Influence of Sleep Deprivation on Activities of Cytochrome P450 in Animal Behavioural Models

Osasan, Josephine Yetunde (2015-05-14)

Thesis

Sleep is a regulated state of the brain that occurs every day and has been implicated in many fundamental processes but the effects of sleep deprivation on Cytochrome P450 (CYP) enzymes have not been investigated. Thus, this study was carried out to determine the relationship between sleep deprivation and drug disposition. Enzyme probe drugs for specific enzyme such as ethanol and diazepam for P450 2E1 and 2C19 metabolizing respectively were used to carry out the investigation using behavioural animal models such as novelty-induced behaviours (locomotion, rearing and grooming), learning and memory tests, (Y-maze) anxiolytic models (hole board and elevated plus maze). Experiments were carried out in mice (n=7-10 per group) in each model, the mice were divided into two major groups of sleep-deprived (6-hours) and non-sleep deprived. The drugs (ethanol (3.5g/kg) and diazepam (2.5mg/kg)] used were administered intraperioteneally (i.p). The results showed that sleep deprivation before and after the administration of ethanol (3.5g/kg i.p) significantly potentiated the inhibitory effects of ethanol on locomotor activity (F(3,34) = 3.47, p<0.05), rearing activity (F(3,34) = 13.54, p<0.001), grooming activity (F(4,34) = 4.48, p<0.01), on explorative activity in hole board (F(3,32) = 14.40, p<0.01) and also on locomotor activity in Y-maze (F(3,34 = 3.53, p<0.05). Sleep deprivation did not have significant effect on ethanol induced anxiolytic effects in elevated plus maze (F(3,31) = 1.82, p=0.167) and percentage alternation of Y-maze in learning and memory activity (F(3,34) = 1.91, p=0.149). In diazepam treated mice, the result also showed that sleep deprivation before and after the administration of diazepam (2.5mg/kg, i.p) significant potentiated the inhibitory effect of diazepam on locomotor activity (F(3,34) = 2.91, p<0.05), rearing activity (F(3,34) = 28.58, p<0.001), grooming activity (F(3,34) = anxiolytic in elevated plus maze as related to number of entries (F(3.36)= 5.56, p<0.01). In conclusion, these results therefore suggested that sleep deprivation have inhibitory effects on these enzymes involved in the metabolism of the probe drugs. There is a possible significant relationship between sleep deprivation and drug disposition. Furthermore, the result obtained clearly indicate that sleep deprivation may significantly inhibit cytochrome P450 2E1 and 2C19 metabolizing enzymes' activities. Therefore, sleep deprivation might cause possible adverse drug effects.

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