Effects of chronic administration of olanzapine, amitriptyline, haloperidol or sodium valproate in naive and anhedonic rats

Abstract

Although in bipolar patients the main therapeutic indication of atypical antipsychotics is the management of acute mania, several observations suggest that these agents may exert antidepressant as well as anti-manic effects. The main goal of the present work was to evaluate the putative antidepressant effect of chronic olanzapine (Ola) (0.02-0.1 or 0.5 mg/kg.d), in comparison to haloperidol (Hal) (0.2 mg/kg.d) and sodium valproate (VPA) (5 or 30 mg/kg.d), in rats exposed to a protocol of chronic mild stress. The tricyclic compound amitriptyline (Ami) (5 mg/kg.d) was used as reference drug. The results indicate that Ola, in a rodent model of depression, has protective effects against the stress-induced anhedonia. Compared to Hal and VPA, Ola shows a greater antidepressant activity and is as effective as Ami in preventing the anhedonic state. The effects of Ola and Ami, however, have a different time-course. A full reversion of the anhedonia by Ami appears after a latency of 4 wk, whereas the effect of Ola is already evident 1 wk after the beginning of the chronic treatment. Moreover, the recovery from anhedonia at the end of the stress protocol and after drug cessation was more rapid in groups of rats pretreated with Ola or VPA than in the group of saline-pretreated rats. In conclusion, the results indicate that 0.02 mg/kg.d Ola causes a rapid and sustained antidepressant-like effect, while all other anti-manic treatments show loss of efficacy at 3 wk. Taken together, these observations support the hypothesis that Ola has a broader pharmacotherapeutic profile than solely as an antipsychotic or anti-manic agent.

Quetiapine Prevents Anhedonia Induced by Acute or Chronic Stress

“…Two recent papers extend these clinical data, suggesting that olanzapine-fluoxetine combination shows rapid and sustained improvement in depressive symptoms in patients with major depressive disorder, including treatment-resistant patients (Corya et al, 2003) and that the same drug combination is effective in the treatment of bipolar I depression (Tohen et al, 2003). We have added further evidence to the antidepressant effect of olanzapine by testing the efficacy of the drug in preventing the onset of anhedonia under experimental conditions similar to those employed in the present study (Orsetti et al, 2006). Compared to that of QTP, the effect of olanzapine (0.02 mg/kg/day) has a more rapid onset, beginning at week 1 of the CMS protocol.…”

Strain-specific battery of tests for domains of mania: effects of valproate, lithium and imipramine

“…All three drugs were previously found to increase sweet solution preference [lithium (Orsetti et al, 2006) valproate (Monleon et al, 1995; Papp et al, 1996) imipramine (Papp et al, 1996)]. However, these ‘antidepressant-like’ effects were found in animals which were previously exposed to depressenogenic stimuli while in the present study BS mice were found to demonstrate excessive baseline sweet solution preference which was suggested to represent strain-specific, ‘manic-like’ high reward-seeking behavior (Flaisher-Grinberg et al, 2009).…”

Gene regulation in the frontal cortex of rats exposed to the chronic mild stress paradigm, an animal model of human depression

“…One of the following stressors was administered daily, in random order, over a period of 6 weeks: crowding (by placing eight animals in standard individual cages for 24 h), food deprivation for 24 h, 45° cage tilt for 5 h, shaker stress (horizontal shakes at high speed for 10 min), soiled cage (200 mL of water in sawdust bedding for 5 h), intermittent overnight illumination (light on and off every 3 h for 24 h), light on overnight, and tail pinch for 2 min. In developing our CMS protocol (Orsetti et al ., 2006), we have made changes to the procedure previously described by Katz (1982), as the severity of the stressors employed was greatly reduced. Indeed, the individual stressors that we have used do not include elements like intense footshock, restraint stress or water/food deprivation for 48 h. In this respect, our CMS protocol is similar to the procedure adopted by Willner et al .…”

“…In this regard, several preclinical models based on chronic stress administration have been developed in order to advance our knowledge of the molecular mechanisms underlying depression. Among these, the chronic mild stress (CMS) paradigm, originally proposed by Katz (1982) and advanced by Willner et al ., 1987), has good face and construct validity and has been proven to be successful in the functional identification of antidepressant drugs, thereby showing good predictive validity (Ferretti et al ., 1995; Ghi et al ., 1995; Przegalinski et al ., 1995; Papp et al ., 1996; Orsetti et al ., 2006, 2007). Although anhedonia is the core feature of the CMS model, other behavioural and neuroendocrine abnormalities that resemble human depression, such as disturbances of locomotor activity, modifications of sleep patterns, impaired sexual behaviour and decreased aggression, are also present (D'Aquila et al ., 1994; Gorka et al ., 1996; Cheeta et al ., 1997).…”