Social isolation of adolescent male rats increases anxiety and K⁺‐induced dopamine release in the nucleus accumbens: Role of CRF‐R1

Abstract

Early life adversity can disrupt development leading to emotional and cognitive disorders. This study investigated the effects of social isolation after weaning on anxiety, body weight and locomotion, and on extracellular dopamine (DA) and glutamate (GLU) in the nucleus accumbens (NAc) and their modulation by corticotropin releasing factor receptor 1. On the day of weaning, male rats were housed singly or in groups for 10 consecutive days. Anxiety‐like behaviors were assessed by an elevated plus maze (EPM) and an open field test (OF). Neurotransmitter levels were measured by in vivo microdialysis. Single‐housed rats spent less time, and entered more, into the closed arms of an EPM than group‐housed rats. They also spent less time in the center of an OF, weighed more and showed greater locomotion. In the NAc, no differences in CRF, or in basal extracellular DA or GLU between groups, were observed. A depolarizing stimulus increased DA release in both groups but to higher levels in isolated rats, whereas GLU increased only in single‐housed rats. Blocking CRF‐R1 receptors with CP‐154,526 decreased DA release in single‐housed but not in group‐housed rats. The corticotropin releasing factor receptor type 1 receptor antagonist also decreased GLU in group‐housed animals. These results show that isolating adolescent rats increases anxiety, body weight and ambulation, as well as the sensitivity of dopaminergic neurons to a depolarizing stimulus. This study provides further evidence of the detrimental effects of social isolation during early development and indicates that dysregulation of the CRF system in the NAc may contribute to the pathologies observed.

The effects of social isolation stress and discrimination on mental health

“…Regarding dopamine, post-weaning social isolation stress in rodents did not alter basal extracellular dopamine levels; however, dopamine concentrations in the nucleus accumbens were increased by a depolarizing stimulus, and the effect was stronger in rodents exposed to social isolation [ 50 ]. In comparison in humans, using psychostimulants to elicit dopamine release revealed increased striatal dopamine levels among in subjects with schizophrenia at onset of illness, independent of previous neuroleptic medication [ 51 ].…”

Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models

“…Despite some attempts to standardize the separation times, the behavioral results of this manipulation vary considerably. Several studies have discussed how maternal separation has differential ↑ "Anxiety-like" and "depressive-like" behavior in rats and mice Murthy et al, 2019Hill et al, 2018Mejía-Chávez et al, 2021Laham et al, 2022Wei et al, 2021Matsumoto et al, 2017Novoa et al, 2021 Mixed -scarcity and abuse (LBN) AMY Striatum ACC ↑"Depressive-like behavior" in rats and mice Raineki et al, 2012Wendel et al, 2021Holschneider et al, 2016 Multiple hitschronic unpredictable stress, chronic social defeat HIP PFC VTA NAc ↑ "Anxiety-like" and "depressive-like" behavior in rats and mice and Coutellier, 2018 Huang et al, 2021Saavedra et al, 2021Isgor et al, 2004Oztan et al, 2011Rodríguez-Arias et al, 2018 , Brain changes associated with behavioral changes; Brain changes without behavioral analyses. ACC, anterior cingulate cortex; AMY, amygdala; HIP, hippocampus; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area.…”

“…Aside from depriving preweaning pups of maternal contact, additional studies have examined deprivation in adolescence by using models of social isolation housing after weaning. These studies have shown that social isolation reduces stress coping, social interaction, and reward seeking, behaviors that may reflect “depressive-like” and “anxiety-like” phenotypes ( Chang et al, 2015 ; Matsumoto et al, 2017 ; Novoa et al, 2021 ; Potrebić et al, 2021 ).…”

“…Studies involving maternal separation during the preweaning period or social isolation during adolescence have revealed brain changes in areas that have been shown to be affected in humans subjected to early life emotional neglect, such as the medial prefrontal cortex, hippocampus, amygdala, and striatum ( Edmiston et al, 2011 ; Morgan et al, 2014 ; Matsumoto et al, 2017 ; Hill et al, 2018 ; Murthy et al, 2019 ; Peña et al, 2019 ; Mejía-Chávez et al, 2021 ; Novoa et al, 2021 ; Laham et al, 2022 ). The extent to which the reported brain changes after maternal separation are similar to those in humans subjected to emotional neglect (compare Table 2 with Table 1 ), beyond the commonalities in the affected brain regions remains unknown.…”

Long-Term Impacts of Post-weaning Social Isolation on Nucleus Accumbens Function

“…Dopamine release into the NAc is a measure of both dopaminergic cell function and responsiveness and SI-R has been shown to affect dopamine release, reuptake and metabolism in reward-associated regions in a region-specific manner [Figure 3; (50)]. With regard to the NAc, SI-R has no effect on extracellular dopamine levels at baseline (89,(108)(109)(110)(111)(112), but increases basal dopamine turnover (110,112), suggesting that SI-R alters baseline dopamine release and uptake mechanisms at least in males.…”