Abstracts

Somatostatin (SRIF) is a neuropeptide involved in multiple peripheral and CNS functions. In the hippocampus, SRIF inhibits excitatory synaptic transmission presynaptically by reducing glutamate release and postsynaptically by affecting calcium and potassium currents. SRIF has inhibitory actions on seizures in rats likely mediated by sst2 receptor subtypes. The recent availability of selective agonists at the different SRIF receptor subtypes allowed us to investigate in detail the role of these receptors in the hippocampus (sst1, sst2, sst3 and sst4) in seizure modulation.
We have investigated the role of sst1,sst2,sst3 and sst4 receptors in seizures induced in rats by intrahippocampal administration of 40 ng kainic acid. This model of seizures has been shown to be very sensitive to the modulatory action of various neuropeptides. SRIF receptor agonists, or their respective vehicles, were administered intrahippocampally in 0.5 [micro]l, 10 min before kainic acid injection. After 15-min baseline recording, drugs were injected and seizures were monitored for 3 h after kainate injection by EEG analysis in freely-moving rats chronically implanted with hippocampal and cortical electrodes.
We used two selective agonists of sst1 receptors: a peptide ligand BIM 23926 (Ki 3.6 nM, Biomeasure Inc) and a non-peptide ligand L797591 (Ki 1.4 nM, Rohrer et al, Science, 282, 1998, 737). Both compounds dose-dependently reduced seizure duration (1.5-12 nmol). Seizure onset was significantly delayed and the total time in seizures was decreased by ~50% by both compounds at doses between 6 and 12 nmol. BIM23120 (1.5-6.0 nmol), a peptide acting at sst2 receptors (Ki 0.34 nM, Biomeasure Inc) at 6 nmol reduced by ~70% the time in seizures without affecting their time to onset. Sst3 receptor s were investigated using two non-peptide agonists, VMB 14-11262 (Ki 120 nM, Ipsen Beaufour) and L796778 (Ki 24 nM, Rohrer et al, 1998). VMB 14-11262 (12-48 nmol) delayed by ~43% the onset time of seizures and reduced seizure activity by ~50% at 48 nmol; these parameters were similarly affected by 6-12 nmol L796778. L8030087, a selective sst4 agonist (Ki 0.7 nM, Rohrer et al, 1998) significantly enhanced seizure duration by ~65% and shortened time of onset by ~20% at 5 nmol while lower doses were ineffective.
Sst1, sst2 and sst3 receptor subtypes in the hippocampus mediate significant inhibitory effects of SRIF on seizure activity. Sst1 and sst3 receptors also affect seizure onset suggesting they are involved in the mechanisms underlying seizure initiation. Similarly to what found in mice (Moneta et al, Eur J Neurosci, 16, 2002, 843), sst4 receptors mediate excitatory effect of SRIF on neuronal activity. Since sst1, sst2 and sst3 receptors have been identified in human limbic areas, our findings suggest that broad spectrum agonists at these receptors may represent novel drugs for controlling limbic seizures.
[Supported by: Institut Henri Beaufour
EC Contract QLG3-CT-1999-00908]