Pharmacology & Therapeutics 94 (2002) 213 – 233

Associate editor: M.A. Rogawski

The role of catecholamines in seizure susceptibility:
new results using genetically engineered mice
David Weinshenkera,*, Patricia Szotb,c
a
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Box 357370, Seattle, WA 98195, USA
b
Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA
c
GRECC, Puget Sound Health Care System, Seattle, WA 98108, USA

Abstract

The catecholamines norepinephrine and dopamine are abundant in the CNS, and modulate neuronal excitability via G-protein-coupled
receptor signaling. This review covers the history of research concerning the role of catecholamines in modulating seizure susceptibility in
animal models of epilepsy. Traditionally, most work on this topic has been anatomical, pharmacological, or physiological in nature. However,
the recent advances in transgenic and knockout mouse technology provide new tools to study catecholamines and their roles in seizure
susceptibility. New results from genetically engineered mice with altered catecholamine signaling, as well as possibilities for future
experiments, are discussed. D 2002 Elsevier Science Inc. All rights reserved.

Keywords: Catecholamine; Norepinephrine; Dopamine; Seizure; Epilepsy; Knockout

Abbreviations: AADC, aromatic acid decarboxylase; AK, amygdala kindling; AR, adrenoreceptor; AUD, audiogenic; BIC, bicuculline; DA, dopamine; DAT,
dopamine transporter; DBH, dopamine b-hydroxylase; DD, dopamine-deficient; 2-DG, [14C]2-deoxyglucose; DOPS, L-3,4-dihydroxyphenylserine; DSP-4, N-
a2-chloroethyl)-N-2-bromobenzylamine; EPI, epinephrine; FLUR, flurothyl; GEPR, genetically epilepsy-prone rat; HK, hippocampal kindling; 5-HT, 5-
hydroxytryptamine (serotonin); KA, kainic acid; KD, ketogenic diet; LC, locus coeruleus; L-DOPA, L-3,4-dihydroxyphenylalanine; ND, normal diet; NE,
norepinephrine; 6-OHDA, 6-hydroxydopamine; PEN, penicillin; PIC, picrotoxin; PTZ, pentylenetetrazole; QA, quinolinic acid; SN, substantia nigra; SNpc,
substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; TH, tyrosine hydroxylase; VTA, ventral tegmental area.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
1.1. Catecholamines in the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . 214
1.2. Catecholamines and seizure susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . 214
2. Norepinephrine and seizure susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
2.1. Anatomical pathways of the central noradrenergic system . . . . . . . . . . . . . . . . 215
2.1.1. The locus coeruleus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
2.1.2. The lateral tegmental noradrenergic neurons . . . . . . . . . . . . . . . . . . . 215
2.2. Activation of noradrenergic neurons in response to seizures . . . . . . . . . . . . . . . 215
2.3. Chemical depletion/lesioning of the noradrenergic system . . . . . . . . . . . . . . . . 216
2.3.1. Reserpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
2.3.2. 6-Hydroxydopamine and N-(2-chloroethyl)-N-2-bromobenzylamine . . . . . . . 216
2.4. Locus coeruleus stimulation/grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

* Corresponding author. Tel.: 206-543-6090; fax: 206-543-0858.

E-mail address: dzw@genetics.washington.edu (D. Weinshenker).

0163-7258/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 1 6 3 - 7 2 5 8 ( 0 2 ) 0 0 2 1 8 - 8
214 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233

2.5. Genetic models of epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

2.5.1. The genetically epilepsy-prone rat . . . . . . . . . . . . . . . . . . . . . . . . 217
2.5.2. Mouse and gerbil mutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2.6. Adrenoreceptor agonists and antagonists . . . . . . . . . . . . . . . . . . . . . . . . . 217
2.6.1. The a2-adrenoreceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2.6.2. The a1-adrenoreceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
2.6.3. The b-adrenoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
2.7. Norepinephrine and clinical anticonvulsant efficacy . . . . . . . . . . . . . . . . . . . . 221
2.8. Tricyclic antidepressants and epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3. The role of dopamine in seizure susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.1. Anatomical pathways of the dopaminergic system . . . . . . . . . . . . . . . . . . . . 221
3.1.1. Mesostriatal pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.1.2. Mesolimbic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.1.3. Mesocortical pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.1.4. Descending pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.2. Activation of dopaminergic neurons in response to seizures . . . . . . . . . . . . . . . 222
3.3. Chemical lesioning of the dopaminergic system. . . . . . . . . . . . . . . . . . . . . . 222
3.4. Dopaminergic agonists and antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.4.1. Mixed D1/D2 agonists/antagonists . . . . . . . . . . . . . . . . . . . . . . . . 222
3.4.2. The D1 receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
3.4.3. The D2 receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
4. The role of catecholamines in cocaine and amphetamine-induced seizures . . . . . . . . . . . . 223
5. New results using genetically engineered mice . . . . . . . . . . . . . . . . . . . . . . . . . . 223
5.1. The dopamine b-hydroxylase knockout mouse . . . . . . . . . . . . . . . . . . . . . . 224
5.1.1. Response to seizure-inducing stimuli . . . . . . . . . . . . . . . . . . . . . . . 224
5.1.2. Pharmacology of pentylenetetrazole-induced seizure susceptibility . . . . . . . . 224
5.1.3. The ketogenic diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
5.2. The a2A mutant mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
5.3. Other knockouts affecting noradrenergic signaling . . . . . . . . . . . . . . . . . . . . 225
5.4. The genetically dopamine-deficient mouse . . . . . . . . . . . . . . . . . . . . . . . . 225
5.4.1. Pentylenetetrazole- and kainic acid-induced seizure susceptibility . . . . . . . . 226
5.4.2. Regional dopamine replacement using viral vectors . . . . . . . . . . . . . . . 226
5.5. The D2 dopamine receptor knockout mouse. . . . . . . . . . . . . . . . . . . . . . . . 226
5.6. The D4 dopamine receptor knockout mouse. . . . . . . . . . . . . . . . . . . . . . . . 227
5.7. Other knockouts affecting dopaminergic signaling . . . . . . . . . . . . . . . . . . . . 227
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

1. Introduction activation of dopaminergic pathways have profound effects

on motor output and mediate motivational state and
1.1. Catecholamines in the nervous system responses to rewarding stimuli.

