Continuing Burden of Refractory Epilepsy.

Epilepsy is one of the most common neurological diseases, and uncontrolled seizures remain a significant problem for one-third of patients with epilepsy on drug therapy. Ongoing seizures affect the morbidity and mortality of patients with epilepsy. Premature death is up to 3 times higher in those with epilepsy than in the general population. Quality of life is affected by refractory epilepsy with physical, social, and psychological consequences. Patients may be stigmatized by society, institutions, and their own shame surrounding seizures. Questions remain on how to treat refractory epilepsy, also called drug-resistant, pharmacoresistant, or intractable epilepsy. Cenobamate, a novel antiseizure medication, may provide additional benefit for refractory epilepsy treatment.

Extracellular dopamine kinetic parameters consistent with amphetamine effects.

Published behavioral experiments document that amphetamine-induced increases in locomotor activity are preserved or enhanced in animals with major depletions of stored dopamine but intact dopamine synthesis. Conversely, amphetamine effects are substantially attenuated after inhibition of dopamine synthesis when most of the dopamine stores are preserved. Such data suggest that amphetamine mobilizes newly synthesized dopamine into extracellular signaling space. The first goal of this project is to determine kinetic parameters of dopamine secretion into and removal from extracellular space compatible with the majority of amphetamine-elicited increases in extracellular dopamine deriving from newly synthesized dopamine. The strategy uses a computational model of extracellular space surrounding a single dopamine varicosity. Model output was compared to published micro-dialysis data for effects of amphetamine on levels of extracellular dopamine. A family of solutions was found, characterized by a biphasic dose-response relationship for rate of dopamine release. Maximum rates of dopamine release occurred at doses of 0.5-1.0 mg/kg amphetamine. The second goal is to develop a hypothesis by which newly synthesized dopamine gains access to extracellular space. The model chosen involves amphetamine-induced shunting of DOPAC secretion to dopamine secretion into extracellular space. The quality of the hypothesis was evaluated by goodness of match of model output to published data for amphetamine alone and after inhibition of dopamine synthesis or storage. In summary, the results provide conditions required for and a potential mechanism for newly synthesized dopamine to be a major fraction of amphetamine-elicited increases in extracellular dopamine.