Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus.
OBJECTIVE
Anterior thalamus (AN) has been shown to mediate seizures in both focal and generalized models. Specific regional increase in AN serotonergic activity was observed following AN-DBS in our pentylenetetrazol (PTZ) rodent model of acute seizures, and this increase may inhibit seizures and contribute to the mechanism of anticonvulsant DBS.


METHODS
Anesthetized rats with AN-directed dialysis cannula with scalp/depth EEG were infused with PTZ at 5.5mg/(kg min) until an EEG seizure occurred. Eight experimental groups of AN-dialysis infusion were evaluated: controls (dialysate-only), 10 and 100 microM serotonin 5-HT(7) agonist 5-carboxamidotryptamine (5-CT), 1, 10 and 100 microM serotonin antagonist methysergide (METH), AN-DBS, and 100 microM METH+AN-DBS.


RESULTS
Latency for seizures in control animals was 3,120+/-770 s (S.D.); AN-DBS delayed onset to 5018+/-1100 (p<0.01). AN-directed 5-CT increased latency in dose-dependent fashion: 3890+/-430 and 4247+/-528 (p<0.05). Methysergide had an unexpected protective effect at low-dose (3908+/-550, p<0.05) but not at 100 microM (2687+/-1079). The anticonvulsant action of AN-DBS was blocked by prior dialysis using 100 microM METH. Surface EEG burst count and nonlinear analysis (H-Statistic) noted significant (p<0.05) increased pre-ictal epileptiform bursts in 5-CT, methysergide, but not DBS group compared to control.


CONCLUSIONS
Increased serotonergic activity in AN raised PTZ seizure threshold, similar to DBS, but without preventing cortical bursting. 5-Carboxamidotryptamine, a 5-HT(7) agonist, demonstrated dose-dependent seizure inhibition. Methysergide proved to have an inverse, dose-dependent agonist property, antagonizing the action of AN-DBS at the highest dose. Anticonvulsant AN-DBS may in part act to selectively alter serotonin neurotransmission to raise seizure threshold.
Mirski
Marek A
MA
Department of Anesthesia and Critical Medicine, Baltimore, MD, USA. mmirski@jhmi.edu
Ziai
Wendy C
WC
Chiang
Jason
J
Hinich
Melvin
M
Sherman
David
D
D000704:Analysis of Variance; D000818:Animals; D046690:Deep Brain Stimulation / Q000379:methods*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D008297:Male; D008784:Methysergide / Q000008:administration & dosage; D010433:Pentylenetetrazole; D051381:Rats; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy*; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000008:administration & dosage; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use; D013788:Thalamus / Q000502:physiology*
D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C047087:5-carboxamidotryptamine; D010433:Pentylenetetrazole; D008784:Methysergide