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 sys-
tem, 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 noradre-
nergic neurons are thought to promote vigilance and
arousal and to mediate responses to stress. Dopaminergic
cell bodies are most abundant in the midbrain, and
1.2. Catecholamines and seizure susceptibility
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 experi-
ments aimed at describing a role for catecholamines in
seizure susceptibility. More recently, molecular genetics
have provided new models for studying this issue: trans-
genic 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
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
Fig. 1. Catecholamine biosynthesis and production of catecholamine
knockout mice. The amino acid tyrosine is converted to L-DOPA by TH,
which is then converted to DA by AADC. In noradrenergic neurons, the
DA is converted to NE within the synaptic vesicle by DBH, which is then
converted to EPI in epinephrinergic neurons by phenylethanolamine-N-
methyltransferase (PNMT). The NE-deficient mouse was created by a
targeted disruption of the Dbh gene. NE can be restored to Dbh
/
mice
by administration of DOPS, which can be converted to NE by AADC. The
DD mouse was created by a targeted disruption of the Th gene. Th function
was restored to noradrenergic neurons by targeting Th to one allele of the
Dbh gene. Thus, Th function was restored only to noradrenergic neurons,
resulting in normal NE levels, but deficient DA production.
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 catecho-
laminergic signaling.
2. 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 neuro-
transmitters, such as glutamate and g-aminobutyric acid
(GABA). Perhaps the lack of consensus in the field about
which receptors and signaling pathways mediate the anti-
convulsant effect of NE contributes to this phenomenon;
an issue that will be addressed in this review. The
following section will document the work of the past 4
decades describing the modulation of seizure susceptibility
by NE.
215
2.1. Anatomical pathways of the central noradrenergic
system
Noradrenergic neurons are found in two primary brain-
stem cell groups: the locus coeruleus (LC) and the lateral
tegmental groups.
2.1.1. The locus coeruleus
More than one-half of all central noradrenergic neurons
are densely packed within the LC. Axons from the LC form
five major tracts, three of which are ascending tracts: the
dorsal noradrenergic bundle, the central gray dorsal longitud-
inal facsiculus tract, and the ventral tegmental-medial fore-
brain bundle. These fiber tracts project primarily to the
diencephalon, basal forebrain, and neocortex. The fourth
tract projects to the cerebellum, and the last descends into the
mesencephalon and spinal cord. To influence seizure sus-
ceptibility, noradrenergic neurons need to innervate critical
brain regions, and fire during seizure initiation and/or
propagation. Importantly, regions of the brain especially
prone to hyperexcitability, such as the hippocampus, cortex,
and amygdala, receive dense innervation from the LC (Jones
& Moore, 1977; Foote et al., 1983; Cooper et al., 1996).
Therefore, NE has the localization required to be a factor in
seizure modulation.
2.1.2. The lateral tegmental noradrenergic neurons
The lateral tegmental neurons lie outside of the LC and
are diffusely scattered throughout the lateral tegmental
fields. The axons from these neurons mingle with those
arising from the LC, some contributing to the innervation of
the mesencephalon and spinal cord and some to the fore-
brain and diencephalon. In the forebrain, noradrenergic
neurons from these groups tend to contribute most to
innervation of the hypothalamus and septum and least to
the hippocampus and cortex (Cooper et al., 1996).
2.2. Activation of noradrenergic neurons in response to
seizures
Do noradrenergic neurons fire at the appropriate time to
affect seizure susceptibility? One way to measure neuronal
activation is by measuring Fos induction by seizure-pro-
ducing stimuli. Fos is an immediate early gene that is used
as a marker for neuronal activation. Increased Fos immu-
noreactivity or mRNA expression has been observed in the
rat LC following seizures induced by sound, pentylenete-
trazole (PTZ), maximal electroshock, kainic acid (KA),
amygdala kindling (AK), picrotoxin (PIC), and flurothyl
(FLUR) (Eells et al., 1997; Szot et al., 1997; Silveira et al.,
1998a, 1998b, 2000; Willoughby & Mackenzie, 1999).
Active neurons utilize more glucose than inactive neurons
due to increased energy requirement. A study using [14C]2-
deoxyglucose (2-DG) uptake as a marker for neuronal
activity has demonstrated increased LC activity following
PTZ-induced seizures (el Hamdi et al., 1992). Noradrenergic
216 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
neurons also show changes in the expression of genes that
regulate NE signaling following seizures. Expression of
both tyrosine hydroxylase (TH), the rate-limiting enzyme
in NE synthesis, and the NE plasma membrane transporter
were elevated in the LC following PTZ- and KA-induced
seizures (Szot et al., 1997; Bengzon et al., 1999). Lastly, in
vivo microdialysis experiments have confirmed the
increased release of NE during seizures in normal animals
and decreased NE release in animals that are kindled or
genetically disposed to having seizures (e.g., Kokaia et al.,
1989; Bengzon et al., 1990; Yan et al., 1993). These results
suggest that LC neurons are likely firing during seizure
initiation and/or propagation. In addition, changes in NE
synthesis and release that occur after seizures may affect the
rate and severity of recurring seizures. In conclusion,
noradrenergic neurons are in the right places and fire at
the right times to modulate seizure susceptibility.
2.3. Chemical depletion/lesioning of the noradrenergic
system
Animals lacking a functional noradrenergic system are
generally more seizure-sensitive than control animals,
strongly suggesting that endogenous NE is anticonvulsant.
This theme will be repeated throughout the rest of the
review. Some of the most convincing evidence that NE is
an important regulator of seizure susceptibility comes from
animal models in which NE has been depleted or the
noradrenergic system has been lesioned.
2.3.1. Reserpine
The first demonstration of the importance of NE was by
Chen and colleagues (1954), who showed that treatment of
mice with the monoamine-depleting agent reserpine lowered
their convulsive threshold to PTZ, caffeine, and electrical
stimuli, and antagonized the anticonvulsant action of Dilan-
tin. Subsequent studies confirmed and extended these results
(Arnold et al., 1973; Blank, 1976; Gross & Ferrendelli,
1982; Shank et al., 1994). One caveat to these experiments
is that reserpine depletes 5-hydroxytryptamine (serotonin, 5-
HT) and DA, in addition to NE, so the increase in seizure
susceptibility by reserpine could involve the absence of
multiple monoamines.
2.3.2. 6-Hydroxydopamine and
N-(2-chloroethyl)-N-2-bromobenzylamine
The inability to demonstrate a specific role for NE using
reserpine, because of its lack of specificity, was solved by
techniques that specifically lesion the noradrenergic system,
while leaving the other monoamines intact. There is a rich
history of testing seizure susceptibility in animals with
noradrenergic neurons ablated using 6-hydroxydopamine
(6-OHDA) and N-(2-chloroethyl)-N-2-bromobenzylamine
(DSP-4). 6-OHDA destroys both dopaminergic and nora-
drenergic neurons, but specificity can be attained either by
injection directly into the LC or by protecting dopaminergic
neurons by pretreatment with a DA transporter (DAT)
blocker, which prevents 6-OHDA from getting into dop-
aminergic neurons. These techniques revealed that animals
lacking intact noradrenergic systems are more susceptible to
seizures induced by sound, PTZ, electroconvulsive shock,
cobalt, penicillin (PEN), AK, and hippocampal kindling
(HK) (Arnold et al., 1973; Corcoran et al., 1974; Jerlicz et
al., 1978; Mason & Corcoran, 1979; Corcoran & Mason,
1980; McIntyre, 1980; McIntyre & Edson, 1982; Corcoran,
1988; Trottier et al., 1988; Sullivan & Osorio, 1991).
Similar results were obtained with DSP-4, a peripherally
