Chronic Stress Triggers Social Aversion via Glucocorticoid Receptor in Dopaminoceptive Neurons

Abstract

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…Increased DA neuron activity is a prerequisite for the subsequent behavioral manifestations of stress outcomes. [24][25][26][27] Indeed, pharmacological or optogenetic inhibition of VTA DA neurons promotes therapeutic-like effects as it reverses SD-induced social aversion and anhedonia. 24,25 Thus, VTA DA neurons are at a crossroad of nicotine's reinforcing effects and social stress-induced aversion.…”

“…[24][25][26][27] Indeed, pharmacological or optogenetic inhibition of VTA DA neurons promotes therapeutic-like effects as it reverses SD-induced social aversion and anhedonia. 24,25 Thus, VTA DA neurons are at a crossroad of nicotine's reinforcing effects and social stress-induced aversion. We hypothesized that nAChRs could be a pivotal molecular target, which would orchestrate the detrimental stress-nicotine interplay at the cellular and behavioral levels.…”

Dopamine Receptor Gene (DRD1-DRD5) Expression Changes as Stress Factors Associated with Breast Cancer

“…Previous study demonstrated that mental and physiological conditions of individuals are important in the promotion and development of cancers and changes in patient's life style could be effective in incidence of stress (Cohen et al, 2007;Mancino et al, 2011;Barik et al, 2013). Cancer cells and nerve fibers have cross-talks and thus could influence on each other.…”

“…It is one of the main reasons of cancer-related mortality in women and its rate in developing countries is annually 70% of which will occur (Haghighat S, 2012). Researchers believe that mental and physiological conditions of individuals are important in the promotion and development of cancers and changes in patient's life style could be effective in incidence of stress (Elenkov et al, 2000;Cohen et al, 2007;Barik et al, 2013). Improvement the quality of life can be effective in reduction of breast cancer patients' distress and the risk of breast cancer (Yavuzsen, 2012).…”

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

“…On the other hand, metyrapone-induced pharmacological adrenalectomy has the opposite effects (Czyrak et al, 1997). Moreover, long-term high levels of GCs under specific conditions of genetic susceptibility could exert a long-term, epigenetic control of ventral tegmental area-originated dopaminergic neurons (Niwa et al, 2013) as well as promote stress-related, dopamine-dependent adaptive changes in dopaminoceptive neurons related with emotional and social behavioural phenotypes (Barik et al, 2013), contributing to psychopathology. Furthermore, disruption of the circadian pattern of GCs' fluctuations and increased systemic GC levels in rats have been shown to increase dopamine release in the PFC possibly as a result of increased synthesis and vesicular storage, providing a mechanistic explanation for prefrontal dysfunction in bipolar and other affective disorders associated with GC dysrhythmia (Minton et al, 2009) (Figure 3).…”