Associate editor: M.A. RogawskiThe role of catecholamines in seizure susceptibility: new results using genetically engineered mice
Introduction
The catecholamines norepinephrine (NE) and dopamine (DA) are derived from the amino acid tyrosine, and share a common biosynthetic pathway (Fig. 1). NE was one of the first neurotransmitters discovered, and is abundant in both the peripheral nervous system and the CNS. It is the primary neurotransmitter of the sympathetic nervous system, where it has profound effects on cardiovascular function and the activity of other tissues and organs (Landsberg & Young, 1992). Noradrenergic neurons are also abundant in the hindbrain of the CNS, and project widely throughout the brain. Classically, central noradrenergic neurons are thought to promote vigilance and arousal and to mediate responses to stress. Dopaminergic cell bodies are most abundant in the midbrain, and activation of dopaminergic pathways have profound effects on motor output and mediate motivational state and responses to rewarding stimuli.
This review focuses on the role of the catecholamines in modulating seizure susceptibility. NE and DA have long been implicated in controlling neuronal excitability during epileptic episodes in animal models. Previously, lesioning and pharmacological techniques have dominated experiments aimed at describing a role for catecholamines in seizure susceptibility. More recently, molecular genetics have provided new models for studying this issue: transgenic and knockout mice in which catecholamine signaling has been genetically manipulated. This genetic approach, coupled with physiology and pharmacology, represents the future of neurological disease research. This review will cover the history of research on catecholamines and seizure susceptibility, discuss recent findings using genetically engineered mice, and suggest future directions for epilepsy research using transgenics and knockouts that alter catecholaminergic signaling.
Section snippets
Norepinephrine and seizure susceptibility
NE has been known to modulate seizure susceptibility in animal models of epilepsy for over 40 years, and in some cases, its effects are quite dramatic. Despite this, NE has not received as much attention lately as other neurotransmitters, such as glutamate and γ-aminobutyric acid (GABA). Perhaps the lack of consensus in the field about which receptors and signaling pathways mediate the anticonvulsant effect of NE contributes to this phenomenon; an issue that will be addressed in this review.
The role of dopamine in seizure susceptibility
The role of DA in seizure susceptibility has been quite difficult to determine, more so than that of NE. A comprehensive review on the role of DA in epilepsy compiled the data concerning the modulation of seizure susceptibility by dopaminergic agonists and antagonists (Starr, 1996). Since that article, very little has been published on the subject. In this portion of our review, a short synopsis of Starr's (1996) article will be followed by information concerning genetically engineered mice
The role of catecholamines in cocaine and amphetamine-induced seizures
Cocaine and amphetamine are psychostimulants and drugs of abuse that increase release and/or decrease uptake of monoamines. Seizures elicited by acute overdose of these drugs are one of the leading causes of psychostimulant-related emergency room incidents and can be lethal (e.g., Earnest, 1993). Therefore, the role of DA and NE in mediating the effects of psychostimulant-induced seizures is of considerable interest, and most animal research has focused on cocaine-induced seizures. One of the
New results using genetically engineered mice
Over the past 10–15 years, transgenic and knockout technology has provided a genetic tool to study neurobiological and other processes in mice. We and others have used genetically engineered mice to alter catecholamine signaling, and asked questions pertaining to seizure susceptibility. In combination with pharmacology, the results from these studies have furthered our understanding of how endogenous catecholamines and catecholamine receptor agonists and antagonists modulate seizure
Conclusion
There is little doubt that catecholamine signaling, especially NE, has profound effects on seizure susceptibility in animal models. There are some provocative hints suggesting that the noradrenergic system can modulate seizures in human epilepsy, yet many of these are anecdotal and have not been followed up. For example, the α2AR agonist clonidine that can decrease LC firing and NE release had proconvulsant effects on patients with intractable focal epilepsies (Kirchberger et al., 1998) and a
Acknowledgements
We thank Sumitomo Pharmaceutical Co. (Osaka, Japan) for their generous donation of DOPS and R. Palmiter for critical reading of the manuscript. D.W. was supported by the Howard Hughes Medical Institute. P.S. was supported by the National Alliance for Research on Schizophrenia and Depression and the Department of Veterans Affairs.
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