administered neurotoxin that, for unknown reasons, pref-
erentially destroys LC neurons (Jonsson et al., 1981; Logue
et al., 1985; Bortolotto & Cavalheiro, 1986; Carre & Harley,
1986; Mishra et al., 1994; Culic et al., 1995).
Taken together, these results suggest that endogenous
NE inhibits seizures elicited by multiple convulsant para-
digms, and that compromising the noradrenergic systems
renders animals prone to seizures. However, there are three
primary caveats associated with these techniques. The first
is that 6-OHDA or DSP-4 lesioning never destroys all of
the noradrenergic neurons, and the surviving neurons can
sprout new arbors. Second, 6-OHDA lesions can result in
pre- and postsynaptic receptor hypersensitivity (De Mon-
tigny et al., 1980; Dalton et al., 1985). Third, lesions
remove not only NE, but other transmitters that are co-
localized with NE in noradrenergic neurons. These include
ATP and the neuropeptides neuropeptide Y and galanin,
which have been shown pharmacologically and genetically
to be potent endogenous anticonvulsants (Murray et al.,
1985; Dichter, 1994; Erickson et al., 1996; Baraban et al.,
1997; Woldbye et al., 1997; Mazarati et al., 1998, 2000).
Therefore, it is not clear from these studies whether the loss
of these co-transmitters contributes to the proconvulsant
effects of LC lesions.
2.4. Locus coeruleus stimulation/grafts
Because LC lesions result in a seizure-sensitive animal, it
follows that activation of the LC in normal animals or
restoration of LC neurons in lesioned animals would have
an anticonvulsant effect. LC activation has been primarily
achieved by electrical stimulation paradigms. Stimulation of
the LC suppresses seizures induced by PTZ, AK, and
hippocampal PEN administration (Libet et al., 1977; Weiss
et al., 1990; Ferraro et al., 1994). Many studies have
examined the effect of fetal LC grafts on seizures in LC-
lesioned animals. These grafts reverse the seizure suscept-
ibility of 6-OHDA lesions of the LC when fetal LC tissue
was implanted into the amygdala/piriform cortex (Barry et
al., 1989), the hippocampus (Bengzon et al., 1990, 1991), or
the ventricle (Clough et al., 1994). In one study, polymer
matrices containing NE were implanted bilaterally into the
hippocampus of rats with 6-OHDA lesions of the LC. No
effect on the development of HK was observed, despite
extracellular NE levels exceeding those of rats with intra-
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
hippocampal LC grafts that previously had been shown to
retard the rate of kindling (Kokaia et al., 1994). The failure
of NE-releasing polymer matrices to suppress kindling
suggests that the anticonvulsant effect of grafts requires
regulated release of NE.
2.5. Genetic models of epilepsy
Additional evidence that the noradrenergic system is
critical for preventing seizures comes from studies using
genetic models of epilepsy. These are situations in which
rodents exhibiting spontaneous seizures were isolated or
animals were selectively bred for increased seizure suscep-
tibility. In some of these cases, the noradrenergic system of
these mutants has been shown to be compromised, and
restoring noradrenergic signaling ameliorates the seizures.
2.5.1. The genetically epilepsy-prone rat
The most extensively studied of these models is the
genetically epilepsy-prone rat (GEPR) (Consroe et al.,
1979). GEPRs have a heritable susceptibility to audiogenic
(AUD) and other induced seizures, and have multiple
deficits in the noradrenergic system, including reduced NE
content in several brain regions (Dailey et al., 1991),
reduced NE turnover (Jobe et al., 1984), reduced expression
and activity of NE biosynthetic enzymes (Dailey & Jobe,
1986; Browning et al., 1989; Lauterborn & Ribak, 1989;
Szot et al., 1996), reduced NE uptake (Browning et al.,
1989), and deficits in noradrenergic neuron development
(Clough et al., 1998). While there are abnormalities in other
neurotransmitter systems in the GEPRs, such as 5-HT and
GABA (Faingold, 1988), restoration of noradrenergic sig-
naling via administration of NE or NE reuptake inhibitors
(Mishra et al., 1993; Yan et al., 1993), noradrenergic
agonists (Ko et al., 1984; Yan et al., 1998), or fetal LC
grafts (Clough et al., 1991) ameliorate AUD seizures in
GEPRs. These results suggest that defects in the NE system
underlie at least part of the inherent seizure susceptibility in
these animals.
2.5.2. Mouse and gerbil mutants
NE appears to be involved in other animal models of
inherited epilepsy. For example, like the GEPRs, El epi-
leptic mice have decreased central NE content. In addition,
seizures in the El mouse, the quaking mouse, and the
seizure-sensitive Mongolian gerbil are ameliorated by nor-
adrenergic agonists (Chermat et al., 1981; Löscher, 1985;
Löscher & Czuczwar, 1987; Tsuda et al., 1990, 1993). One
paradoxical case involves the tottering mouse mutant, which
has hyperinnervation of some LC targets. 6-OHDA lesions
of the LC in mutant mice ameliorate the epileptic phenotype
(Noebels, 1984), implying that in contrast to most other
epilepsy models, NE is proconvulsant. However, it is likely
that the seizure phenotype of the tottering mouse is due to
an interaction between noradrenergic neuron hyperarboriza-
tion and network excitability defects in LC target regions
217
such as the hippocampus (Noebels & Rutecki, 1990; Hele-
kar & Noebels, 1992).
2.6. Adrenoreceptor agonists and antagonists
The noradrenergic signaling system is extremely com-
plex; three distinct classes of receptor with multiple sub-
types have been cloned, and each class activates different
G-proteins. The a1 class of adrenoreceptors (ARs) are
linked to Go/Gq and activate phospholipase C and intra-
cellular Ca2 + release. a2ARs are linked to Gi and inhibit
adenylate cyclase. bARs (b1AR and b2AR) are linked to
Gs and activate adenylate cyclase (reviewed by Cooper et
al., 1996). All of these receptor classes are widely dis-
tributed throughout the brain, and are found in regions
implicated in regulating seizures, such as the hippocampus,
cortex, and amygdala.
Pharmacology has been the most extensively used tool
by investigators over the years to examine the role of NE
in seizure susceptibility, but it has also yielded the most
conflicting results, for reasons that will be discussed.
Table 1 is meant to be a comprehensive summary of all
pharmacological experiments on seizure susceptibility using
agonists and antagonists. However, due to the vastness of
the literature and the limitations of the searches employed,
it is likely that some studies were inadvertently omitted.
The studies listed are ones that reported pro- or anticon-
vulsant effects of AR agonists and antagonists. For space
and organizational considerations, studies that found no
effect on seizure susceptibility of any particular drug were
not included. Perusal of Table 1 highlights one of the main
conclusions of this review: there is no single anticonvulsant
AR. Agonists and antagonists for nearly every known AR
have been shown to have both pro- and anticonvulsant
effects in at least one instance, and for many drugs, multiple
conflicting results are reported. There are two primary
reasons for this confusion. First, vast differences exist in
AR distribution between animal species, strain, and the
brain regions(s) affected by seizure-inducing paradigms.
Each class of convulsant agent likely elicits seizures by
distinct mechanisms that probably involve different neur-
onal networks. Because nearly every region of the brain
receives noradrenergic innervation and expresses different
sets of AR subtypes, it is not surprising that there is no
universal anticonvulsant receptor. Second, the lack of
agonist and antagonist specificity for different classes of
a2ARs makes many experiments with these drugs nearly
impossible to interpret. The a2ARs are discussed in greater
detail in the following section. The following sections give
a summary of the studies listed in Table 1 for each AR
subtype. Only selected papers of considerable interest are
discussed in more detail.
2.6.1. The a2-adrenoreceptor
The a2AR is probably the most promiscuous anticon-
vulsant AR in terms of efficacy across species, strain, and
218 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233

