1. Inhibition of phosphodiesterase-4 mitigates stress-re-stress-paradigm induced mitochondrial perturbations in rats exhibiting PTSD-like symptoms.
- Author
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Prajapati, Santosh Kumar, Chippala, Raviteja, and Krishnamurthy, Sairam
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MITOCHONDRIA ,POST-traumatic stress disorder ,MEMBRANE potential ,MITOCHONDRIAL membranes ,RATS - Abstract
Mitochondria are involved in the pathogenesis of post-traumatic stress disorder (PTSD). Phosphodiesterase-4 (PDE-4) regulates mitochondrial-dependent intracellular cAMP levels in neuropsychiatric disorders. Inhibition of PDE-4 with rolipram (RPM) has anxiolytic and psycho-mimetic properties. However, the role of PDE-4 inhibitor in PTSD remains unclear. Therefore, it may be useful in the treatment of comorbidities that resemble PTSD. The effects of RPM (PDE-4 inhibitor) and paroxetine (PAX) on mitochondrial dysfunction in the amygdala were investigated using the stress re-stress (SRS) model of PTSD. On day 2 (D-2), male rats were exposed to foot shock at intensity 2 mA for 10-second followed by halothane anesthesia. The rats were then subjected to re-stress of foot shock on D-8 to D-32 at 6-day intervals. RPM (0.5, 1, and 2 mg/kg) and PAX (10 mg/kg) treatments given orally from D-8 to D-32. RPM (1 and 2mg/kg) significantly attenuated SRS-induced PTSD-like symptoms like fear response, anxiety-like behavior, cognitive deficits and hypocorticosteronism. The SRS-induced decrease in mitochondrial respiratory complex (I, II, IV, and V) activity, respiratory control rate (RCR) and cAMP level in the amygdala were ameliorated by RPM. Further, sub-chronic treatment with RPM reduced the SRS-induced rise in ADP/ATP ratio in the amygdala. RPM ameliorated the SRS-induced alteration in mitochondrial membrane potential (MMP) and cytochrome-c levels in the amygdala. Thus, findings suggested that cAMP-dependent regulation of ADP/ATP ratio and mitochondrial function could be a potential mechanism for the anti-PTSD-like effect of RPM in the SRS model. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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