|dc.description.abstract||Anxiety disorders are extremely prevalent and co-morbid in psychiatric disorders with a complex neurobiology and aetiology. Current treatment options are not sufficiently effective and there is therefore a demand for new and improved anxiolytic treatments. Agomelatine is a new generation antidepressant that acts as a serotonin 5-HT2C antagonist and a melatonin MT1/MT2 agonist, where it acts to re-entrain circadian rhythms purported to be dysregulated in mood disorders. Although it has been shown to have anxiolytic effects in clinical and preclinical studies and may possibly be beneficial as an alternative anxiolytic compound, there remains a paucity of preclinical studies in this regard. Animal models make it possible to study and determine the mechanism underlying the neurobiology, aetiology and pharmacological interventions of anxiety disorders. Adverse life-events are believed to play a particular important role in increasing the vulnerability to develop an anxiety disorder. Social isolation rearing (SIR) is an animal model that resembles early-life adversity and results in behavioural alterations akin to that observed in schizophrenia, depression and anxiety. SIR involves isolating a rat from post-natal day (PND) 21 for 8 weeks, thereby inducing neurodevelopmental abnormalities in the rat culminating in late-life emergent pathological behaviour. These behavioural alterations can be measured by means of specific behavioural tests, such as those to determine anxiety-like behaviours and applied in the current study. This study therefore used the SIR animal model to evaluate the effect of early life social isolation on the development of anxiety-like behaviours later in life as well as on neurotransmitters and endocrine bio-markers important in anxiety. Clinical studies have demonstrated that females are twice as prone to developing an anxiety disorder, and subsequent preclinical studies have identified gender as an important susceptibility factor in the development of anxiety. Consequently, the current study has investigated gender-related differences concerning anxiety-like behaviours and response to agomelatine treatment in the SIR model.
Animals were bred and housed at the DST/NWU PCDDP Vivarium and all experiments were approved by the AnimCare animal research ethics committee of the NWU (Ethics approval number NWU-00347-15-S5). Male and female Sprague-Dawley rats were randomly allocated into 6 groups, consisting of 12 rats per group. Rats were randomly divided into either socially reared groups (3 animals per cage) or SIR groups (1 animal per cage). Socially reared animals only received vehicle treatment, whereas SIR animals were divided into groups receiving agomelatine treatment (40 mg/kg/day) or vehicle treatment, administered at 16:00 daily. Treatment commenced on PND 61 and continued for 16 days. Thereafter animals were subjected to the open field test (OFT) on day 13 of treatment to access general locomotor activity, social interaction (SIT) on day 14 of treatment to access interactive behaviour with peers, and the elevated plus maze (EPM) on day 15 of treatment to access avoidance behaviour. Together these tests provide an overall impression of the animal’s general state of awareness and level of anxiety. Rats were euthanized (via decapitation) 36 hours after the last behavioural test, followed by the collection of trunk blood and dissection of frontal cortices for neuroendocrine analysis. N-methyl-D-aspartate (NMDA) receptor density and γ-amino butyric acid (GABA) levels were measured in the frontal cortices of male rats by radioligand binding and high performance liquid chromatography with electrochemical detection (HPLC-EC), respectively. Corticosterone was measured in the plasma of both genders using HPLC with ultraviolet (UV) detection.
The results indicate that SIR tends to increase locomotor activity in both genders compared to socially reared animals in the OFT, with agomelatine significantly reducing SIR-induced locomotor hyperactivity in both genders. SIR, in both male and female rats, induces anxiety-like behavioural alterations in the EPM and SIT. In the SIT SIR significantly decreased social interaction in both genders compared to their social reared counterparts. Agomelatine significantly increased the time spent anogenital sniffing in male rats and a trend towards increased time spent together and times approaching each other in male rats. Agomelatine tended to increase the time spent together in female rats. Rearing behaviour (self-directed behaviour) in the SIT was also significantly decreased in SIR rats in both genders with agomelatine significantly increasing such behaviour in both genders. SIR significantly increased anxiogenic behaviour in the EPM compared to socially reared animals, with agomelatine showing a trend in both genders towards reversal of this behaviour.
SIR significantly decreased the plasma corticosterone in both genders vs. socially reared animals, although agomelatine did not correct this anomaly. The results indicated no differences between SIR and socially reared animals with regard to GABA levels and NMDA receptor density in the frontal cortex, although agomelatine did show a trend to increase GABA levels and NMDA receptor density in male rats.
This study indicates that SIR is a reliable neurodevelopmental animal model to resemble anxiety-like behaviours akin to symptoms observed in anxiety disorders, with anxiety being evident to a similar extent in both genders. Agomelatine decreased SIR-induced anxiety-like behaviours in both genders, although the treatment response in male rats was superior and more consistent. The study further suggests that the behavioural alteration observed in the SIR animals were arguably not associated with alterations regarding GABA, glutamate or corticosterone, but further research in this regard is warranted||en_US