Table 1
Proconvulsant and anticonvulsant effects of adrenoreceptor agonists and antagonists
Receptor Species Seizure model Effect Reference
a1 agonists
Phenylephrine Rat GEPR Anticonvulsant Ko et al., 1984; Yan et al., 1998;
Faingold & Casebeer, 1999
Mouse El Anticonvulsant Tsuda et al., 1990
QM Anticonvulsant Chermat et al., 1981
Methoxamine Rat GEPR Anticonvulsant Yan et al., 1998
QA Anticonvulsant Wu et al., 1987
St 587 Rat AK Anticonvulsant Löscher & Czuczwar, 1987
SPMS Anticonvulsant Micheletti et al., 1987
Mouse EC Proconvulsant Jackson et al., 1991
PTZ Proconvulsant Gadie & Tulloch, 1985
Gerbil ABS Anticonvulsant Löscher & Czuczwar, 1987
Cirazoline Rat SPMS Anticonvulsant Micheletti et al., 1987
a1 antagonists
Prazosin Rat KA Anticonvulsant Baran et al., 1985
PEN Proconvulsant Neuman, 1986
SPMS Proconvulsant Micheletti et al., 1987
Mouse PTZ Proconvulsant Weinshenker et al., 2001
QM Proconvulsant Chermat et al., 1981
SPON Proconvulsant Horton et al., 1980
STR Anticonvulsant Amabeoku & Chandomba, 1994
Corynanthine Gerbil ABS Proconvulsant Löscher & Czuczwar, 1987
a2 agonists
Clonidine Rat AK Anticonvulsant Gellman et al., 1987;
Löscher & Czuczwar, 1987;
McIntyre & Giugno, 1988;
Pelletier & Corcoran, 1993;
Yoshioka et al., 2000
AK Proconvulsant Yoshioka et al., 2000
EC Anticonvulsant Kulkarni, 1981
EC Proconvulsant Crunelli et al., 1981;
Löscher & Czuczwar, 1987
KA Anticonvulsant Baran et al., 1985
PTZ Anticonvulsant Papanicolaou et al., 1982a, 1982b;
Lazarova et al., 1984;
Scotti de Carolis et al., 1986
QA Proconvulsant Wu et al., 1987
PIC Anticonvulsant Kulkarni, 1981
SPMS Proconvulsant Micheletti et al., 1987
STR Anticonvulsant Kulkarni, 1981
Mouse AUD Anticonvulsant Horton et al., 1980
EC Anticonvulsant Kulkarni, 1981; Jackson et al., 1991
El Anticonvulsant Tsuda et al., 1990
FLUR Proconvulsant Greer & Alpern, 1980
MET Anticonvulsant Homeida & Cooke, 1982
NMDA Anticonvulsant Czuczwar et al., 1985
PTZ Anticonvulsant Löscher & Czuczwar, 1987;
Amabeoku et al., 1994
PTZ Proconvulsant Oishi et al., 1979
PTZ Proconvulsant Weinshenker et al., 2001
QM Proconvulsant Chermat et al., 1981
PIC Anticonvulsant Kulkarni, 1981
STR Anticonvulsant Kulkarni, 1981;
Amabeoku & Chandomba, 1994
Gerbil ABS Anticonvulsant Löscher, 1985; Löscher & Czuczwar, 1987
Cat AK Anticonvulsant Shouse et al., 1996
Mouse AUD Anticonvulsant Horton et al., 1980
UK 14,304 Mouse EC Anticonvulsant Jackson et al., 1991
Rat PTZ Anticonvulsant Papanicolaou et al., 1982b
44-549 Rat PTZ Anticonvulsant Papanicolaou et al., 1982b
Lofexidine Rat PTZ Anticonvulsant Papanicolaou et al., 1982b
Guanfacine Rat PTZ Anticonvulsant Papanicolaou et al., 1982b
(continued on next page)
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233 219

