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. 2013 Mar;37(6):1022-31.
doi: 10.1111/ejn.12113. Epub 2013 Jan 8.

Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats

Jordan T Yorgason  1 , Rodrigo A España, Joanne K Konstantopoulos, Jeffrey L Weiner, Sara R Jones
Affiliations

Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats

Jordan T Yorgason et al. Eur J Neurosci. 2013 Mar.

Abstract

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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Figures

Fig. 1
Fig. 1
Schematic model of housing paradigm and experimental timeline. Rats were obtained on postnatal day (PD) 21 and placed in group-housed (GH) conditions until PD 28. Two groups maintained GH, while another two groups were socially isolated (SI) for the remainder of the study. At PD 74 all rats were tested on the elevated plus-maze (EPM). A set of SI and GH rats were killed, and slice voltammetry experiments were performed to examine release, uptake and autoreceptor activity (PD = 84 ± 7). The second set of SI and GH rats were isolated for four additional months (PD = 77–174), and examined again on the EPM and in similar voltammetry experiments to the previous group (PD = 181 ± 7).
Fig. 2
Fig. 2
Effect of isolation rearing on anxiety-like behavior on the EPM. Bar graph illustrating the effect of adolescent rearing condition on mean (± SEM) open- and closed-arm time, and number of closed-arm entries in the EPM at two separate time points, PD 74 (A) and PD 174 (B) in group-housed (GH n = 7) and socially isolated (SI n = 7) rats. *P < 0.05.
Fig. 3
Fig. 3
NAc core stimulated dopamine overflow in socially isolated (SI; young n = 8; adult n = 7) and group-housed (GH; young n = 8; adult n = 7) rats. (A) Averaged background subtracted voltammetric color plots for SI and GH rats, with applied potential (y-axis) plotted against time (x-axis) and current (z-axis). (B) Mean (± SEM) concentration vs. time traces for GH- and SI-reared rats. Solid line is mean data, whereas the lighter outline represents the SEM.
Fig. 4
Fig. 4
Effect of isolation rearing on stimulated dopamine release and uptake rate within the NAc. (A) Bar graph of mean (± SEM) stimulated dopamine release in socially isolated (SI) and group-housed (GH) rats at young (left; PD = 84 ± 7; GH n = 8; SI n = 8) and adult (right; PD = 181 ± 7; GH n = 7; SI n = 7) time points. (B) Bar graph of mean (± SEM) dopamine uptake rates (Vmax) in SI and GH rats at young (left; PD = 84 ± 7; GH n = 8; SI n = 8) and adult (right; PD = 181 ± 7; GH n = 7; SI n = 7) time points. *P < 0.05, **P < 0.01.
Fig. 5
Fig. 5
Relationship between dopamine function and anxiety-like behavior. NAc dopamine release (A) and rate of uptake (Vmax; B) from voltammetric studies were significantly correlated with open-arm time on the EPM in data combined from young (PD 74) and adult (PD 174) group-housed (GH; blue) and socially isolated (SI; green) reared rats n = 30. Release P = 0.0099; Uptake P = 0.0164.
Fig. 6
Fig. 6
NAc dopamine D2 autoreceptor activity in group-housed (GH) and socially isolated (SI) reared rats. Electrically stimulated dopamine overflow was measured while bath-applying increasing concentrations of the D2-type dopamine receptor agonist quinpirole (10 nm–1 μm). (A) Mean μm dopamine release peak amplitude and (B) percent baseline stimulated dopamine in young (left; PD = 84 ± 7; GH n = 5; SI n = 5) and adult (right; PD = 181 ± 7; GH n = 4; SI n = 4) SI and GH rats. Quinpirole significantly reduced dopamine signals to the same extent in GH- and SI-reared rats for both young and adult cohorts.
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