Activation of excitatory amino acid receptors may mediate the folate-induced stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens

Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) have been shown previously to produce a marked stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens. This study was designed to determine whether the hypermotility response produced by the folates is mediated through the activation of excitatory amino acid receptors in the nucleus accumbens. Although FA stimulated locomotor activity, pteroic acid, a congener of FA that lacks the glutamine moiety, was ineffective, suggesting that the glutamine portion of the molecule is essential for the hypermotility response. The N-methyl-D-aspartic acid (NMDA) receptor antagonists, D-α-aminoadipic acid, D-α-ε-diaminopimelic acid and MgCl₂, at doses that attenuated NMDA-induced hypermotility, were ineffective in decreasing the folate-induced hypermotility response. This behavorial observation is consistent with the biochemical observation that the folates, at a 1 mM concentration, were unable to stimulate the release of [³H]acetylcholine from striatal slices, a model system that is sensitive to the activation of NMDA receptors. In contrast to the ineffectiveness of the NMDA antagonists in inhibiting the response to the folates, the antagonist, glutamic acid diethylester, which inhibited the response to quisqualic acid, but not NMDA, also inhibited the response to both FA and FTHF. Two recently characterized dipeptides, γ-D-glutamylaminomethylsulfonic acid and γ-D-glutamyltaurine, antagonized the stimulation of locomotor activity produced by quisqualic acid, FA and FTHF. However, these dipeptides also inhibited the response to NMDA, suggesting that these compounds are not able to distinguish between quisqualate and NMDA receptors in the nucleus accumbens. These studies show that the hypermotility response to both the FA and FTHF can be inhibited by known excitatory amino acid antagonists. Because antagonists of the NMDA-type receptor were ineffective in inhibiting the folate-induced hypermotility response, the folates may activate another type of excitatory amino acid receptor, possibly the quisqualate-type receptor.