Table 1 (continued )
Receptor Species Seizure model Effect Reference
a2 agonists
CP-14,304-18 Mouse AUD Anticonvulsant Horton et al., 1980
Oxymetazoline Mouse AUD Anticonvulsant Horton et al., 1980
a2 antagonists Rat AK Proconvulsant Gellman et al., 1987
Yohimbine Rat EC Anticonvulsant Crunelli et al., 1981
KA Proconvulsant Baran et al., 1985
PEN Anticonvulsant Neuman, 1986
PTZ Proconvulsant Lazarova & Samanin, 1983
QA Anticonvulsant Wu et al., 1987
SPMS Anticonvulsant Micheletti et al., 1987
Mouse BIC Anticonvulsant Lloyd & Worms, 1982
BIC Proconvulsant Lloyd & Worms, 1982
El Anticonvulsant Tsuda et al., 1990
PIC Proconvulsant Lloyd & Worms, 1982
PTZ Anticonvulsant Lloyd & Worms, 1982
PTZ Proconvulsant Lloyd & Worms, 1982;
Gadie & Tulloch, 1985;
Fletcher & Forster, 1988;
Gross & Ferrendelli, 1982
QM Anticonvulsant Chermat et al., 1981
Rat AK Proconvulsant Gellman et al., 1987
Idazoxan GEPR Anticonvulsant Yan et al., 1998
HK Proconvulsant Kokaia et al., 1989; Bengzon et al., 1990
Mouse AK Proconvulsant Janumpalli et al., 1998
BIC Proconvulsant Fletcher & Forster, 1988
EC Proconvulsant Jackson et al., 1991
PTZ Proconvulsant Gadie & Tulloch, 1985;
Fletcher & Forster, 1988
STR Proconvulsant Amabeoku & Chandomba, 1994
Phentolamine Rat AK Proconvulsant Gellman et al., 1987
Mouse PTZ Anticonvulsant Oishi et al., 1979;
Gross & Ferrendelli, 1982
STR Anticonvulsant Amabeoku & Chandomba, 1994
Rauwolscine Mouse BIC Proconvulsant Fletcher & Forster, 1988
Wy 26392 Mouse PTZ Proconvulsant Fletcher & Forster, 1988
EC Proconvulsant Jackson et al., 1991
Efaroxan Mouse EC Proconvulsant Jackson et al., 1991
RX811059 Mouse EC Proconvulsant Jackson et al., 1991
RX821002 Mouse EC Proconvulsant Jackson et al., 1991
b agonists Rat PEN Anticonvulsant Ferraro et al., 1994
Isoproterenol Mouse EC Proconvulsant Jackson et al., 1991
PTZ Anticonvulsant Weinshenker et al., 2001
Albuterol Rat GEPR Anticonvulsant Ko et al., 1984
Dobutamine Rat GEPR Anticonvulsant Ko et al., 1984
Terbutaline Rat GEPR Anticonvulsant Ko et al., 1984
b antagonists Rat HK Anticonvulsant Kokaia et al., 1989
Propanolol Rat KA Anticonvulsant Baran et al., 1985
LEP Anticonvulsant Papanicolaou et al., 1982c
PTZ Anticonvulsant Louis et al., 1982
Mouse AUD Anticonvulsant Lints & Nyquist-Battie, 1985
EC Anticonvulsant Murmann et al., 1966;
Madan & Barar, 1974
El Anticonvulsant Tsuda et al., 1990
LEP Anticonvulsant Murmann et al., 1966
PTZ Proconvulsant Gross & Ferrendelli, 1982
QM Anticonvulsant Chermat et al., 1981
SNS Proconvulsant Ryan, 1985
STR Anticonvulsant Amabeoku & Chandomba, 1994
Rat PTZ Anticonvulsant Louis et al., 1982
Pindolol Mouse AUD Anticonvulsant Lints & Nyquist-Battie, 1985
Rat PTZ Anticonvulsant Louis et al., 1982
Timolol Rat PTZ Anticonvulsant Louis et al., 1982
ABS, air blast stimulation; EC, electroconvulsions; El, El mouse mutant; LEP, leptazol; MET, metaldehyde; NMDA, N-methyl-D-aspartate; QM, quaking
mouse mutant; SPMS, spontaneous petit-mal seizures; SPON, spontaneous; STR, strychnine.
220 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
seizure paradigm, although proconvulsant effects have also
been reported (e.g., Oishi et al., 1979; Löscher & Czuczwar,
1987; Wu et al., 1987). A major difficulty in interpreting
these results is that three different subtypes of a2AR exist
(a2A, a2B, a2C), and they are localized both pre- and
postsynaptically. Activation of presynaptic a2AR autore-
ceptors decreases noradrenergic firing and NE release (e.g.,
L’Heureux et al., 1986; Jorm & Stamford, 1993), while
activation of postsynaptic a2ARs inhibits the firing of target
cells (e.g., Gobert et al., 1998). Unfortunately, the a2AR
agonists and antagonists cannot distinguish between a2AR
subtypes or pre- versus postsynaptic a2ARs. Therefore, in
many cases, it is difficult to say whether agonist/antagonist
effects are due to changes in NE release or direct effects on
the excitability of target cells.
Because NE depletion and lesioning studies have almost
uniformly indicated an anticonvulsant role for endogenous
NE, it is likely that proconvulsant effects of a2AR agonists
are due to activation of a2ARs that decrease NE release, and
that anticonvulsant effects of a2AR agonists reflect the
activation of a2ARs on target cells. Likewise, proconvulsant
effects of a2AR antagonists may be due to blockade of
a2ARs on target cells, while the anticonvulsant effects of
a2AR antagonists may be mediated by the blockade of a2
autoreceptors and increased NE release. However, these
hypotheses have rarely been tested. One way to address this
issue is to eliminate the effects of a2AR agonists on
autoreceptors by using animals with LC lesions. McIntyre
and Giugno (1988) found an anticonvulsant effect of the
a2AR agonist clonidine on AK development that persisted
after a 6-OHDA lesion, demonstrating a postsynaptic site of
a2AR anticonvulsant action. Oishi et al. (1979) found an
anticonvulsant effect of the nonselective aAR antagonist
phentolamine on PTZ seizures in mice that was abolished by
6-OHDA lesions, suggesting that phentolamine was acting
by blocking a2 autoreceptors. However, they also reported a
proconvulsant effect of clonidine that persisted in 6-OHDA-
lesioned animals. 6-OHDA lesions potentiated both the pro-
(high dose) and anticonvulsant (low dose) effects of the
clonidine on electrically induced focal cortical seizures
(Dalton et al., 1985). They suggested that 6-OHDA lesions
produce supersensitivity of postsynaptic a2- and a1ARs, the
former mediating the anticonvulsant effect and the latter the
proconvulsant effect. However, because they did not use
a2AR- and a1AR-selective antagonists to block the effects
of clonidine, this result is open to interpretation. Another
result that is difficult to reconcile comes from amygdala-
kindled kittens. Shouse et al. (1996) found an anticonvulsant
effect of clonidine when infused into either the amygdala or
the LC. Activation of a2ARs in the LC typically decreases
LC firing and NE release, so the mechanism of this anticon-
vulsant effect remains obscure. Knockout mouse models that
alter NE signaling have shed some light on the role of a2ARs
in seizure susceptibility, and will be discussed in Section 5.2.
One particularly elegant and informative set of experi-
ments examined the role of the a2AR in AK development
(Gellman et al., 1987). These investigators showed that
clonidine suppressed, while idazoxan (a2AR antagonist)
facilitated kindling development. Idazoxan had no effect
on kindling development in rats lesioned with DSP-4,
suggesting that endogenous NE suppresses kindling devel-
opment via postsynaptic a2ARs. Interestingly, neither clo-
nidine nor idazoxan modified seizures from previously
kindled animals. This result may be explained by a parallel
experiment in which the same group of investigators found
decreases in the number of a2ARs in discrete brain regions
of kindled rats, suggesting that an attenuation of a2AR-
mediated seizure suppression may contribute to the devel-
opment of kindling (Chen et al., 1990).
2.6.2. The a1-adrenoreceptor
a1AR-acting drugs have not been nearly as extensively
studied as those acting on a2ARs. However, the anticon-
vulsant effect of a1AR agonists and the proconvulsant effect
of a2AR antagonists is nearly unanimous (Table 1). The
a1AR has also been implicated in the effects of high doses
of clonidine. For example, clonidine (1 mg/kg) had a
proconvulsant effect on PTZ-induced seizures in rats that
was blocked by the selective a1AR antagonist prazosin
(Papanicolaou et al., 1982a). An anticonvulsant effect of
high-dose clonidine against quinolinic acid (QA) in rats was
mimicked by the a1AR-selective agonist methoxamine and
was blocked by prazosin (Wu et al., 1987). Two other
examples (Oishi et al., 1979; Dalton et al., 1985) were
discussed in the previous section, although the activity of
clonidine on a1ARs in those studies was purely speculative.
Interestingly, the density of a1ARs in the brain changes
during and after seizure development, suggesting that endo-
genous NE is signaling through this subtype during these
critical periods. Repeated electroconvulsive seizures caused
an increase in a1AR density in the rat cerebral cortex,
followed by a transient (2– 4 hr) decrease after the last
seizure. The authors proposed that the sustained increase
was a compensation for the drop in synaptic levels of NE
observed after repeated electroconvulsive seizures, while the
transient decrease was a result of desensitization to acute
seizure-induced LC firing and increased NE release (Sher-
win et al., 1989). Similar results were obtained in amygdala-
kindled rats (Gundlach et al., 1995). In addition, a1AR
density is decreased in the brains of both GEPRs and the
AUD seizure-sensitive DBA/2J mouse strain, suggesting
that decreased a1AR signaling may be partially responsible
for the seizure-sensitive phenotype of these strains (Jazrawi
& Horton, 1986; Nicoletti et al., 1986).
2.6.3. The b-adrenoreceptors
There are only a handful of studies examining the effects
of bAR-acting drugs on seizure susceptibility. In addition,
drugs capable of distinguishing b1ARs from b2ARs were
rarely employed. Oddly, both bAR agonists and antagonists
tend to be anticonvulsant (Table 1). However, the use of
propranolol as the bAR antagonist taints these results in
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
many cases. Propranolol at high doses is known to possess
membrane stabilizing and local anesthetic activity, which
themselves appear to be anticonvulsant and are unrelated to
the bAR blockade (Murmann et al., 1966; Madan & Barar,
