Exogenous daytime melatonin modulates response of adolescent mice in a repeated unpredictable stress paradigm

Abstract

The immediate and short-term behavioural and physiological implications of exposure to stressful scenarios in the adolescent period are largely unknown; however, increases in occurrence of stress-related physiological and psychological disorders during puberty highlight the need to study substances that may modulate stress reactivity during a crucial stage of maturation. Seven groups of mice (12-15 g each) were administered distilled water (DW) (non-stressed and stressed controls), sertraline (10 mg/kg), diazepam (2 mg/kg) or one of three doses of melatonin (5, 10 and 15 mg/kg). Mice were exposed to 30 min of chronic mild stress (25 min of cage shaking, cage tilting, handling and 5 min of forced swimming in tepid warm water at 25 °C, in a random order) after administration of DW or drugs, daily for 21 days. Behavioural assessments were conducted on day 1 and day 21 (after which mice were sacrificed, blood taken for estimation of corticosterone levels and brain homogenates used for estimation of antioxidant activities). Administration of melatonin resulted in an increase in horizontal locomotion and self-grooming, while rearing showed a time-dependent increase, compared to non-stress and stress controls. Working memory improved with increasing doses of melatonin (compared to controls and diazepam); in comparison to setraline however, working memory decreased. A dose-related anxiolytic effect is seen when melatonin is compared to non-stressed and stressed controls. Melatonin administration reduced the systemic/oxidant response to repeated stress. Administration of melatonin in repeatedly stressed adolescent mice was associated with improved central excitation, enhancement of working memory, anxiolysis and reduced systemic response to stress.

Melatonin and Major Neurocognitive Disorders: Beyond the Management of Sleep and Circadian Rhythm Dysfunction

“…Melatonin exerts its effects on biologic systems or the brain through its ability to bind to melatonin receptors (MT 1 and MT 2 ) ( Jockers et al, 2008), orphan nuclear receptors (Ekmekcioglu, 2006) and intracellular proteins, like calmodulin (Pandi-Perumal et al, 2008). Documented effects of endogenous or exogenous melatonin include the control of anxiety-related behaviours (El Mrabet et al, 2012;Onaolapo AY et al, 2017a, modulation of memory and memory formation (He et al, 2013;Onaolapo OJ et al, 2014;Onaolapo AY, et al, 2017b), neurogenesis (Liu Jetal., 2013), neuroprotection (Kondoh et al, 2002), anti-inflammation (Genovese et al, 2005), antitumour (Blask et al, 2002) and antioxidant properties (Sofic et al, 2005). Stimulation of the visual cortex might have effects on melatonin secretion, circadian rhythmicity, sleep, and by extension, memory; and in an experiment using mice, it was found that stimulation of the visual cortex (using gratings and dot) affects neuronal inhibitionexcitation balance, eventually disturbing memoryprocessing and short-term plasticity (Etindele Sosso, 2017b).…”

Melatonin, adolescence, and the brain: An insight into the period‐specific influences of a multifunctional signaling molecule

“…Its use is supported by studies that confirm a strong association between low early‐morning serum melatonin levels and sleep disturbances in adolescents (Inigo, Lestari, Masloman, & Lolombulan, ). In humans, irrespective of age, the most widely studied aspect of exogenous melatonin administration is perhaps in relation to sleep promotion or management of sleep disorders; however, in rodents, several studies have reported beneficial effects on several aspects of behavior (El Mrabet et al, ; Mantovani, Pertile, Calixto, Santos, & Rodrigues, ; Onaolapo, Adebayo, et al, ; Onaolapo, Aina et al, ; Yildirim & Marangoz, ), and also deleterious effects like impairment of acquisition, but not the expression of contextual fear in rats (Yang, Li, & Huang, ), proconvulsant effects (Stewart & Leung, ), and suppression of night‐time memory formation (Rawashdeh, de Borsetti, Roman, & Cahill, ).…”

“…However, some studies have reported no significant improvement in behavior, mood, or cognition (Van der Heijden et al, ). In two studies from our laboratory, we reported the mitigation of behavioral alterations secondary to exposure to physical stressors or chemically induced schizophrenia‐like behaviors in mice (Onaolapo, Adebayo, et al, ; Onaolapo, Aina, et al, ). Administration of exogenous melatonin during daylight modulated behavioral response to physical stress during the adolescent period in mice, as its administration was associated with a reversal of the behavioral (locomotor activity, self‐grooming, anxiety‐related behaviors, and memory) and systemic effects of exposure of mice to chronic unpredictable stress (Onaolapo, Adebayo, et al, ).…”

“…In two studies from our laboratory, we reported the mitigation of behavioral alterations secondary to exposure to physical stressors or chemically induced schizophrenia‐like behaviors in mice (Onaolapo, Adebayo, et al, ; Onaolapo, Aina, et al, ). Administration of exogenous melatonin during daylight modulated behavioral response to physical stress during the adolescent period in mice, as its administration was associated with a reversal of the behavioral (locomotor activity, self‐grooming, anxiety‐related behaviors, and memory) and systemic effects of exposure of mice to chronic unpredictable stress (Onaolapo, Adebayo, et al, ). In another study using slightly older mice, melatonin administration was associated with a reversal of behavioral changes secondary to repeated ketamine injection, leading to decreased open‐field behaviors (such as horizontal locomotion, rearing and stereotypic grooming), and improved working‐memory/social‐interaction (Onaolapo, Aina, et al, ).…”

“…Regulation of the mammalian biologic rhythms, such as sleep–wake cycle, seasonal adaptation, and pubertal development, is the major function of melatonin (Chan and Wong, ; Pandi‐Perumal et al, ). In humans or rodents, melatonin is also known to influence numerous biologic processes, such as locomotion (Onaolapo, Adebayo, & Onaolapo, ), memory formation (He et al, ; Onaolapo, Onaolapo, Akanni, & Eniafe, ), anxiety (Comai & Gobbi, ; Onaolapo, Adebayo, et al, ), depression (El Mrabet, Ouakki, Mes_Oui, El Hessni, & Ouichou, ), nociception (Yoon et al, ), and control of body posture and balance (Fraschini, Cesarani, Alpini, Esposti, & Stankov, ). Melatonin plays important roles in neurogenesis (Tocharus et al, ), neuroprotection (Pandi‐Perumal et al, ), maintenance of oxidant/antioxidant balance (Onaolapo, Aina, & Onaolapo, ), modulation of cardiovascular and/or immune system (Sánchez‐Barceló, Mediavilla, Tan, & Reiter, ), and diabetes control (Lyssenko et al, ).…”