Effects of a gastrin-releasing peptide receptor antagonist on d-amphetamine-induced oxidative stress in the rat brain

Previous studies have suggested that bipolar disorder may be associated with oxidative stress. Administration of d-amphetamine (AMPH) has been put forward as an animal model of mania, and has shown to increase oxidative stress parameters in the rat brain. Thus, we have used the gastrin-releasing peptide receptor antagonist D-Tpi⁶Leu¹³psi (CH₂NH)-Leu¹⁴] bombesin (RC-3095) as a pharmacological tool to investigate the role of bombesin-like peptides in the redox balance in the hippocampus and cortex of rats treated with AMPH. Rats were given a single 10 ml/kg intraperitoneal (i.p.) injection of saline (SAL) or RC-3095 (0.1, 1.0 or 10.0 mg/kg) followed by an i.p. injection of SAL or amphetamine (AMPH 2.0 mg/kg) 30 min later. Locomotor activity was evaluated 2 h after the last drug injection. The thiobarbituric acid reactive substances (TBARS), protein carbonyl formation, superoxide dismutase and catalase (CAT) activity were measured in hippocampus, striatum and cortex as markers of oxidative stress. The results show that RC-3095 blocks AMPH-induced hyperlocomotion. Moreover, specific doses of RC-3095 alone increased the levels of oxidative stress in the dorsal hippocampus and cortex. However, when AMPH was subsequently administrated, RC-3095 decreased TBARS and protein carbonyls formation and increased the superoxide dismutase and CAT activity in the hippocampus, striatum and cortex. The effects of GRPR antagonist seemed to be region and dose specific. In conclusion, the results suggest that GRPR antagonists might display antioxidant properties in the brain.