Antidepressants with different mechanisms of action show different chronopharmacological profiles in the tail suspension test in mice

Abstract

The circadian system regulates sleep/wake cycles, metabolism, mood, and other functions. It also influences medication efficacy. In this study, we studied the chronopharmacological profiles of antidepressants with various modes of action. We also investigated the effects of dosing time on the pharmacological activity of several antidepressants acting on serotonergic, noradrenergic, and/or dopaminergic neurons. C57BL/6 mice were intraperitoneally administered fluoxetine, imipramine, venlafaxine, or bupropion at 08:00 h (morning), 14:00 h (mid-day), 20:00 h (evening), or 02:00 h (mid-night). Antidepressant activity was evaluated by the tail suspension test. All antidepressants reduced immobility, and their activities varied according to the dosing time. Fluoxetine and imipramine induced relatively strong rhythms with high amplitudes. Their maximal effects were observed in the morning and evening, respectively. Venlafaxine and bupropion induced weak rhythms with maximal effects in the evening and dawn, respectively. These results suggest that the antidepressant activity is associated with circadian fluctuation, and antidepressants with different modes of action have different chronopharmacological profiles. They affect locomotor activity in animals placed in novel (unfamiliar) environments. Fluoxetine, imipramine, and venlafaxine reduced locomotor activity, whereas bupropion increased it. The effects on locomotor activity also vary with circadian rhythm, and the tested drugs showed a maximal effect during the light phase. The peak time was different from that in TST. Plasma and brain levels of all drugs were slightly 3 higher in the morning than in the evening. The dosing time dependency of the antidepressant activity did not correlate with the sedative/stimulatory activity or tissue drug level. Therefore, these latter two factors may have only a small impact on circadian antidepressant activity fluctuations. The relative activity of the serotonergic, noradrenergic, and dopaminergic systems may determine the chronopharmacological profiles of each drug. These results suggest the possibility that drug therapy be optimized by considering the dosing time when the antidepressant activity is high and other pharmacological activities leading to adverse effects are low. Further studies using animal models of depression and in clinical settings are necessary to confirm the effects of dosing time on depressed subjects.

The Anti-depressant Activity of Fixed Oil of Phaseolus vulgaris Linn. in Mice

“…In the open field study conducted on PVFO (2 mL/Kg and 4 mL/Kg), it produced calming effect shown by significant decrease in number of boxes crossed (Salma et al, 2018). According to another research anti-depressants Fluoxetine, Imipramine and Venlafaxine reduce the locomotor activity in unfamiliar environment (Kawai et al, 2019). Which support the finding of current study of PVFO and shows anti-depressant activity and decreases locomotor activity.…”

Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test

“…Although the modes of action of the test pharmaceuticals may be comparable among vertebrate classes, the extrapolation of the observed effects in zebrafish embryos to humans requires additional investigation, e.g., regarding a human relevance analysis of the observed effects following a standardized protocol. The study compounds also affect locomotor activity in rodent models [ 76 , 77 ], though this has not (yet) been confirmed as a DNT effect. Further study is needed to assess whether the observed effects in the zebrafish embryos can be linked to irreversible effects in brain development and whether such effects on locomotor activity in zebrafish embryos are predictive for DNT-related locomotor effects in mammals.…”

Circadian Rhythms, Disease and Chronotherapy

“…Rodent models show that antidepressants are more effective at specific times of day (e.g. milnacipran, fluoxetine, imipramine, venlafaxine, or bupropion) (Kawai et al, 2018a(Kawai et al, , 2018b(Kawai et al, , 2019. There does not appear to be a common mode of circadian regulation as dosing time dependency is seen with drugs that have different modes of action in serotonergic, noradrenergic, and dopaminergic neurons.…”

“…There does not appear to be a common mode of circadian regulation as dosing time dependency is seen with drugs that have different modes of action in serotonergic, noradrenergic, and dopaminergic neurons. Moreover, drugs show different chrono-pharmacological profiles (Kawai et al, 2018a(Kawai et al, , 2018b(Kawai et al, , 2019. The action of neuropsychiatric drugs (eg, lithium, selective serotonin reuptake inhibitors [SSRIs]) is also affected by polymorphisms in circadian clock genes, chronotype, and cellular circadian rhythms, supporting a general role of circadian biology in neuropsychiatric disorders (Rybakowski et al, 2014;McCarthy et al, 2019).…”