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.