Voltage-dependent calcium channel and NMDA receptor antagonists augment anticonvulsant effects of lithium chloride on pentylenetetrazole-induced clonic seizures in mice.
Although lithium is still a mainstay in the treatment of bipolar disorder, its underlying mechanisms of action have not been completely elucidated. Several studies have shown that lithium can also modulate seizure susceptibility in a variety of models. In the present study, using a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice, we investigated whether there is any interaction between lithium and either calcium channel blockers (CCBs: nifedipine, verapamil, and diltiazem) or N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine and MK-801) in modulating seizure threshold. Acute lithium administration (5-100mg/kg, ip) significantly (P<0.01) increased seizure threshold. CCBs and NMDA receptor antagonists also exerted dose-dependent anticonvulsant effects on PTZ-induced seizures. Noneffective doses of CCBs (5mg/kg, ip), when combined with a noneffective dose of lithium (5mg/kg, ip), exerted significant anticonvulsant effects. Moreover, co-administration of a noneffective dose of either MK-801 (0.05mg/kg, ip) or ketamine (5mg/kg, ip) with a noneffective dose of lithium (5mg/kg, ip) significantly increased seizure threshold. Our findings demonstrate that lithium increases the clonic seizure threshold induced by PTZ in mice and interacts with either CCBs or NMDA receptor antagonists in exerting this effect, suggesting a role for Ca(2+) signaling in the anticonvulsant effects of lithium in the PTZ model of clonic seizures in mice.
Ghasemi
Mehdi
M
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. mghasem2@jhmi.edu
Shafaroodi
Hamed
H
Nazarbeiki
Saeed
S
Meskar
Hossein
H
Heydarpour
Pouria
P
Ghasemi
Abbas
A
Talab
Saman Shafaat
SS
Ziai
Pouya
P
Bahremand
Arash
A
Dehpour
Ahmad Reza
AR
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D018021:Lithium Chloride / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D018021:Lithium Chloride; D010433:Pentylenetetrazole