Amitriptyline, desipramine, cyproheptadine and carbamazepine, in concentrations used therapeutically, reduce kainate- and N-methyl-D-aspartate-induced intracellular Ca2+ levels in neuronal culture.
The glutamate receptor agonists, kainate and N-methyl-D-aspartate (NMDA) result in the elevation of intracellular calcium levels ([Ca2+]i) in primary cultures of cerebellar granule neurons. Several tricyclic antidepressants (TCAs), amitriptyline (0.5-1 microM), desipramine (1 microM) and doxepine (1 microM) partially prevent this elevation induced by both of these excitatory amino acids (EAAs), but not elevations of [Ca2+]i induced by another EAA, quisqualate. Evidence suggests that this EAA-tricyclic interaction may involve voltage-dependent Ca2+ channels since amitriptyline also partially blocks the elevation of [Ca2+]i induced by membrane depolarization with 40 mM KCl. However, the blockade is not reversed in high concentrations of extracellular Ca2+ ([Ca2+]o) as would be predicted by a direct interaction with Ca2+ channels. Cyproheptadine (0.5-1 microM), a serotonin antagonist that is structurally similar to amitriptyline, causes similar effects as reported above for the TCAs; however, ketanserine (10 microM), also a serotonin antagonist but without the tricyclic nucleus, is less effective in this regard. Carbamazepine, an anticonvulsant with a tricyclic nucleus, produces similar effects as the above three compounds only in higher, yet therapeutic, concentrations (50 microM). Neither 5-hydroxytryptamine nor norepinephrine (100 microM, each) had effects on the EAA-induced elevation of [Ca2+]i. This is the first report to show an interaction of tricyclic antidepressants with the function of glutamate receptors in concentrations which are consistent with therapeutic dosages.
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Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
McCaslin
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D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D003533:Cyproheptadine / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D002121:Calcium Channel Blockers; D016194:Receptors, N-Methyl-D-Aspartate; D000639:Amitriptyline; D003533:Cyproheptadine; D002220:Carbamazepine; D016202:N-Methylaspartate; D007608:Kainic Acid; D002118:Calcium; D003891:Desipramine