Effects of different intensities of treadmill exercise on cued fear extinction failure, hippocampal BDNF decline, and Bax/Bcl-2 ratio alteration in chronic-morphine treated male rats.

Chronic morphine impairs cued fear extinction, which may contribute to the high prevalence of anxiety disorders and the replase of opiate addiction. This work investigated the effects of forced exercise with different intensities on cued fear extinction impairment and alternations of hippocampal BDNF and apoptotic proteins induced by chronic morphine. Rats were injected with bi-daily doses of morphine or saline for ten days and then received a cued or contextual fear conditioning training, which was followed by fear extinction training for four consecutive days. Cued, but the not contextual fear response was impaired in morphine-treated rats. Then, different saline or morphine-treated rats underwent forced exercise for 4-weeks with light, moderate or high intensities. Subsequently, rats received a cued fear conditioning followed by four days of extinction training, and the expression of hippocampal BDNF and apoptotic proteins was determined. A relatively long time after the last injection of morphine (35 days), rats again showed cued fear extinction failure and reduced hippocampal BDNF, which recovered by light and moderate, but not high exercise. Light and moderate, but not high-intensity treadmill exercise enhanced the up-regulation of Bcl-2 and down-regulation of the Bax proteins in both saline- and morphine-treated rats, which shifted the balance between pro-apoptotic and anti-apoptotic factors in favor of cell survival. These findings highlight the impact of exercise up to moderate intensity in the recovery of cued extinction failure, more likely via BDNF in addicted individuals.