A GLT-1 mediated mechanism is implicated in the effects of chronic variable stress on an inbred rat model of the novelty-seeking phenotype

Aydin C, Medina A, Frohmader K, Watson SJ, Akil H
Society for Neuroscience. 2013.


Individual differences exist in vulnerability to develop affective and addictive behaviors. While there is no single trait that underlies these behaviors, certain temperamental traits have been shown to be involved. One such personality trait, novelty-seeking, is modeled in rodents by identifying experimentally naïve outbred rats as high (HR) versus low (LR) responders according to their locomotor reactivity to the mild stress of a novel environment, with HRs displaying lower anxiety-, lower depressive-like behavior and higher addiction vulnerability compared to LRs. Moreover, our laboratory has employed a selective breeding strategy to selectively breed LRs and HRs to amplify these naturally-occurring differences in the LRHR rats, and created a unique animal model to study the neurobiological underpinnings of addictive and affective disorders, such as major depression disorder (MDD). Growing evidence implicates dysregulation of the glutamatergic system in pathophysiology of MDD. Likewise, we have recently shown that the expression of the membrane transporters SLC1A2, the human analog of rodent glutamate transporter 1 (GLT-1), was diminished in the hippocampi of subjects with MDD compared to controls (Medina et al., 2013), suggesting that drugs that increase GLT-1 may be of therapeutic value in treating this disease. The present study tests this hypothesis by, using a chronic variable stress (CVS) paradigm, a clinically-relevant procedure to induce depressive-like behavior in rodents. We ask whether there are basal differences in GLT-1 expression in various brain regions, including the hippocampus in bred LRs (bLR) and HRs (bHR) that could contribute to the observed phenotype differences in depressive-like behavior. We also ask whether CVS exposure affects bLRs and bHRs equally, and ascertain coordinate changes in the levels of GLT-1, along with several markers of fibroblast growth factor (FGF) signaling in these rats. The focus on the FGF system is based on the role this system plays in the interactions between neurons and glia, and on strong evidence linking changes in this system to the pathophysiology of depression (Turner, 2013; Turner et al., 2008; Evans et al., 2004). Finally, the effectiveness of pharmacological induction of GLT-1 in interfering with behavioral and neurobiological impact of CVS in bLRs and bHRs is investigated.