Social Defeat Stress (SDS) in Mice: Using Swiss Mice as Resident.

[Abstract] Due to the high prevalence and great economic impact of depression, studies with animal models have been increasingly used to identify neurobiological mechanisms associated with this disorder. However, many animal models use stressful conditions that are not consistent with what we observe in the modern human world. Examples are the chronic unpredictable stress and the electric shock model used in rodents. It's well established the social stress as the major cause of depressive disorder in human, in this way a social defeat stress model was recently standardized and can induce depressive-like behavior of social avoidance, a typical human depressive behavior. In this model, mice are exposed on consecutive days to an aggressor mouse, suffering brief periods of physical aggression followed by longer periods of visual and olfactory (sensory) contact and, as a consequence, a relationship of social submission is characterized. Thus, the objective of this work is to describe a social defeat stress protocol using swiss mice as resident, also describing valuable procedural suggestions that will help researchers to reproduce the model easily.

Social defeat stress induces hyperalgesia and increases truncated BDNF isoforms in the nucleus accumbens regardless of the depressive-like behavior induction in mice.

Epidemiological studies have shown a close association between pain and depression. There is evidence showing this association as patients with depression show a high chronic pain prevalence and vice versa. Considering that social stress is critical for the development of depression in humans, we used a social defeat stress (SDS) model which induces depressive-like behavior in mice. In this model, mice are exposed to an aggressor mouse for ten days, suffering brief periods of agonistic contact and long periods of sensory contact. Some mice display social avoidance, a depressive-like behavior, and are considered susceptible, while some mice do not, and are considered resilient. Thus, we investigated the nociceptive behavior of mice submitted to SDS and the neuroplastic changes in dopaminergic mesolimbic system. Our results showed that the stressed mice (resilient and susceptible) presented a higher sensitivity to pain than the control mice in chemical and mechanical tests. We also verified that susceptible mice have higher Bdnf mRNA in the VTA compared to the resilient and control mice. The stressed mice had less mature BDNF and more truncated BDNF protein in the NAc compared with control mice. Although social stress may trigger the development of depression and hyperalgesia, these two conditions may manifest independently as social stress induced hyperalgesia even in mice that did not display depressive-like behavior. Also, increased Bdnf in the VTA seems to be associated with depressive-like behavior, whereas high levels of truncated BDNF and low mature BDNF appear to be associated with hyperalgesia induced by social defeat stress.

Nucleus accumbens dopaminergic neurotransmission switches its modulatory action in chronification of inflammatory hyperalgesia.

Dopaminergic neurotransmission in the nucleus accumbens, a central component of the mesolimbic system, has been associated with acute pain modulation. As there is a transition from acute to chronic pain ('chronification'), modulatory structures may be involved in chronic pain development. Thus, this study aimed to elucidate the role of nucleus accumbens dopaminergic neurotransmission in chronification of pain. We used a rat model in which daily subcutaneous injection of prostaglandin E2 in the hindpaw for 14 days induces a long-lasting state of nociceptor sensitization that lasts for at least 30 days following the end of the treatment. Our findings demonstrated that the increase of dopamine in the nucleus accumbens by local administration of GBR12909 (0.5 nmol/0.25 µL), a dopamine reuptake inhibitor, blocked prostaglandin E2 -induced acute hyperalgesia. This blockade was prevented by a dopamine D2 receptor antagonist (raclopride, 10 nmol/0.25 µL) but not changed by a D1 receptor antagonist (SCH23390, 0.5, 3 or 10 nmol/0.25 µL), both co-administered with GBR12909 in the nucleus accumbens. In contrast, the induction of persistent hyperalgesia was facilitated by continuous infusion of GBR12909 in the nucleus accumbens (0.021 nmol/0.5 µL/h) over 7 days of prostaglandin E2 treatment. The development of persistent hyperalgesia was impaired by SCH23390 (0.125 nmol/0.5 µL/h) and raclopride (0.416 nmol/0.5 µL/h), both administered continuously in the nucleus accumbens over 7 days. Taken together, our data suggest that the chronification of pain involves the plasticity of dopaminergic neurotransmission in the nucleus accumbens, which switches its modulatory role from antinociceptive to pronociceptive.