title: Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus.
abstract: 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.
authors.affiliation: Department of Anesthesia and Critical Medicine, Baltimore, MD, USA. mmirski@jhmi.edu
authors.forename: Marek A
authors.initials: MA
authors.lastname: Mirski
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Ziai
authors.forename: Jason
authors.initials: J
authors.lastname: Chiang
authors.forename: Melvin
authors.initials: M
authors.lastname: Hinich
authors.forename: David
authors.initials: D
authors.lastname: Sherman
mesh_terms: 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*
chemical_list: D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C047087:5-carboxamidotryptamine; D010433:Pentylenetetrazole; D008784:Methysergide