1974). However, two groups used additional experiments to
show that the bAR-blocking activity of propranolol was at
least partially involved. One showed that at low doses (0.5 –
1 mg/kg), the anticonvulsant effect of propranolol was
selective for the (
)-isomer, which has bAR-blocking
activity, over the (+)-isomer, which does not. However, at
high doses (20 mg/kg), which most other studies used, both
isomers had profound anticonvulsant effects (Louis et al.,
1982; Papanicolaou et al., 1982c). Another study showed
stereoselectivity and confirmed the anticonvulsant effects of
propranolol with pindolol, which is a more potent bAR-
blocker, but a less potent membrane stabilizer (Lints &
Nyquist-Battie, 1985). Because the effects of subtype-
selective bAR-acting drugs have not been studied with
many different seizure paradigms, the role of bARs in
seizure susceptibility is largely undetermined.
2.7. Norepinephrine and clinical anticonvulsant efficacy
Because NE is so potent at protecting against seizures in
many animal models of epilepsy, it would not be surprising
if NE were involved in the anticonvulsant activities of
therapies used clinically to treat epilepsy. If this were true,
anticonvulsants would be expected to (1) increase central
NE signaling and (2) would require NE for at least part of
their efficacy. Both of these requirements are fulfilled in a
number of cases. Treatment of rodents with the anticonvul-
sant sodium valproate increases TH expression in the LC
(Sands et al., 2000). Valproate, as well as the anticonvul-
sants carbamazepine and phenytoin, and the ketogenic diet
(KD), increase central NE levels (Baf et al., 1994a,b;
Meshkibaf et al., 1995; Sands et al., 2000; unpublished
data). In addition, the anticonvulsant effects of phenobar-
bital, phenytoin, vagus nerve stimulation, and the KD are
attenuated in the absence of functional noradrenergic sys-
tems (Waller & Buterbaugh, 1985; Krahl et al., 1998; Szot
et al., 2001). These results suggest that these therapies used
to treat epilepsy clinically may utilize the endogenous
noradrenergic system as part of their anticonvulsant mech-
anism. A caveat to the experiments demonstrating increases
in central NE levels is that tissue NE was measured, which
may or may not represent an increase in release. Preliminary
studies suggest that basal NE release, as measured by
microdialysis, is increased in the ventral hippocampus of
rats fed the KD (unpublished data).
2.8. Tricyclic antidepressants and epilepsy
Could NE reuptake blockers such as tricyclic antidepres-
sants be effective anticonvulsants? Some studies in rodents
and humans suggest that tricyclics are anticonvulsant (e.g.,
Chermat et al., 1981; Clifford et al., 1985; Dailey & Jobe,
221
1985; Applegate et al., 1986; Sakakihara et al., 1995; Dailey
& Naritoku, 1996), yet others report proconvulsant effects
(e.g., Peterson et al., 1985; Krijzer et al., 1984; Applegate et
al., 1986). In fact, seizures are a rare, but dangerous, side-
effect of antidepressant treatment, and can occur after an
overdose (e.g., Rosenstein et al., 1993; Dailey & Naritoku,
1996). How can NE be a potent endogenous anticonvulsant
while drugs that potentiate NE release such as tricyclics be
proconvulsant under some conditions? One explanation may
lie in the fact that while acute NE reuptake treatment increases
extracellular NE, chronic treatment with these drugs can dec-
rease TH activity in the LC and can decrease noradrenergic
firing under conditions that, similar to seizures, elicit strong
LC activation (e.g., Huang et al., 1980; Valentino & Curtis,
1991; Schultzberg et al., 1991; Komori et al., 1992; Melia et
al., 1992). Desensitization of noradrenergic receptors by
chronic antidepressant treatment may also be involved.
3. 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 compre-
hensive 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 genetic-
ally engineered mice with altered dopaminergic signaling,
which could contribute information to the role of DA in
seizure susceptibility.
3.1. Anatomical pathways of the dopaminergic system
The majority of the dopaminergic neurons in the CNS are
found in the midbrain region substantia nigra (SN) and
ventral tegmental area (VTA) nuclei. The SN is composed
of two regions, the SN pars compacta (SNpc) and the SN
pars reticulata (SNpr). SNpc consists mainly of dopaminer-
gic neurons, while the SNpr consists mainly of neurons that
contain the transmitter GABA. Ascending dopaminergic
projections from the SNpc/VTA are broken down into three
major projections: the mesostriatal, mesolimbic, and meso-
cortical pathways.
3.1.1. Mesostriatal pathway
The mesostriatal pathway is the major dopaminergic
pathway in the CNS, and it plays an important role in
locomotion, emotion, and cognition (e.g., Simon & Le Moal,
1984). The vast majority of dopaminergic neurons from the
SNpc, and some from the VTA, project to the dorsal striatum.
These neurons degenerate in Parkinson’s disease and cause
the locomotor disturbances (Hornykiewicz, 1966). These
dopaminergic terminals innervate both the GABAergic and
cholinergic neurons that are located in the caudate putamen.
222 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
3.1.2. Mesolimbic pathway
The SNpc and the VTA innervate a variety of other
forebrain regions, including the nucleus accumbens, olfact-
ory tubercle, septum, and bed nucleus of the stria terminalis
(Ungerstedt, 1971; Beckstead, 1976, 1979; Fallon & Moore,
1978a, 1978b; Fallon et al., 1978; Lindvall & Bjorklund,
1978). It is also believed that the SNpc/VTA sends afferent
projections to the median eminence, paraventricular nuc-
leus, arcuate, and hypothalamus (Kizer et al., 1976; Simon
et al., 1979b), although there is some controversy concern-
ing this pathway because a small number of dopaminergic
neurons are also localized to the zona incerta, an area known
to innervate these areas.
3.1.3. Mesocortical pathways
Scattered neurons from the VTA and medial SNpc
densely innervate the prefrontal, cingulate, suprarhinal,
and entorhinal corticies (Thierry et al., 1973: Fuxe et al.,
1974; Hökfelt et al., 1974; Lindvall et al., 1974). In addition
to the cortical areas, the hippocampus also receives a dense
innervation from the SNpc/VTA (Simon et al., 1979a;
Scatton et al., 1980; Swanson, 1982).
3.1.4. Descending pathways
The dopaminergic neurons in the SNpc and VTA also
have descending pathways to the dorsal raphe nucleus, the
major loci for serotonergic neurons, and to the LC, the
major noradrenergic loci (Simon et al., 1979a, 1979b;
Swanson, 1982; De Guerce & Milon, 1983). Therefore, all
three biogenic amines (DA, NE, and 5-HT) are intercon-
nected; when the activity of one monoamine is altered the
other two are also affected.
3.2. Activation of dopaminergic neurons in response to
seizures
The effect of a seizure on dopaminergic neurons is
different than that observed in the noradrenergic LC neu-
rons. Seizures induced by a variety of convulsant agents and
their severity (i.e., single acute seizure and status epilepti-
cus) do not increase the expression of the immediate early
gene c-fos in dopaminergic neurons (White & Price, 1993;
Applegate et al., 1995; Szot et al., 1997). The SN/VTA has
the capability of expressing c-fos mRNA when a stimulus
other than a convulsant agent such as reserpine is adminis-
tered (Wessel & Joh, 1992) or when the convulsant agent is
placed directly near the SN (Applegate et al., 1995). The
absence of c-fos mRNA expression in response to a seizure
injection suggests that the dopaminergic neurons are not
stimulated immediately following a seizure. Arguing against
this interpretation is the increase in 2-DG labeling observed
in the SN/VTA following a seizure induced by a variety of
convulsant agents (Ben-Ari et al., 1981; Gale, 1988; White
& Price, 1993; Handford & Ackermann, 1995). A possible
explanation for this discrepancy is that 2-DG reflects
general metabolic activity, whether it is induced by excit-
atory or inhibitory influences, whereas c-fos appears to
reflect only excitatory activity. The SN/VTA receives
intense GABAergic innervation, and the action of GABA
on postsynaptic receptors could result in increased 2-DG
labeling in the SN/VTA. The inhibitory action of GABA on
these neurons may then inhibit the expression of the c-fos.
Even though dopaminergic neurons do not show
increased activity following a seizure, there is other evi-
dence to indicate that the dopaminergic neurons are modi-
fied by epileptic activity. Bonhaus et al. (1986) showed an
increase in the firing (bursting) of the dopaminergic neurons
during a kindled seizure. PTZ-induced seizures result in a
transient increase in TH and DAT mRNA expression in the
SNpc/VTA (Szot et al., 1997). Kindling increases the
density of D2 DA receptors in the nucleus accumbens
(Csernansky et al., 1988a,b), with concomitant increase in
D2 DA receptor mRNA (Gelbard & Applegate, 1994).
3.3. Chemical lesioning of the dopaminergic system
The initial studies that involved lesioning the dopami-
nergic pathways with reserpine or 6-OHDA were difficult to
interpret because the noradrenergic nervous system was also
lesioned. When the noradrenergic pathways were protected,
lesioning the dopaminergic pathways had little effect on
seizure susceptibility, indicating a more important role for
NE. The use of the selective dopaminergic neurotoxin 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in
mixed findings, with the majority of the findings showing
no change in seizure susceptibility (Bonuccelli et al., 1991,
1994; Fariello et al., 1987; Van Ness et al., 1989).
