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
Source: PubMed


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.

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    • "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 [20] [21] [22]. 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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    ABSTRACT: Background: 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. Methods: 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. Results: 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.
    Biochimica et Biophysica Acta (BBA) - General Subjects 09/2015; DOI:10.1016/j.bbagen.2015.09.009 · 4.38 Impact Factor
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    • "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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    ABSTRACT: Background 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.
    Alcoholism Clinical and Experimental Research 11/2014; 38(11). DOI:10.1111/acer.12555 · 3.21 Impact Factor
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    • "That is, compared to animals GH during adolescence, SI engenders robust increases in anxiety-like behaviors and alcohol intake in male rodents (Chappell et al., 2013; McCool and Chappell, 2009). This behavioral phenotype is not only robust, but enduring in nature, and has marked effects on measures of neural plasticity (Miyazaki et al., 2012; Whitaker et al., 2013; Yorgason et al., 2013). This model is very simple to use and is effective in at least 2 rodent strains using male rodents. "
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    ABSTRACT: Background Clinically, early life stress and anxiety disorders are associated with increased vulnerability for alcohol use disorders. In male rats, early life stress, imparted by adolescent social isolation, results in long-lasting increases in a number of behavioral risk factors for alcoholism, including greater anxiety-like behaviors and ethanol (EtOH) intake. Several recent studies have begun to use this model to gain insight into the relationships among anxiety measures, stress, EtOH intake, and neurobiological correlates driving these behaviors. As prior research has noted significant sex differences in the impact of adolescent stress on anxiety measures and EtOH drinking, the current study was conducted to determine if this same model produces an “addiction vulnerable” phenotype in female rodents.Methods Female Long Evans rats were socially isolated (SI; 1/cage) or group housed (GH; 4/cage) for 6 weeks during adolescence. After this housing manipulation, behavioral assessment was conducted using the elevated plus maze, response to novelty in an open field environment, and the light/dark box. After behavioral testing, home cage EtOH drinking was assessed across an 8-week period.ResultsNo group differences were detected in any of the behavioral measures of unconditioned anxiety-like behavior. Greater EtOH intake and preference were observed in SI females but these differences did not persist.Conclusions The SI/GH model, which results in robust and enduring increases in anxiety measures and EtOH self-administration in male Long Evans rats, did not result in similar behavioral changes in female rats. These data, and that of others, suggest that adolescent social isolation is not a useful model with which to study neurobiological substrates linking antecedent anxiety and addiction vulnerability in female rats. Given the compelling epidemiological evidence that the relationship between chronic adolescent stress and alcohol addiction is particularly strong in women, there is clearly an urgent need to identify a more effective model with which to study these clinically important relationships in female rodents.
    Alcoholism Clinical and Experimental Research 08/2014; 38(8). DOI:10.1111/acer.12476 · 3.21 Impact Factor
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