Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA. European Journal of Neuroscience
(Impact Factor: 3.18).
01/2013; 37(6). DOI: 10.1111/ejn.12113
Social isolation (SI) rearing, a model of early life stress, results in profound behavioral alterations, including increased anxiety-like behavior, impaired sensorimotor gating and increased self-administration of addictive substances. These changes are accompanied by alterations in mesolimbic dopamine function, such as increased dopamine and metabolite tissue content, increased dopamine responses to cues and psychostimulants, and increased dopamine neuron burst firing. Using voltammetric techniques, we examined the effects of SI rearing on dopamine transporter activity, vesicular release and dopamine D2-type autoreceptor activity in the nucleus accumbens core. Long-Evans rats were housed in group (GH; 4/cage) or SI (1/cage) conditions from weaning into early adulthood [postnatal day (PD) 28-77]. After this initial housing period, rats were assessed on the elevated plus-maze for an anxiety-like phenotype, and then slice voltammetry experiments were performed. To study the enduring effects of SI rearing on anxiety-like behavior and dopamine terminal function, another cohort of similarly reared rats was isolated for an additional 4 months (until PD 174) and then tested. Our findings demonstrate that SI rearing results in lasting increases in anxiety-like behavior, dopamine release and dopamine transporter activity, but not D2 activity. Interestingly, GH-reared rats that were isolated as adults did not develop the anxiety-like behavior or dopamine changes seen in SI-reared rats. Together, our data suggest that early life stress results in an anxiety-like phenotype, with lasting increases in dopamine terminal function.
Available from: Maryam Rahimi Balaei
- "On the other hand, a number of studies have reported that impairment in neurotransmitter systems (mostly serotonergic system) plays a role in development of aggression, anxiety and fear in socially isolated rodents   . Evidence suggests that 5-hydroxytryptamine3 (5-HT3) receptors, as ligand gated ion channels, are involved in development and maturation of the brain mostly formation of the inhibitory networks. "
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Early social isolation stress (SIS) is associated with the occurrence of anxiety behaviors. It seems interaction between the nitrergic system and mitochondrial function plays a role in mediating the anxiety-like behaviors. In this study, we aimed to investigate the anxiolytic effects of tropisetron in animal model of SIS and we try to illustrate the possible role of nitrergic system and mitochondrial function.
We applied early social isolation paradigm to male NMRI mice. Animals treated with various doses of tropisetron, nitric oxide agents or their combination and anxiety-like behaviors of animals were assessed using valid behavioral tests including elevated plus maze (EPM), open-field test (OFT) and hole-board test (HBT) in their adulthood. Effects of housing conditions and drug treatments on the mitochondrial function were investigated in the hippocampus by assessing the ATP, GSH, ROS and nitrite levels.
anxiogenic effects of early SIS were assessed in the EPM, OFT, and HBT. Also, SIS disrupted mitochondrial function and caused oxidative stress in the hippocampus of stressed animals. Tropisetron showed an anxiolytic effect in the stressed mice. Also, these effects were mediated by nitrergic system by affecting mitochondrial function and modulating the oxidative stress. L-arginine, a nitric oxide precursor, abolished the anxiolytic effects of tropisetron in the behavioral tasks and blocked the protective effects of it against mitochondrial and oxidative challenge.
Conclusions and general significance:
Our results demonstrated tropisetron attenuated the anxiogenic effects of SIS by mitigation of the negative effects of nitric oxide on mitochondrial function.
