Pharmacology of ionotropic and metabotropic glutamate receptors on neurons involved in feeding behavior in the pond snail, Helisoma trivolvis.

Glutamate is a key regulatory neurotransmitter in the triphasic central pattern generator controlling feeding behavior in the pond snail, Helisoma trivolvis. It excites phase two motor neurons while inhibiting those in phases one and three. However, the receptors that mediate this regulation are only partially characterized. The purpose of these experiments was to further characterize the glutamate receptors on three buccal neurons modulated by glutamate. Intracellular recordings from B5, B19 and B27 neurons were taken during the perfusion of isolated buccal ganglia with agonists that are selective for different vertebrate glutamate receptors. The firing rate of all three neurons was inhibited in a dose-dependent manner by glutamate, including that of B27, a phase 2 motor neuron known to be excited by glutamate in vivo. Quisqualate also reduced the firing rate in all three neurons, and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a relatively non-selective metabotropic glutamate receptor (mGluR) agonist, reduced the firing rate in B5 neurons, but not in B19 or B27 neurons. Agonists selective for vertebrate group I, II and III mGluRs did not affect the firing rate in any of the Helisoma buccal neurons tested, suggesting that mGluR agonist binding sites on these neurons do not closely resemble those on any vertebrate mGluR subtypes. An increase in frequency of action potentials was observed in all three cell types in the presence of 100 micromol l(-1) kainate (KA), suggesting the presence of excitatory (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/KA-like receptors. However, electrotonic coupling between B19 and B27 neurons, and a lack of effect of KA on isolated B19 neurons suggest the excitatory effects of KA on this neuron are indirect. These findings suggest the presence of multiple glutamate receptor subtypes in molluscan neurons that do not always resemble vertebrate receptors pharmacologically.

NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats.

RATIONALE AND OBJECTIVES: To test the hypothesis that excess glutamatergic transmission at NMDA receptors may contribute to the pathogenesis of Parkinson's disease (PD), we examined the effects of various NMDA receptor antagonists on a recently developed rat model of PD. METHODS: Following unilateral injections of 12 microg 6-OHDA into the medial forebrain bundle of male Long Evans rats, stepping with both front paws was measured separately as the paws were dragged backwards and laterally. The effects of i.p. injections of varying doses of L-dopa, the non-competitive NMDA receptor antagonist dizocilpine [(+)-MK-801], the competitive NMDA receptor antagonist CPP, and combinations of L-dopa and NMDA receptor antagonists were then examined on stepping in three separate groups of rats. RESULTS: The lesioned rats stepped less often with their contralateral paw than with their ipsilateral paw, and the magnitude of this stepping deficit was positively correlated with the amount of DA depletion in the ipsilateral dorsal striatum. L-dopa (1-25 mg/kg) dose dependently enhanced stepping with the contralateral paw, and 0.15-0.3 mg/kg dizocilpine and 1.5-6.25 mg/kg CPP enhanced stepping with the contralateral paw as much as did 8 mg/kg L-dopa. The combinations of L-dopa and each of the NMDA receptor antagonists did not significantly improve stepping more than either drug alone. Moreover, none of the drugs completely eliminated the stepping deficits, and high doses began to impair stepping with the ipsilateral paw by inducing turning. CONCLUSIONS: These data indicate that deficits in contralateral stepping are a reliable and sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats, and they support the hypothesis that excess glutamatergic transmission at NMDA receptors may play a role in the expression of PD symptomology.