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Modulatory Role of Neuropeptides in Seizures Induced in Rats by Stimulation of Glutamate Receptors¹

Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy

²To whom correspondence should be addressed.

Stimulation of glutamate receptors has been reported to modulate the expression of neuropeptides and their receptors in neurons. On the other hand, neuropeptides are known to regulate the presynaptic glutamate release and neuronal responses to excitatory neurotransmission. This evidence indicates a functional interaction between glutamatergic and neuropeptidergic transmission in the central nervous system (CNS). In this report, we provide pharmacologic evidence in experimental models of seizures, suggesting that somatostatin (SRIF) and neuropeptide Y (NPY) are endogenous modulators of glutamate-mediated hyperexcitability in the CNS. Electroencephalographic (EEG) and behavioral seizures were induced in rats by intrahippocampal or systemic injection of kainic acid, a glutamate analog. The number of EEG seizures and their total duration were inhibited significantly by intracerebral application of a SRIF₁ receptor agonist. Similarly, kainate seizures were reduced by N[-2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl-D-arginamide] (BIBP 3226), a NPY Y₁ receptor antagonist. Enhanced seizure susceptibility to pentylentetrazol, ensuing in rats after a systemic administration of kainic acid, was reduced significantly by intracerebral application of RC 160, a SRIF₁ receptor agonist, or NPY 13–36, a Y₂/Y₅ receptor agonist. This evidence suggests that neuropeptide analogs may be of value for controlling seizures and possibly in other pathologic conditions associated with excessive glutamate function.

KEY WORDS: • somatostatin receptors • neuropeptide Y receptors • epilepsy • neuropeptide Y • somatostatin • rats