The Effects Of Propofol On The Antidepressant-like Effects Induced By Ketamine In Rats

Objective: Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-D-aspartate (NMDA) receptor. Clinical findings and animal experiments point to a rapid onset of action for ketamine on the treatment of major depression and suggest that the NMDA receptor and acute increase of brain-derived-neurotrophic factor (BDNF) protein levels in hippocampus might be critical to the antidepressant-like effects induced by ketamine. Ketamine has been demonstrated to induce schizophrenia-like symptoms and cognitive impairment in humans, partly resulting from persistent increase in brain superoxide caused by ketamine. Anti-superoxide may represent a novel target for the treatment of ketamine-induced psychosis. Propofol ( 2,6-diisopropylphenol ) is a general anesthetic possessing actions inhibiting phosphorylation of NMDA Receptor NR1 Subunits and against oxidative stress in neurons, so the agent is presumed to interact with ketamine and hence to enhance the antidepressant-like effects involved in ketamine. Therefore, to test the possibility, this experiment has examined the behavioral effects and the BDNF protein levels in hippocampus of acute administration of ketamine and acute administration of ketamine after propofol pretreatment in rats. Methods: Rats were randomly divided into group I and group II (n=50/each), Rats in group I or II were again randomly divided into group A (sodiumChloride), group B (ketamine 20mg/kg), group C (imipramine 30mg/kg), group D (propofol 10mg/kg), group E (propofol 20mg/kg), group F (propofol 10mg/kg+ketamine 20mg/kg) and group G (propofol 20mg/kg+ketamine 20mg/kg ) (n=6/each). Rats in different groups were administered intraperitoneally (i.p.) with the corresponding drugs 60 minutes before the test sessions, i.e. open-field or forced swimming tests. All treatments were administered in 3ml volume. In group F and G, the interval time between propofol and ketamine administration was 15 min. In the open-field test, rats were treated with the corresponding drugs 60 min before the exposure to the open-field apparatus, in order to assess possible effects of drug treatment on spontaneous locomotor activity. Analysis of rat spontaneous activity was carried out in an open cardboard box, which is an arena 66×50 cm surrounded by 40 cm high walls. The floor of the open field was divided into 25 rectangles (13×10cm each) by black lines. Animals were gently placed on the center of floor, and left to explore the arena for 5 min. The number of horizontal (crossings) and vertical (rearings) activity performed by each rat during the 5 min observation period was counted. The forced swimming test involves two individual exposures to a cylindrical tank with water in which rats cannot touch the bottom of the tank or escape. The tank is made of transparent Plexiglas, 50 cm tall, 20 cm in diameter, and filled with water ( 23-25°C ) to a depth of 20 cm. Water in the tank was changed after each rat. For the first exposure, rats without drug treatment were placed in the water for 15 min ( pre-test session ). Twenty-four hours later, rats were placed in the water again for a 5 min session ( test session ), and the immobility time of rats were recorded in seconds. Rats were treated with ketamine, propofol + ketamine, imipramine or saline only 60 min before the second exposure to the cylindrical tank of water ( test session ). Immediately after the forced swimming test, acutely saline, ketamine, propofol + ketamine, imipramine -treated rats were sacrificed and the skulls were removed and hippocampus was dissected and stored at -20℃for biochemical analyses. The BDNF protein levels in hippocampus were measured by anti-BDNF sandwich-ELISA . Results:①Open-field test: In this test, the treatment with ketamine,propofol+ketamine and imiprimine did not modify the number of crossings and rearings compared with saline treated-rats ( n=6, P>0.05);②Forced swimming test:The immobility time in group A, B, C, D, E, F, G was (132.67±5.13), (68.17±6.05),(97.33±10.88),(126.50±4.09), (124.83±7.65), (54.67±8.29) and (55.83±6.11) s, respectively. The immobility time in group B, C, F, G was lower than that in group A ( n=6, P<0.01); Compared with group C,the immobility time in group B, F, G was decreased ( n=6, P<0.01); The immobility time in group F, G was also lower than that in group B ( n=6, P<0.01).③The BDNF protein levels in hippocampus measured by anti-BDNF sandwich-ELISA: the BDNF levels in hippocampus in group A, B, C, D, E, F, G was (84.50±4.85), (118.33±4.68), (89.67±4.68), (80.17±4.49), (79.17±4.36), (115.00±6.20) and (113.67±5.89) pg/ml, respectively. the BDNF levels in hippocampus in group B, F, G was higher than that in group A (n=6, P<0.05), but had no differences among group B, F, G (n=6, P>0.05). Conclusions: Propofol could increase the antidepressant-like effects induced by acute administration of ketamine in rats, but the mechanism might not be not related to the BDNF levels in hippocampus.