Behavioral, neuroendocrine and neurochemical studies on agomelatine in social isolation reared rats

Abstract

1. Introduction. There is currently a large body of evidence suggesting that stressful early life experiences, such as maternal separation and social isolation, may play a role in the development of major depressive disorder (MDD) (Fone & Porkess, 2008). Such experience adversely affects brain development as well as multiple neurobiological systems (aan het Rot et al., 2009) that lead to maladaptive behaviour in adulthood (Weiss et al., 2003). The understanding of MDD is currently based on the classic monoamine-deficiency hypothesis which proposes that MDD follows as a result of sustained deficits in the monoamine transmitters, serotonin (5-HT), noradrenalin (NA) and dopamine (DA) (Cai et al., 2015). However, the relationship between stress and affective disorders can be more fully understood from an integrative perspective (Juruena, 2014). In fact, over and above the above-mentioned monoamine deficits, the impact of psychosocial stress on brain-derived neurotrophic factor, inflammatory, redox and metabolic processes, as well as structural brain changes (Palazidou 2012) are now considered important contributory factors in MDD. During psychological stress, adaptive physiological responses occur through activation of the hypothalamic-pituitary-adrenal (HPA) axis (Cai et al., 2015) culminating in an increase in cortisol (Juruena 2011, Martins et al., 2011). Cortisol in turn is known to disturb a number of the above-mentioned processes, also mediating structural brain changes such as hippocampal shrinkage (Campbell et al., 2014). Disturbances in the circadian release of cortisol, as well as other neuroendocrine messengers, is now strongly implicated in depressive symptomology and pathology, so that targeting the central biorhythm centre of the brain has important significance for novel antidepressant drug action. The social isolation rearing (SIR) model in rats produces various symptoms and deficits in line with MDD, such as anhedonic-like behavior (Hall et al., 1997), depressive-like behaviors (Hall et al., 1998), cognitive deficits (Bianchi et al., 2006) and monoaminergic alterations (as reviewed by (Fone & Porkess, 2008). Agomelatine is a new generation antidepressant with melatonin (MT1 and MT2) receptor agonist and 5-HT2C receptor antagonist properties, exerting its antidepressant effects through the re-entrainment of altered circadian rhythms and a very specific action on frontal cortical monoamines (Cai et al., 2015). To the best of our knowledge, the antidepressant capabilities of agomelatine have not been studied in a neurodevelopmental animal model of depression, viz. SIR. 2. Methods. Male Sprague-Dawley (SD) rats (12 rats/group) were used. The study was divided into two arms consisting of (1) a behavioral cohort, and (2) a neurochemical and neuroendocrine cohort. Eight groups of rats, divided into 4 behavioral and 4 neurochemical groups, were randomly separated at weaning (postnatal day (PND 21), and exposed to either 8 weeks of SIR or 8 weeks social rearing. Agomelatine (40mg/kg/day) or 1% hydroxyethylcellulose (HEC) vehicle was administered at 16h00 by intraperitoneal injection for the last 14 days of rearing (PND 63-77). Behavioral analysis of anhedonia, memory, locomotor activity and behavioural despair were analysed on the final 4 days of rearing, using the sucrose preference test (SPT), novel object recognition test (NORT), open field test (OFT) and forced swim test (FST), respectively. The remaining groups were sacrificed at 8 weeks and plasma and brain tissue harvested for analysis of regional brain monoamine concentrations and lipid peroxidation (LPX) by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively, and plasma corticosterone and superoxide dismutase (SOD) activity both done by ELISA respectively. A one-way ANOVA with a suitable post-hoc test were performed. 3. Results. SIR significantly increased immobility in the FST without affecting locomotor activity, and showed a trend in reducing swimming and climbing behaviors, although no significant effects were seen in the NORT. SIR also showed a significant decrease in sucrose preference compared to the social control. Cortico-hippocampal monoamines remained unaffected, except for a trend towards reduced striatal 5-HT and increased hippocampal 5-HIAA. No changes in LPX, SOD or CORT levels were found in SIR rats. For the most, agomelatine treatment had minimal to no effect in socially reared animals. Agomelatine had no effect on locomotor activity, but significantly reduced immobility in SIR rats, and selectively increased struggling behaviour without affecting swimming behaviour. Agomelatine significantly decreased sucrose preference vs. socially reared rats receiving vehicle, but did not affect memory. Agomelatine significantly increased both LPX activity and basal CORT levels in SIR rats vs. SIR rats receiving vehicle, but had no effect on SOD activity. Agomelatine significantly increased striatal dihydroxyphenylacetic acid (DOPAC) levels in SIR rats vs. SIR rats receiving vehicle. 4. Conclusion and Discussion. SIR produced depressive-like bio-behavioral changes in rats, specifically behavioural despair with reduced behavioural coping strategies, anhedonia-like manifestations and regional brain monoamine alterations. However, it failed to engender cognitive deficits, or alter lipid peroxidation, superoxide dismutase activities or basal corticosterone levels. These findings establish some albeit weak face validity for MDD. Agomelatine demonstrated antidepressant-like effects in this model, indicative of a reversal of SIR-related immobility and attenuated coping strategies, especially reduced struggling (NAergic-related) behaviors. Interestingly, the latter corresponds with its purported noradrenergic mode of action. On this point, agomelatine showed no obvious 5-HTergic activity with respect to behaviour in the FST (swimming) as well as 5-HT related changes in the frontal cortex, striatum and hippocampus of SIR rats. Rather agomelatine decreased hippocampal 5-HT levels in the social reared rats. Although plasma corticosterone was unaltered by SIR, agomelatine increased basal corticosterone levels in SIR rats, an unexpected observation. However, this action could be linked to both cognitive deficits in the NORT and an increase in lipid peroxidation observed in SIR rats receiving agomelatine. Agomelatine significantly decreased sucrose preference in both social and SIR rats, which is contradictory to its clinical profile in treating anhedonia, as well as its supposedly dopaminergic profile. Finally, agomelatine did not affect SOD activity in either social or SIR animals. Thus, agomelatine does show antidepressant-like effects in the SIR model, especially in the FST, with evidence of cortico-hippocampal monoamine changes related to the monoamine hypothesis of MDD. However, failure of the SIR model to reproduce the desired MDD-related pathology in other behavioural tests, as well as with respect to corticosterone and redox analysis, precludes a more comprehensive interpretation of the findings, and further study is warranted