Abstracts

The Anterior Thalamic Group (AN) has been shown to modulate generalized seizures in rodents (1-3). AN deep brain stimulation (DBS) raises seizure threshold in both PTZ [amp] pilocarpine convulsant animal models (4-5), and has demonstrated potential efficacy in human pilot trials (6-7). How DBS prevents seizures in AN is unclear. Direct electrical perturbation vs. transmitter alterations may be involved. Our laboratory has recently shown that anticonvulsant DBS resulted in site-specific and selective increase in serotonergic activity in AN (8). We thus suspect that regional AN serotonergic systems, particularly 5-HT[sub]7[/sub], may play a role in DBS seizure modulation. P[amp]V Sprague-Dawley male rats (200-300 gm) were anesthetized with halothane and implanted with surface EEG and bipolar AN [amp] posterior thalamic (PT, as control) electrodes. Non-stimulated (NOSTIM) animals were treated, with and without the 5-HT[sub]7 [/sub]receptor agonist 5-carboxamidotryptamine (5-CT, n=7) or 5-HTantagonist methysergide (n=5), and compared to AN-DBS (STIM) animals (n=7), each under 0.5% halothane and infused with i.v. PTZ (5.5 mg/kg/min). Microdialysis samples (1 uL/min) were collected in AN every 20 min and measured by HPLC for 5-HT, 5-HIAA (5-HT metabolite), norepinephrine, dopamine. 5-CT (50 :M) or Methysergide (100 :M) was delivered into mock-CSF infusion medium starting 40 minutes prior to PTZ administration. Bilateral 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. 5-CT infusion resulted in an increase in 5-HIAA (but not 5-HT) in AN during PTZ infusion to the first seizure. AN DBS during PTZ produced higher elevations of 5-HIAA in AN (but not PT). Although PTZ infusion alone resulted in an increase in norepinephrine (NE) in both STIM and NOSTIM animals, 5-CT infusion did not alter NE or dopamine (DA) levels. In controls, PTZ resulted in EEG seizures at 3832[plusmn]300s (total 319 mg/kg PTZ). AN DBS delayed the onset (4980[plusmn]240s) and 5-CT was similarly effective (4920[plusmn]480s) (p=0.02). AN-Methysergide lowered PTZ seizure threshold (2795[plusmn]293). AN DBS during PTZ infusion raises 5-HIAA levels, and thus suggests that stimulation is effective by means of AN serotonergic mechanisms. In support, the data also show that serotonin agonism within AN blocks PTZ seizures as effectively as DBS, while antagonism lowers the convulsant threshold. These data suggest DBS mechanisms of action, and may implicate new pharmacological approaches towards clinical seizure control.
Ref:
1}Mirski [italic]Science,[/italic] 1984;226:72-74. 2}Mirski [italic]Brain Research[/italic], 1986;399:212-223. 3}Mirski [italic]Epilepsia[/italic], 2003;44:355-365. 4}Mirski [italic]Epilepsy Research[/italic] 1997;28:89-100. 5}Hamani [italic]Neurosurgery[/italic] 2004;54:191-5. 6}Hodaie [italic]Epilepsia[/italic] 2002;43:603-608. 7}Kerrigan [italic]Epilepsia[/italic]. 2004;45:346-54. 8}Ziai [italic]Epilepsia[/italic], in press. (Supported by NIH Grant RO1-NS35528)