Effects of 5-HT1A Receptor Antagonist and 5-HT2A Receptor Agonist on Morphine Withdrawal

Chronic administration of morphine causes physical dependence, possibly through serotonin 5‑HT_1A receptor (5-HT_1AR) and 5-HT_2A receptor (5-HT_1AR). The aim of this study was to evaluate the effect of 5-HT_1AR antagonist, NAD 299 hydrochloride (NAD 299), and 5-HT_2A R agonist (TCB-2) on the withdrawal syndrome in morphine-dependent mice. Adult male mice were randomly divided into five groups. Three groups of mice were treated with NAD-299 (0.3 mg/kg, i.p.) and TCB-2 (0.3 mg/kg, i.p.) 15 min before naloxone injection (3 mg/kg, s.c.) to investigate the effect of the 5-HT_1AR antagonist and 5-HT_2AR agonist on morphine withdrawal syndrome. Morphine was administered subcutaneously with increasing daily doses at 12-h intervals for five days to induce dependence. The withdrawal symptoms, including jumping, abdomen writhing, body weight loss, and head shakes, were recorded for 30 min. Cortisol and total antioxidant levels were assessed 2 h after the morphine withdrawal test. There was a reduction in total withdrawal score and an increase in head shakes and total antioxidant capacity in the NAD-299 + morphine group compared to the morphine group. The TCB-2 + morphine group exhibited an increase in jumping and a decrease in writhing, head shakes, and withdrawal score compared to the morphine group. The NAD-299 + TCB-2 + morphine group showed a decrease in the number of jumping and total withdrawal score, and an increase in the head shakes and cortisol levels compared to the morphine group. The combined treatment with NAD-299 and TCB-2 modulates the morphine withdrawal syndrome and increases cortisol levels.