lithium-chloride and ifenprodil

Ifenprodil as a specific antagonist of NMDA receptors containing a dominant NR2B subunit exhibits age-dependent anticonvulsant action. Possible changes of this action due to status epilepticus (SE) elicited at early stage of development were studied using cortical epileptic afterdischarges (ADs) as a model.. Lithium-pilocarpine SE was induced at postnatal day 12 and effects of ifenprodil were studied 3, 6, 9, and 13 days after SE in rat pups with implanted epidural electrodes. Controls (LiPAR) received saline instead of pilocarpine. ADs were elicited by low frequency stimulation of sensorimotor cortex. Intensity of stimulation current increased in 18 steps from 0.2 to 15 mA. Ifenprodil (20 mg/kg) was administered intraperitoneally (ip) after the stimulation with 3.5-mA current. Threshold for four different phenomena as well as duration of ADs were evaluated.. The threshold for the transition into the limbic type of ADs was higher in 15-day-old SE rats than in LiPAR controls. Opposite difference was found in 18-day-old animals, older rats did not exhibit any difference. Isolated significant changes in total duration of ADs were found after high stimulation intensities. These changes appeared in 18-day-old rats where ADs were shorter in SE than in control LiPAR rats.. Changes in ifenprodil action were found only in the first week after SE but not in the second week. Interpretation of the results is complicated by failure of significant differences between SE and LiPAR rats probably due to a high dose of paraldehyde.

Topics: Age Factors; Animals; Animals, Newborn; Anticonvulsants; Brain Waves; Cerebral Cortex; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Lithium Chloride; Male; Pilocarpine; Piperidines; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Status Epilepticus

Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P < 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P < 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P < 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Ketamine; Lithium Chloride; Male; Mice; Models, Animal; Motor Activity; N-Methylaspartate; Piperidines; Receptors, N-Methyl-D-Aspartate; Swimming; Time Factors