- "The consequences of social isolation have been extensively studied, particularly in relation to the effects on HPA activity. Social isolation housing in various strains of rats results in increases in anxiety-like   and aggressive behaviors  , increases in plasma ACTH    and CORT levels  , as well as sex-specific increases in adrenal weights . Chronic isolation housing in the prairie vole (Microtus ochrogaster) is associated with increases in anxiety-like behavior and aggression   , increases in CORT levels [41,42,44–47], and increases in CRH-immunoreactive (CRH-ir) cell densities in the PVN    and CRH mRNA . "
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ABSTRACT: The early life experiences of an organism have the potential to alter their developmental trajectories. Perhaps one of the most powerful influences during this period is the parent-offspring relationship. Previous work in several mammalian species has demonstrated that parental care in early life and specifically maternal behavior can influence several adult outcomes in offspring, including affiliative and aggressive behavior, parental behavior, hypothalamic-pituitary-adrenal (HPA) functioning and risk of psychopathology. We have previously demonstrated that naturally occurring variation in the type and amount of care given to offspring in a biparental species, the prairie vole (Microtus ochrogaster), is related to social, anxiety-like, aggressive behaviors as well as HPA response to chronic and acute social stressors. Here we aim to determine the effects of early biparental care on HPA functioning and the interaction between early care and later reactivity to a forced swim test, an acute non-social stressor. Behavior during the swim test as well as several indicators of HPA activity, including plasma corticosterone (CORT), corticotropin releasing hormone immunoreactivity (CRH-ir), and vasopressin immunoreactivity (AVP-ir) were measured. Results here indicate an effect of early experience on AVP-ir but not CRH-ir or plasma CORT. There were no differences in CORT levels between high-contact (HC) and low-contact (LC) males or females for either control animals or after a swim stressor. CRH-ir was higher in the central amygdala following a swim test but was not influenced by early care. However, AVP-ir was not influenced by exposure to a swim stressor but was affected by early parental care in a sex-dependent manner. Female HC offspring had increased AVP-ir in the SON while HC male offspring had decreased AVP-ir in the PVN compared to their LC counterparts. The differential response of CRH and AVP to early experience and later stress, and the lack of an interaction early care rearing and later adult stress, suggest an independence in response of some components of the HPA system. In addition, these findings expand our understanding of the relationship between naturally occurring variation in early biparental care and sexual dimorphisms in adult outcomes.
Copyright © 2015. Published by Elsevier Inc.
Available from: Anushree N. Karkhanis
- "For example, most EtOH drinking studies are conducted in single-housed rodents and these rats begin drinking during adolescence (Simms et al., 2008), which may influence the intake of EtOH such that there is an overall greater EtOH consumption. It is important to note that social isolation during adulthood does not alter NA DA signaling (Yorgason et al., 2013; Whitaker et al., 2013) or anxiety-like behaviors in Long–Evans rats. Moreover, environmental enrichment decreases intake of EtOH in rodents (Rockman et al., 1983), and group housing is a form of environmental enrichment. "
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Early-life stress is associated with increased vulnerability to alcohol addiction. However, the neural substrates linking chronic childhood/adolescent stress and increased risk of alcohol addiction are not well understood. In the nucleus accumbens (NAc), dopamine (DA) and norepinephrine (NE) signaling can be profoundly influenced by stress, anxiety, and drugs of abuse, including ethanol (EtOH). Here, we employed a rodent model of early-life stress that results in enduring increases in behavioral risk factors of alcoholism to gain a better understanding of how chronic adolescent stress may impact the EtOH sensitivity of DA and NE release in the NAc.Methods
Male Long–Evans rats were either group housed (GH; 4 rats/cage) or socially isolated (SI; 1 rat/cage) for 6 weeks beginning on postnatal day 28. SI and GH rats were tested in adulthood for anxiety-like behaviors (elevated plus maze), and the effects of EtOH (1 and 2 g/kg; intraperitoneally.) on NAc DA and NE were assessed by microdialysis.ResultsSI animals showed increased anxiety-like behavior compared to GH animals. Although SI had no effect on baseline levels of DA or NE, baseline DA levels were positively correlated with anxiety measures. In addition, while no significant differences were observed with 1 g/kg EtOH, the 2 g/kg dose induced significantly greater DA release in SI animals. Moreover, EtOH (2 g/kg) only elevated NAc NE levels in SI rats.Conclusions
These results suggest that chronic early-life stress sensitizes accumbal DA and NE release in response to an acute EtOH challenge. A greater EtOH sensitivity of DA and NE release dynamics in the NAc may contribute to increases in behavioral risk factors of alcoholism, like greater EtOH self-administration, that are observed in SI rats.
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