Strain-Dependent Variations in Stress Coping Behavior Are Mediated by a 5-HT/GABA Interaction within the Prefrontal Corticolimbic System

Abstract

Background:Serotonin and γ–aminobutyric acid (GABA) transmission is crucial in coping strategies.Methods:Here, using mice from 2 inbred strains widely exploited in behavioral neurochemistry, we investigated whether serotonin transmission in medial prefrontal cortex and GABA in basolateral amygdala determine strain-dependent liability to stress response and differences in coping.Results:C57BL/6J mice displayed greater immobility in the forced swimming test, higher serotonin outflow in medial prefrontal cortex, higher GABA outflow in basolateral amygdala induced by stress, and higher serotonin 1A receptor levels in medial prefrontal cortex accompanied by lower GABAb receptor levels in basolateral amygdala than DBA/2J mice. In assessing whether serotonin in medial prefrontal cortex determines GABA functioning in response to stress and passive coping behavior in C57BL/6J and DBA/2J mice, we observed that selective prefrontal serotonin depletion in C57BL/6J and DBA/2J reduced stress-induced GABA outflow in basolateral amygdala and immobility in the forced swimming test.Conclusions:These results show that strain-dependent prefrontal corticolimbic serotonin/GABA regulation determines the strain differences in stress-coping behavior in the forced swimming test and point to a role of a specific neuronal system in genetic susceptibility to stress that opens up new prospects for innovative therapies for stress disorders.

The Key Role of the Amygdala in Stress

“…With regard to individual coping styles to stress, GABArgic transmission in the BLA has been shown to function in the response of C57BL/6 and DBA/2 mice in the forced swimming test. C57BL/6 mice exhibit the highest levels of passive-coping behavior [58,59,[66][67][68]. We have found that C57BL/6 mice show greater immobility in the forced swimming test (an index of passive-coping behavior), likely due to greater GABA outflow in the BLA, compared with DBA/2 mice [59].…”

“…Wellman and colleagues showed that the loss of 5-HTT function in mice compromises their ability to cope with environmental stress and effects morphological abnormalities in the BLA and mpFC-changes that were related to amygdalar hyperactivity and hypofunction in the pFC [132]. Further, regarding the function of the prefrontal 5-HT system in modulating the amygdalar stress response, we have demonstrated that bilateral selective 5-HT depletion in the mpFC in mice decreases the BLA GABA release that is induced by restraint stress and passive coping in the forced swimming test, implicating 5-HT and GABA transmission-mediated pFC/amygdala connectivity as a critical neural mechanism of stress-induced behavior [58,59].…”

“…GABAergic transmission in the amygdala is an important pathway by which the flow of information, activity, and function can be controlled [54][55][56], and considerable evidence has shown that this neurotransmitter in the amygdala is critical in mediating several aspects of the stress response. Studies in rats have demonstrated that acute restraint stress increases GABA efflux in the BLA [57][58][59][60]. Conversely, GABAergic transmission in the BLA declines the following exposure to chronic or repeated stress [57].…”

“…The impact of stress is also determined by the ability of the organism to cope with its situation [63]. Several reports have highlighted the function of GABAergic transmission in the mouse amygdala, particularly the BLA, in shaping an individual's coping style to stress [58,59], which, with other factors, can in turn affect one's predisposition to affective disorders, such as anxiety (for review, see [64]). Rats having more passive strategy of coping with an aversive event (i.e., a longer freezing response in the conditioned freezing test) are associated with upregulation of c-Fos (an index of neuronal activation) in the BLA and CeA, as a result of lower GABAergic activity in the amygdala [65].…”

Stress and Sensitization in Chronic Pain

“…Consistent with this viewpoint, impaired corticolimbic modulation has been suggested to be an important mechanism of stress-induced (p.199) hyperalgesia (Wang et al, 2013). Interestingly, this corticolimbic system was found to be related to strain differences in stress-coping behavior in mice (Andolina et al, 2014). Hence, reward/motivational circuits can be targeted by employing real-time feedback of neural activity, by fMRI (Chapin et al, 2012) or brain stimulation using TMS or deep brain stimulation; and these procedures hold promise for advancing future pain management (Navratilova & Porreca, 2014).…”