Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles

Abstract

BackgroundExtensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles.MethodsJuvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1 day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15 days. Social behaviors were assessed at 1 and 15 days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress.ResultsStress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects.ConclusionsThese findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

Mechanisms of Shared Vulnerability to Post-traumatic Stress Disorder and Substance Use Disorders

“…It has also been reported that patients who are less responsive to PTSD therapy have salivary cortisol responses to trauma-related imagery that actually strengthens over the course of treatment rather than decreasing or remaining constant (Rauch et al, 2017). Animal studies suggest that, especially with repeated re-exposure to trauma-related cues, these conditioned stress responses can become progressively stronger and expand to other central neurochemical systems such as norepinephrine (Anisman and Sklar, 1979;Jedema et al, 2008;Chen et al, 2012) and serotonin (Adell et al, 1988;Zhang et al, 2014;Hasegawa et al, 2018).…”

Resting-state dopaminergic cell firing in the ventral tegmental area negatively regulates affiliative social interactions in a developmental animal model of schizophrenia

“…These monoamines are known to independently and/or interactively regulate animal social behaviors through cognitive and/or instinctive processes 8 – 11 . The fact that the treatment effects of antipsychotics and antidepressants only emerge after their long-term intake suggests a pathological role of chronic dysregulation of monoaminergic neurotransmission in these disorders 12 – 15 . However, the pathophysiological nature of chronic monoaminergic dysfunctions underlying social deficits remains to be elucidated in schizophrenia 16 , 17 .…”

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“…The stress-induced stimulus of serotonergic and dopaminergic systems has been observed as plasticity that aids the brain reorganize its neuronal network (Hasegawa, 2018). The increase in DA levels in cortex and hippocampus tissue of noiseexposed rats (Figure 2) may reduce the plasticity of synapses resulting in impairment of memory.…”