration of PCP, and that this effect can be reversed by previous administration of compounds with 5-HT1A receptor agonist properties. As evidence for clinical efficacy of both agents on the negative symptoms of schizophrenia is weak or lacking, the current findings do not allow a definite conclusion to be drawn on the validity of this procedure as a model of this aspect of schizophrenia.
本研究的目的是检验一种观点，即给予拟精神病药物苯环己哌啶（PCP）后，幼鼠挠痒引起的50千赫兹超声发声减少可能代表精神分裂症阴性症状的有效模型。啮齿动物发出的50千赫兹叫声被认为是人类笑声的一种古老模型。我们的结果表明，每天的挠痒会使50千赫兹发声逐渐增加，从第3天起这种效应达到统计学显著水平。腹腔注射PCP（1毫克/千克）减弱了连续4天挠痒诱导的50千赫兹叫声。研究了几种临床有效或有潜力的抗精神病药物逆转PCP作用的能力。5-羟色胺1A受体部分激动剂丁螺环酮（腹腔注射0.3和1毫克/千克）、D2/5-羟色胺1A受体双重配体SSR181507（腹腔注射0.5 - 0.75毫克/千克），但非典型抗精神病药物阿立哌唑（腹腔注射0.1 - 1毫克/千克）、5-羟色胺2A受体拮抗剂依普利万色林（腹腔注射0.3 - 3毫克/千克）以及甘氨酸转运体1抑制剂SSR103800（腹腔注射0.3 - 3毫克/千克）均显著减弱了PCP对50千赫兹叫声的作用。重要的是，在未用PCP处理的动物中，这些药物均未影响首次处理 - 挠痒引起的50千赫兹叫声，这表明丁螺环酮和SSR181507的作用无法用内在效应来解释。为进一步研究这些药物作用的特异性，我们在此实验过程中分别测试了抗焦虑和抗抑郁药物地西泮（腹腔注射0.1 - 1毫克/千克）和氟西汀（腹腔注射1 - 10毫克/千克）。这两种药物在未处理或PCP处理的大鼠中均未影响挠痒诱导的50千赫兹叫声。总之，本研究结果证实，急性给予PCP可减少大鼠多次挠痒引起的50千赫兹叫声，且这种效应可被先前给予的具有5-羟色胺1A受体激动剂特性的化合物逆转。由于这两种药物对精神分裂症阴性症状临床疗效的证据薄弱或缺乏，目前的研究结果无法就该实验作为精神分裂症这一方面模型的有效性得出明确结论。