3.4. Dopaminergic agonists and antagonists
There are two main types of DA receptors: D1-like (D1
and D5) and D2-like (D2, D3, and D4), which are classified
based on binding of pharmacological agonists, coupling to
second messengers, and nucleotide sequence. The D1-like
receptors activate adenylate cyclase, while the D2-like
receptors inhibit adenylate cyclase.
3.4.1. Mixed D1/D2 agonists/antagonists
Apomorphine is the prototype nonselective agonist for
D1/D2 receptors, and under most circumstances, it has an
anticonvulsant effect (Stull et al., 1973; Maynert et al.,
1975; Löscher & Czuczwar, 1986; Turski et al., 1988;
Ogren & Pakh, 1993), although this response can vary
depending on the species of animal and the convulsant
agent used (McKenzie & Soroko, 1972; Kleinrok et al.,
1978; Gyoergy, 1979; Legeza et al., 1982).
The data with D1/D2 antagonists have been the most
conclusive evidence that the dopaminergic system can
modulate seizure activity. Mixed D1/D2 antagonists, such
as haloperidol, chlorpromazine, and thioridazine, produce a
profound proconvulsant effect in many species and with a
wide variety of convulsant agents (Kilian & Frey, 1973;
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
Kleinrok et al., 1978; Sato et al., 1980; Turski et al., 1988;
Burke et al., 1990; Ogren & Pakh, 1993). One problem with
these pharmacological agents is that they are not selective
for any of the dopaminergic receptor subtypes, so it cannot
be determined which receptor subtype may be responsible
for the modulation of seizure activity. To determine which
receptor subtype is modulating seizure activity, selective
dopaminergic agents need to be administered.
3.4.2. The D1 receptor
There are several selective D1 DA agonists (SKF 38393,
SKF 77434, SKF 75670, SKF 82958, SKF 80723, SKF
82526, and CY 208-243), with SKF 38393 being the most
studied. This D1 DA agonist has shown either no effect or a
proconvulsant effect in different models of epilepsy and in
different species (Löscher & Czuczwar, 1986). The other D1
DA agonists have been tested only against pilocarpine-
induced seizures, and a strong proconvulsant response is
typically observed (Burke et al., 1990; Starr & Starr, 1993).
The proconvulsant effect of D1 DA agonists is selectively
blocked by the D1 DA antagonist SCH 23390 (Al-Tajir
et al., 1990a, 1990b; Barone et al., 1990; Burke et al., 1990).
Administration of the D1 DA antagonists alone have an
anticonvulsant effect against pilocarpine-induced seizures
(Al-Tajir et al., 1990a; Barone et al., 1990; Turski et al.,
1990). Because the majority of the studies with selective
dopaminergic agonists have used the pilocarpine model of
epilepsy, it remains to be determined what effect these drugs
would have on seizures induced by other convulsant agents.
Central administration of selective D1 DA agents has
identified specific regions that are important in modulating
seizures. Administration of either the D1 agonists SKF
38393 or CY 208-243 into the striatum, nucleus accumbens,
or hippocampus has no effect on pilocarpine-induced sei-
zures (Turski et al., 1988; Al-Tajir & Starr, 1990; Alam &
Starr 1992, 1993), but administration of these agents into the
SN resulted in a strong proconvulsant effect (Al-Tajir et al.,
1990b; Turski et al., 1990; Barone et al., 1992). Adminis-
tration of the D1 DA antagonist SCH 23390 into the
striatum, hippocampus, nucleus accumbens, or SN produced
an anticonvulsant effect (Al-Tajir & Starr, 1990; Al-Tajir
et al., 1990b; Barone et al., 1992; Alam & Starr, 1992).
3.4.3. The D2 receptor
In contrast to agonists at the D1 receptor, D2 DA receptor
agonists, such as lisuride and quinpirole, possess a pro-
nounced anticonvulsant effect that is blocked by D2 DA
antagonists (Farjo & McQueen, 1979; Löscher & Czuczwar,
1986; Al-Tajir et al., 1990a; Burke et al., 1990; Al-Tajir &
Starr, 1991a). D2 antagonists, on the other hand, do not
affect seizure susceptibility (Löscher & Czuczwar, 1986;
Satoh et al., 1987; Burke et al., 1990; Barone et al., 1992;
Ogren & Pakh, 1993).
Central administration of D2 DA agents revealed a
slightly different pattern than the D1 agents. Injection of
the D2 agonist quinpirole into the SN had no effect on
223
pilocarpine-induced seizures (Turski et al., 1990; Al-Tajir &
Starr, 1991a), but when injected into the anterior striatum,
nucleus accumbens, or olfactory tubercle, it had an anticon-
vulsant effect (Turski et al., 1988; Al-Tajir & Starr, 1991a,
1991b; Alam & Starr, 1994). These effects are opposite to
those observed with D1 DA agonists. Administration of the
D2 DA antagonist raclopride into the hippocampus had a
proconvulsant effect (Alam & Starr, 1993).
Although these results indicate that activation of the D1
DA receptor is proconvulsant and that activation of the D2
DA receptor is anticonvulsant, dopaminergic signaling is
more complicated than that. As stated in Section 3.4,
classification of the D1 receptor encompasses both the D1
and D5 subtype, while D2 includes D2, D3, and D4. Most
pharmacological agents used for the previous studies do not
differentiate between the subtypes.
4. 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 first studies
examining this issue found no effect of lesioning the
noradrenergic or dopaminergic system on cocaine-induced
seizures, and it was concluded that the mechanism of these
seizures was unrelated to catecholamines (Mason & Cor-
coran, 1979). The degree of lethality associated with
cocaine-induced seizures may have noradrenergic and dop-
aminergic components based on pharmacological studies,
but no effects on seizures per se were observed (Derlet &
Albertson, 1990; Witkin et al., 1993). Recently, the 5-HT2C
receptor has been implicated in cocaine-induced seizures.
The 5-HT reuptake inhibitor fluoxetine was shown to
enhance cocaine-induced seizures, while 5-HT2C antago-
nists were anticonvulsant (Ritz & George, 1997; O’Dell et
al., 2000). However, it may be worthwhile to revisit this
issue using the genetically engineered mice lacking DA or
NE (see the following section). This is especially relevant
for amphetamine, which has not been studied extensively,
but which elicits seizures that are qualitatively and pharma-
cologically distinct from those induced by cocaine (Hanson
et al., 1999).
5. New results using genetically engineered mice
Over the past 10– 15 years, transgenic and knockout
technology has provided a genetic tool to study neuro-
224 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
Fig. 2. Effects of AR agonists on PTZ-induced seizure susceptibility of
Dbh
/
mice. PTZ (40 mg/kg) was administered i.p. and the animals
were observed for 10 min. Shown is latency to first myclonic jerk (MJ) and
clonic/tonic seizure (C/T). Saline or agonists were administered i.p. 30 min
prior to PTZ. Dbh
/
mice have shorter latency to MJ and C/T than Dbh
+/
mice, and latency is normalized in Dbh
/
mice by the a1AR
agonist cirazoline (0.2 mg/kg) and the b2AR agonist albuterol (10 mg/kg),
but not the a2AR agonist clonidine (0.1 mg/kg) or the b1AR agonist
dobutamine (10 mg/kg). * P < 0.05 compared with Dbh
/
saline
control. Data from Weinshenker et al. (2001).
biological and other processes in mice. We and others
have used genetically engineered mice to alter catechol-
amine signaling, and asked questions pertaining to seizure
susceptibility. In combination with pharmacology, the re-
sults from these studies have furthered our understanding
of how endogenous catecholamines and catecholamine
receptor agonists and antagonists modulate seizure suscept-
ibility and represent a valuable tool for the future of
epilepsy research.
5.1. The dopamine b-hydroxylase knockout mouse
Mice lacking NE were generated via a targeted disruption
of the DA b-hydroxylase (Dbh) gene. DBH is required to
convert DA to NE; therefore, mice homozygous for this
mutation (Dbh
/
) completely lack NE and epinephrine
(EPI) (Fig. 1) (Thomas et al., 1995).
5.1.1. Response to seizure-inducing stimuli
To examine the role of NE in seizure susceptibility
using a genetic model, we tested the Dbh
/
mice for
susceptibility to PTZ, FLUR, KA, and sound-induced
seizures. Our results indicate that Dbh
/
mice were
more susceptible than controls to all forms of seizure
induction tested (Szot et al., 1999). These results con-
firmed and extended previous pharmacological findings
that endogenous NE is anticonvulsant. However, there are
unique caveats associated with the Dbh
/
mice. First,
it is not simply a knockout, but a neurotransmitter switch.
Because DBH converts DA to NE, noradrenergic neurons
synthesize DA instead of NE in the knockout (Fig. 1).
Therefore, the seizure susceptibility phenotype could be
associated with increased DA and could be unrelated to
the absence of NE. We addressed this caveat by restoring
NE via administration of L-3,4-dihydroxyphenylserine
(DOPS), which can be converted to NE by the enzyme
aromatic acid decarboxylase (AADC), thus bypassing the
requirement for DBH (Fig. 1) (Thomas et al., 1998).
DOPS administration restored normal FLUR-induced seiz-
ure sensitivity to Dbh
/
mice and also abolished the
increased c-fos mRNA induction seen in the knockouts
following seizures (Szot et al., 1999). Because the seizure
susceptibility of the Dbh
/
mice was normalized by
replacing NE, we conclude that the phenotype was caused
by a lack of NE and not excess DA. Second, because NE
itself is a precursor for EPI, Dbh
/
mice lack EPI, as
well as NE. However, the amounts of EPI in the brain are
very low compared with NE, including areas implicated
in seizure modulation, so the loss of EPI in the Dbh

