Local distribution and toxicity of prolonged hippocampal infusion of muscimol.
OBJECTIVE
The activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the efficacy and safety of regional selective neuronal suppression, the authors infused muscimol, a GABA-A receptor agonist, directly into the hippocampus of nonhuman primates using an integrated catheter electrode.


METHODS
Ten rhesus monkeys were divided into three groups: 1) use of catheter electrode alone (four monkeys); 2) infusion of escalating concentrations of muscimol followed by vehicle (three monkeys); and 3) infusion of vehicle and subsequent muscimol mixed with muscimol tracer (three monkeys). Infusions were begun 5 days after catheter electrode placement and continued for 5.6 days before switching to the other agent. Head magnetic resonance (MR) images and electroencephalography recordings were obtained before and during the infusions. Brain histological studies and quantitative autoradiography were performed. Neurological function was normal in controls and when muscimol concentrations were 0.125 mM or less, whereas higher concentrations (0.5 and 1 mM) produced reversible apathy and somnolence. Fluid distribution was demonstrated on MR images and muscimol distribution was demonstrated on autoradiographs throughout the hippocampus and adjacent white matter.


CONCLUSIONS
Targeted modulation of neuronal activity is a reasonable research strategy for the investigation and treatment of medically intractable epilepsy.
Heiss
John D
JD
Surgical Neurology Branch, Electroencephalography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA. heissj@ninds.nih.gov
Walbridge
Stuart
S
Morrison
Paul
P
Hampton
Robert R
RR
Sato
Susumu
S
Vortmeyer
Alexander
A
Butman
John A
JA
O'Malley
James
J
Vidwan
Param
P
Dedrick
Robert L
RL
Oldfield
Edward H
EH
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000009:adverse effects; D004569:Electroencephalography; D005260:Female; D018755:GABA Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000506:poisoning*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D009118:Muscimol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000506:poisoning*; D009994:Osmolar Concentration; D014018:Tissue Distribution
D018755:GABA Agonists; D009118:Muscimol