Diazepam, a positive allosteric modulator of the GABAA receptor induces strain-specific responses in object recognition, ultrasonic vocalizations and monoaminergic profiles in the Wistar Kyoto rat model of endogenous depression.
TL;DR
Strain-specific differences of the dopaminergic response to DZP are investigated and the finding that DZP's affected more cognitive measures in Wistar than in WKY underscores the importance of strain and individual variability in translational research.
Abstract
Major depressive disorder (MDD) involves cognitive impairment, altered affective states and dysregulation of neurotransmitter homeostasis. The Wistar Kyoto (WKY) rat is characterized by inherent depressive-like behaviour, anxiety, cognitive deficits and dysregulated monoaminergic/GABAergic neurotransmission. This study investigated strain-specific differences in learning and memory, affective states and neurochemical responses to Diazepam (DZP), a positive allosteric modulator of the GABAA receptor, in Wistar and WKY rats. Learning and memory were assessed using the novel object recognition (NOR) paradigm, affective states through ultrasonic vocalizations (USVs) emitted, and monoaminergic levels in implicated brain areas using HPLC. DZPs significantly impaired NOR in Wistar, evidenced by reduced discrimination and recognition index (p < 0.05). DZP also increased contacts and approaches to familiar objects in Wistar (p < 0.05) and reduced approaches to novel objects in both Wistar (p < 0.01) and WKY (p < 0.001). DZP lowered bandwidth of 50-kHz USVs across both strains, though no DZP × strain interactions were observed on all acoustic and spectral parameters analyzed. WKYs displayed significantly lower baseline dopamine (DA) and serotonin (5-HT) in both PFC (DA: p < 0.001; 5-HT: p < 0.01) and hippocampus (DA: p < 0.01; 5-HT: p < 0.05). DZP reduced prefrontal (p < 0.001) and hippocampal DA (p < 0.001) levels in Wistar, with no effect in WKY, though DZP × strain interaction indicated differential effects on DA levels. Prefrontal 5-HT (p < 0.05) was also reduced in DZP-treated Wistars. Thus, strain-specific differences of the dopaminergic response to DZP and the finding that DZP's affected more cognitive measures in Wistar than in WKY underscores the importance of strain and individual variability in translational research.