Zidovudine reduces ketamine-induced psychotic symptoms in mice

Abstract

Introduction: Infection with human immuno-deficiency virus (HIV) is associated with several neurological disorders including psychotic symptoms. Treatment or therapeutic management of these symptoms with conventional anti-psychotic drugs (APDs) is associated with drug-drug interaction and side effects that may cause treatment failure. Zidovudine (AZT) an anti-retroviral (ARV) drug, is a nucleoside analogue reverse transcriptase inhibitor (NRTI) with highest CNS penetrating ability, but few or nothing is known about its CNS effects.

Objective of study: To evaluate the effect of AZT on ketamine-induced depression, hyperkinesia, and cognitive function in mice.

Method: Acute toxicity was conducted for oral and intraperitoneal administration using Lorke’s (1983) method. Acute zidovudine alone and its concurrent (AZT + Ketamine) sub-chronic (7 days) administration was investigated using forced swim test, open field locomotor test and Y-maze test. Olanzepine (5mg/kg), Haloperidol (1 mg/kg) and Eserine (0.03 mg/kg) were used as standard controls respectively with saline as normal control. Eserine was administered intraperitoneal 30 minutes before the test, while the 5 tested zidovudine doses (12.5, 25, 50, 100 and 200 mg/kg) were administered singly orally for 60 minutes prior to the acute test while ketamine 30mg/kg intraperitoneal administered concurrently for 7 days for the sub-chronic test

Result: The LD50 for oral and intraperitoneal administration were determined to be 3807.88 mg/kg and 2154 mg/kg respectively. Concurrent AZT administration with ketamine for 7 days, significantly (p<0.001) reduced immobility time at AZT doses of 25 mg/kg and 12.5 mg/kg compared to the control. The 7-days AZT concurrent treatments with ketamine reduced locomotion at all AZT test groups, compared to normal control group. The mean percent alternation was severely reduced in acute AZT treatments, but increased in concurrent AZT-ketamine administration.

Conclusion: AZT ameliorate ketamine-induced psychotic-like symptoms in mice, but was found to cause cognitive deficits in normal controls.