Abstracts

RATIONALE: The Anterior Thalamic Nucleus (AN) is a key thalamic site mediating experimental seizures. Studies have demonstrated that AN DBS is effective in raising seizure threshold. Little is known about the anticonvulsant mechanisms of DBS, or the specific biochemical and synaptic mechanisms underlying seizure propagation. We proposed to determine the alterations in the underlying regional microchemistry of the AN resulting from experimental seizures and the anticonvulsant action of AN electrical stimulation. We tested the hypothesis that AN has a distinct neurochemical response, particularly serotonergic inhibition and facilitation of noradrenergic systems, early during EEG seizure propagation, and a unique response to local electrical stimulation compared to other brain regions.
METHODS: Paralyzed and ventilated Sprague-Dawley male rats (200-300 gm), anesthetized with halothane, underwent stereotactically guided bilateral placement of bipolar stimulating steel electrodes in AN and posterior thalamus (PT), introduction of dialysis probes-guide cannulae in AN and PT, and placement of four epidural EEG screw electrodes 24 hrs prior to experiments. Both stimulated (STIM) and non-stimulated (NOSTIM) animals (N=7 per group), under 0.5% halothane, were infused with i.v. pentylenetetrazol (PTZ) (5.5 mg/kg/min). Simultaneous AN and cortical EEG were recorded and microdialysis samples (2[mu]l/min) were collected in AN and PT every 20 min. AN Stimulation was delivered using a Grass Instruments Constant Current stimulator: 0.1-10 V; 150mA; 0.1 msec pulse duration beginning 40 minutes prior to PTZ infusion.
RESULTS: Bilateral AN stimulation delayed the onset of EEG seizures by 82[plusminus]8 vs. 58[plusminus]5 min (p=0.02) despite low current settings. PTZ infusion alone resulted in a steady increase in norepinephrine (NE), but not dopamine, in both STIM and NOSTIM animals. The rise in NE was maintained following onset of PTZ seizures. Although levels of serotonin were extremely low and did not change with PTZ or seizures, extracellular levels of 5-hydroxyindoleacetic acid (5-HIAA) increased in AN (but not PT) with PTZ and decreased following the first seizure to very low levels. The difference between 5-HIAA levels in AN and PT was significant in both STIM (p=.03) and NOSTIM (p=.04) groups. AN stimulation did not alter serotonin levels as much as the effects of PTZ infusion. Levels of glutamate and other measured amino acids showed no substantive change during PTZ or stimulation.
CONCLUSIONS: This data suggests that seizures enhance NE activity while suppressing serotonin-mediated AN transmission. Low serotonin levels at baseline and during PTZ infusion may indicate efficient re-uptake systems for serotonin, with 5-HIAA serving as a surrogate marker for serotonergic activity. This data suggests that manipulation of AN serotonergic activity may alter PTZ seizure threshold.
Objective: Participants should be able to discuss microchemical changes induced by anticonvulsant thalamic deep brain stimulation (DBS).
[Supported by: NIH Grant RO1-NS35528]; (Disclosure: Grant - NIH Grant RO1-NS35528)