Risperidone Attenuates Modified Stress-Re-stress Paradigm-Induced Mitochondrial Dysfunction and Apoptosis in Rats Exhibiting Post-traumatic Stress Disorder-Like Symptoms.
Mitochondria play a significant role in the pathophysiology of post-traumatic stress disorder (PTSD). Risperidone and paroxetine were evaluated for their effect on mitochondrial dysfunction and mitochondria-dependent apoptosis in discrete brain regions in modified stress re-stress (SRS) animal model of PTSD. Male rats were subjected to stress protocol of 2 h restraint and 20 min forced swim followed by halothane anesthesia on day 2 (D-2). Thereafter, rats were exposed to re-stress (forced swim) on D-8 and at 6-day intervals on D-14, D-20, D-26, and D-32. The rats were treated with risperidone (0.01, 0.1, and 1.0 mg/kg p.o.) and paroxetine (10.0 mg/kg p.o.) from D-8 to D-32. Risperidone at median dose and paroxetine ameliorated modified SRS-induced depressive-like symptom (increase in immobility period) in forced swim, anxiety-like behavior (decrease in percentage of open arm entries and time spent) in elevated plus maze and cognitive deficits (loss in spatial recognition memory) in Y-maze tests on D-32. Risperidone, but not paroxetine, attenuated modified SRS-induced decreases in plasma corticosterone levels. Risperidone ameliorated increase in the activity of mitochondrial respiratory complex (I, II, IV, and V), decreases in the levels of mitochondrial membrane potential, cytochrome-C and caspase-9 in the hippocampus, hypothalamus, pre-frontal cortex, and amygdala. However, both drugs attenuated modified SRS-induced increase in the number of apoptotic cells and caspase-3 levels in all the brain regions indicating anti-apoptotic activity of these drugs. Hence, these results suggest that anti-apoptotic activity could be a common mechanism for anti-PTSD-like effect irrespective of the pathways of apoptosis in the modified SRS model.
Neurotherapeutics Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221 005, UP, India.
Debapriya
D
Garabadu
Ausaf
A
Ahmad
Sairam
S
Krishnamurthy
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D008297:Male; D018782:Maze Learning; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017374:Paroxetine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018967:Risperidone / Q000494:pharmacology* / Q000627:therapeutic use; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy*
D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D017374:Paroxetine; D018967:Risperidone; D003345:Corticosterone