Chronic Social Isolation Stress during Peri-Adolescence Alters Presynaptic Dopamine Terminal Dynamics via Augmentation in Accumbal Dopamine Availability

Abstract

Chronic peri-adolescent stress in humans increases risk to develop a substance use disorder during adulthood. Rats reared in social isolation during peri-adolescence (aSI; 1 rat/cage) period show greater ethanol and cocaine intake compared to group housed (aGH; 4 rats/cage) rats. In addition, aSI rats have a heightened dopamine response in the nucleus accumbens (NAc) to rewarding and aversive stimuli. Furthermore, single pulse electrical stimulation in slices containing NAc core elicits greater dopamine release in aSI rats. Here, we further investigated dopamine release kinetics and machinery following aSI. Dopamine release, across a wide range of stimulation intensities and frequencies, was significantly greater in aSI rats. Interestingly, subthreshold intensity stimulations also resulted in measurable dopamine release in accumbal slices from aSI but not aGH rats. Extracellular [Ca2+] manipulations revealed augmented calcium sensitivity of dopamine release in aSI rats. The readily releasable pools of dopamine, examined by bath application of Ro-04-1284/000, a vesicular monoamine transporter 2 (VMAT2) inhibitor, were depleted faster in aGH rats. Western blot analysis of release machinery proteins (VMAT2, Synaptogyrin-3, Syntaxin-1, and Munc13-3) showed no difference between the two groups. Tyrosine hydroxylase (TH) protein expression levels, however, were elevated in aSI rats. The greater dopamine release could potentially be explained by higher levels of TH, the rate-limiting step for dopamine synthesis. This augmented responsivity of the dopamine system and heightened dopamine availability post-aSI may lead to an increased risk of addiction vulnerability.

Comparison of neurotransmitter levels, physiological conditions, and emotional behavior between isolation‐housed rats with group‐housed rats

“…Interestingly, there were no significant differences in the DAergic system between the two groups in this study, although some previous studies have reported that social isolation stress alters the DAergic system in several brain areas, such as the prefrontal cortex, nucleus accumbens, or hippocampus (Han et al., 2011; Heidbreder et al., 2000; Karkhanis et al., 2019; Lapiz et al., 2003; Leng, Feldon, & Ferger, 2004). The review by Fone and Porkess (2008) reported that there are few consistent alterations in tissue levels of DA (and also 5‐HT and NA).…”

Social Isolation Stress in Adolescence, but not Adulthood, Produces Hypersocial Behavior in Adult Male and Female C57BL/6J Mice

“…Adolescent social isolation in rats has emerged as a preclinical model that recapitulates many of the deleterious behavioral outcomes linked to chronic adolescent stress in humans (Lukkes et al, 2009b ; Butler et al, 2016 ; Walker et al, 2019 ). In male rats, this paradigm has been shown to increase anxiety-like behavior and drug and ethanol intake and decrease fear memory extinction (McCool and Chappell, 2009 ; Whitaker et al, 2013 ; Butler et al, 2014a , 2016 ; Karkhanis et al, 2015 , 2019 ; Skelly et al, 2015 ; Yorgason et al, 2016 ), although these effects were not recapitulated in female rats (Butler et al, 2014b ). Isolation during adolescence has also been linked to decreased social interaction in rats (Ferdman et al, 2007 ).…”

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

“…Changes in its expression are often interpreted as a reflection of the dopamine available for release. In rats, SI-R increases TH protein-expression in synaptoneurosomes from the NAc when compared to GH males ( 120 ), which could explain the increased evoked dopamine observed after SI-R discussed above (section Adolescent Social Isolation and Disruption of Cellular Function With in the NAc). However, these effects may be species, molecule, and/or isolation type specific as a recent study investigating gene expression changes in mice ( 121 ), found that Th mRNA expression was unaffected by aSI in males and females in both the NAc and VTA.…”

“…Vesicular monoamine transporter (VMAT) is the protein necessary for packaging dopamine into vesicles ( Figure 3A ). Studies investigating VMAT protein levels ( 120 ) and RNA levels ( 121 ) found that adolescent social isolation has no effect on expression in the NAc of adult male rats ( 120 ) or male and female mice ( 121 ). However, aSI induced sex-specific changes in gene expression of VMAT (gene name: Slc18a2 ) in the VTA ( Figure 3B ), the presumed source of VMAT protein in terminals of dopaminergic neurons ( Figure 3A ).…”