Inherent vulnerabilities in monoaminergic pathways predict the emergence of depressive impairments in an animal model of chronic epilepsy

Abstract

The objective was to determine whether the depression comorbid with epilepsy could be predicted based on inherent premorbid patterns of monoaminergic transmission. In male Wistar rats, despair-like and anhedonia-like behaviors were examined using forced swimming and taste preference tests, respectively. Serotonergic raphe nucleus (RN)-prefrontal cortex (PFC) and dopaminergic ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathways were interrogated by fast scan cyclic voltammetry (FSCV). The assays were performed before and 2 months after pilocarpine status epilepticus. In a subset of naive rats, FSCV, coupled with the intensity-dependent stimulation paradigm, detected specific deviations in each pathway (six rats for RN-PFC and seven rats for VTA-NAcc, with overlap in two, of 19 total subjects) in the absence of behavioral impairments. During epilepsy, animals with preexisting deviations in RN-PFC invariably developed despair, and rats with deviations in VTA-NAcc developed anhedonia. Serotonergic and dopaminergic pathways, respectively, showed signs of explicit deterioration. We suggest that epilepsy triggers decompensations in the already vulnerable depression-relevant neuronal circuits, which culminate in depression. The established connection between the identified specific signatures in monoamine transmission in naive rats and specific symptoms of epilepsy-associated depression may help in understanding causes of comorbidity and in developing its early biomarkers.

Keywords: Biomarkers; Depression; Dopamine; Epilepsy; Serotonin.

Figure 1. Patterns of monoamine transmission

A. Plot of responses from individual animals (n=19) measured before SE in the RN-PFC and VTA-NAcc pathways. The amount of the released neurotransmitter (Y-axis) is plotted against stimulus intensity (X- axis). The data best fit the 5^th order polynomial nonlinear models, which are shown by the color-matched lines. Inset shows Mean±SD. B. Fifth order polynomial nonlinear model built on the stimulus intensity-dependent responses detected by FSCV in the animals of different categories. In resistant subjects (the rest of animals on A), the pattern was nearly linear throughout the stimulation range. In vulnerable subjects, (indicated by solid boxes on A) the responses followed sigmoidal pattern, with less progressive increase occurring at lower stimulus intensities, and more linear- at higher intensities. After the induction of epilepsy and the development of depressive-like behaviors, in the vulnerable animals the response pattern was still sigmoidal, however it shifted downward and became saturated at 350 μV. Resistant animals, which developed no behavioral impairments after SE, retained the same response pattern as before SE.

Figure 2. Performance in behavioral tests and its relationship with monoaminergic transmission

A- behavior in the TPT and D- behavior in the FST before and after SE. Shown are Mean±SD, **-p<0.05; ***- p<0.01; ****0 p<0.001, Epilepsy vs. Before Epilepsy; †- p<0.05, normal vs. respective vulnerable (2-Way ANOVA+Tukey’s). Sample sizes: All n=19; 5-HT-vulnerable n=6; 5-HT-resistant n=13; DA-vulnerable n=7; DA-resistant n=12. FST interaction F (2, 70) = 3.1, p<0.05; effects of animal category F (2, 70) = 3.388, p<0.05; effects of epilepsy F (1, 70) = 28.58, p<0.0001. TPT interaction F (2, 70) = 5.420, p<0.01; effects of animal category F (2, 70) = 2.574, p<0.05; effects of epilepsy F (1, 70) = 62.44, p<0.0001. B and E- individual plots of dopaminergic and serotonergic responses to 200 μV stimulus prior to SE vs. behavior in TPT and FST after SE. At this stimulus intensity, lower inherent monoamine responses correlated with more severe behavioral abnormalities (Pearson correlation coefficients “r” are shown on respective panels). No such correlation was detected for other stimulus intensities. C- dopaminergic transmission in the VTA-NAcc pathway and F- serotonergic transmission in the RN-PFC measured by FSCV in resistant and vulnerable rats before and after the development of epilepsy and behavioral impairments. Shown are Mean± SD. *- p<0.05 (paired t-tests). Sample sizes: 5-HT vulnerable, n=6; 5-HT-resistant n=6; DA-vulnerable n=7; DA vulnerable n=5.