/
mice probably does not contribute to the seizure-
sensitive phenotype.
5.1.2. Pharmacology of pentylenetetrazole-induced seizure
susceptibility
Dbh
/
mice have also been used to address which
receptor is responsible for mediating the anticonvulsant
effects of NE against PTZ-induced seizures. When Dbh

/
mice were treated with subtype-selective AR ago-
nists, we found that a1AR and b2AR, but not a2AR or b1AR
agonists restored normal PTZ sensitivity (Fig. 2) (Wein-
shenker et al., 2001). In parallel, we found that an a1AR
antagonist, but not a bAR antagonist conferred increased
PTZ-induced seizure sensitivity on control mice (Fig. 3)
(Weinshenker et al., 2001). These results suggest that the
a1AR mediates the anticonvulsant effect of endogenous NE
against PTZ-induced seizures. Agonist-induced b2AR
activation is also anticonvulsant, but endogenous NE prob-
ably does not signal through this receptor in this paradigm.
Using this unique combination of genetics and pharmaco-
logy, the anticonvulsant AR can be identified for multiple
seizure-inducing paradigms.
Fig. 3. Effects of AR antagonists on PTZ-induced seizure susceptibility of
control mice. Vehicle, the bAR antagonist propranolol (10 mg/kg) or the
a1AR antagonist prazosin (1 mg/kg), was administered 30 min prior to PTZ
(40 mg/kg). Blockade of a1AR, but not bAR, signaling in control mice
increased seizure susceptibility. MJ, myclonic jerk; C/T, clonic/tonic
seizure. * P < 0.05 compared with vehicle control. Data from Weinshenker
et al. (2001).
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
5.1.3. The ketogenic diet
The Dbh
/
mice were also used to examine the role
of NE in mediating the anticonvulsant effect of the KD. The
KD is a high-fat, low-protein, low-carbohydrate diet that
induces ketosis, and is very effective in treating epilepsy
refractory to conventional anticonvulsants, although the
mechanism is unknown (e.g., Schwartzkroin, 1999). To test
whether the KD might exert its anticonvulsant effects via the
noradrenergic system, control and Dbh
/
mice were fed
either the KD or a calorically matched normal diet (ND).
While the control mice fed the KD received significant
protection against FLUR-induced seizures compared with
control mice fed the ND, the KD failed to confer seizure
protection to Dbh
/
mice, despite the fact that they
attained similar levels of ketosis to that of control mice fed
the KD (Szot et al., 2001). These results imply that ketosis
alone is insufficient to produce an anticonvulsant effect and
that endogenous NE is required for the efficacy of the KD.
Preliminary experiments in rats fed the KD has revealed an
 2-fold increase in extracellular NE levels in the ventral
hippocampus compared with rats fed the ND (unpublished
data), although the mechanism (increased TH activity,
decreased uptake, etc.) is not known. These results suggest
that the KD increases basal release of the endogenous
anticonvulsant NE that confers anticonvulsant efficacy.
Similar experiments with other anticonvulsant drugs may
reveal a general role for synergy between the noradrenergic
and other systems in mediating the efficacy of drugs used to
treat epilepsy clinically. A failure of many typical anticon-
vulsant drugs to protect Dbh
/
mice against seizures
would suggest that the Dbh
/
mice would be a useful
model for drug-resistant epilepsy.
5.2. The a2A mutant mouse
Given the confusion surrounding the effects of a2AR
agonists and antagonists on seizure susceptibility (see
Section 2.6.1), genetic models such as knockouts of
a2AR subtypes may improve our understanding of the
function of this receptor. An a2A mutant mouse was created
and tested for susceptibility to electrical AK (MacMillan et
al., 1996; Janumpalli et al., 1998). The a2A mutants kindled
more quickly than controls, and the proepileptogenic effects
of the a2AR antagonist idazoxan on controls were absent in
the mutants. These results support earlier results in rats
using pharmacology demonstrating that the anticonvulsant
effect of endogenous NE is mediated by the a2AR in this
model of epilepsy (Gellman et al., 1987). However, the
results with the a2A mutant mice must be interpreted with
caution for three reasons. First, this mutant mouse is not a
traditional knockout in which 100% of the receptor is
absent. Rather, a point mutation (D79N) was introduced
into the endogenous a2A gene, and this point mutation does
not abolish all a2A signaling. This mutation blocks coupling
to K + , but not Ca2 + , currents; a loss of retrograde
information transfer from G-proteins to the receptor and
225
reduced, but not absent, agonist-stimulated GTPase activity
in vitro; and an 80% reduction in receptor density in vivo
(Surprenant et al., 1992; Ceresa & Limbird, 1994; Janum-
palli et al., 1998). Therefore, mice bearing this mutant
receptor may retain some a2A signaling capability, and this
signaling may be altered and may produce unexpected
effects on neuronal excitability. Second, the critical experi-
ment, demonstrating that the anticonvulsant effect of cloni-
dine on kindling development is abolished in the a2A
mutant mice, was not done. Third, the a2A receptor func-
tions as both a presynaptic autoreceptor and a postsynaptic
heteroreceptor (e.g., Winzer-Serhan et al., 1997). Because
the mutation affected all a2A receptors, it is still unclear
which ones mediate the anticonvulsant effect, although for
reasons discussed in Section 2.6.1, the receptors on LC
target neurons are the most likely to do so. These caveats
must be taken into account before the results presented in
this paper can be considered conclusive. Since this paper
was published, true a2A, a2B, and a2C knockout mice have
been produced. It will be interesting to revisit the question
of a2AR function in seizure susceptibility using these new
genetic models, perhaps testing them in multiple seizure-
inducing paradigms.
5.3. Other knockouts affecting noradrenergic signaling
Knockout mice exist for all ARs except for a1A and a1D
(Link et al., 1995, 1996; Susulic et al., 1995; Rohrer et al.,
1996; Cavalli et al., 1997; Altman et al., 1999; Chruscinski
et al., 1999) and the NE transporter (Wang et al., 1999).
These mice will be invaluable for determining the roles of
different AR subtypes, as well as for further defining the
occasionally ambiguous and paradoxical effects of AR
agonists and antagonists in epilepsy models. In addition, it
is now possible to make regional-specific and inducible
knockouts, which will aid in the understanding of how,
when, and where the noradrenergic system exerts its anti-
convulsant effects.
5.4. The genetically dopamine-deficient mouse
To study the consequences of a loss of DA, a genetically
engineered mouse that specifically lacks DA was developed.
These DA-deficient (DD) mice were produced by deleting
the Th gene and then re-expressing Th specifically in
noradrenergic neurons by targeting Th to one allele of the
Dbh locus (Fig. 1) (Zhou & Palmiter, 1995). Thus, DA
production is blocked because Th is absent specifically from
dopaminergic neurons, but normal NE levels are main-
tained. These animals offer the opportunity to determine
the effect of complete DA deficiency. The loss of DA does
not affect normal development during embryogenesis, but
at  3 – 4 weeks of life, they become hypoactive and
hypophagic, and will ultimately die without pharmaco-
logical intervention (Zhou & Palmiter, 1995). To study adult
DD mice, L-3,4-dihydroxyphenylalanine (L-DOPA), the
226 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
product of TH activity, was administered on a daily basis,
thus bypassing the requirement for TH in DA production
(Zhou & Palmiter, 1995). The chronic loss of DA in DD
mice results in a DA receptor supersensitivity (Szczypka
et al., 1999b; Kim et al., 2000). At present, the most likely
explanation for this hyper-response of the DD to DA is a
change downstream of dopaminergic receptors because
receptor-binding studies (D1 and D2) and the DAT are
unchanged in DD mice at the protein and message level
(Zhou & Palmiter, 1995; Kim et al., 2000). The DD mice
offer the opportunity to study seizure sensitivity when
dopaminergic signaling is either virtually absent (24 hr after
the last L-DOPA treatment) or during enhanced DA signal-
ing (1 –4 hr after L-DOPA administration).
5.4.1. Pentylenetetrazole- and kainic acid-induced seizure
susceptibility
Preliminary studies determining seizure susceptibility
with these mice indicate that neither the loss of DA nor
hyperdopaminergic signaling affects PTZ- or KA-induced
seizures under most conditions tested (Figs. 4 and 5). The
exception was at a high dose of PTZ, where an absence of
DA was anticonvulsant (DD mice 24 hr after L-DOPA), and
Fig. 4. PTZ-induced seizure susceptibility of DD mice. (A) PTZ (40 mg/kg)
or (B) PTZ (50 mg/kg) was administered to wild-type mice (WT, n = 6),
mice with deficient dopaminergic signaling (DD mice + saline 24 hr after
last 50 mg/kg L-DOPA treatment, n = 6), and mice with hyperdopaminergic
signaling (DD mice 1 hr after last 50 mg/kg L-DOPA treatment, n = 6). A
lack of dopaminergic signaling had an anticonvulsant effect only at the high
dose of PTZ, which was partially reversed by L-DOPA treatment. MJ,
myclonic jerk; C/T, clonic/tonic seizure. * P < 0.05 compared with WT
control. * * * P < 0.001 compared with WT control. y P < 0.05 compared
with DD + saline group.
Fig. 5. KA-induced seizure susceptibility of DD mice. KA (30 mg/kg) was
administered to wild-type mice (WT, n = 6), mice with deficient
dopaminergic signaling (DD mice + saline 24 hr after last 50 mg/kg L-
DOPA treatment, n = 6), and mice with hyperdopaminergic signaling (DD
mice 1 hr after last 50 mg/kg L-DOPA treatment, n = 6). Mice were
observed for 2 hr, and maximal seizure severity was scored on a modified
Racine scale (Racine, 1972): 1 = staring, 2 = head nodding or twitch,
3 = forelimb clonus, 4 = rearing and falling, 5 = generalized clonic/tonic
seizure, 6 = death.
restoration of DA to DD mice partially reversed this effect
(DD mice 1 hr after L-DOPA) (Fig. 4B). When dopaminergic
neurons were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetra-
hydropyridine, either an anticonvulsant or no effect was
observed with PTZ (Fariello et al., 1987; Van Ness et al.,
1989), while an anticonvulsant effect was observed with KA-
induced seizures (Bonuccelli et al., 1994). It will be impor-
tant to test the DD mice with higher doses of KA and in other
seizure-inducing paradigms to fully examine the role of DA
in seizure susceptibility.
5.4.2. Regional dopamine replacement using viral vectors
To further define if hypoactivity and hypophagia are
possible due to different dopaminergic pathways, Th has
been reintroduced into specific brain regions using recom-
binant viral vectors. When this was done, it became apparent
that hypophagia involves the innervation of the caudate
putamen by the SNpc, while hypoactivity involves the
innervation of the nucleus accumbens by the VTA (Szczypka
et al., 1999a, 2001). Because different dopaminergic path-
ways are involved in these two distinctly different physio-
logical responses, it is possible that different dopaminergic
pathways mediate effects on seizure susceptibility, which
could be dissected using this viral-mediated Th-replacement
technology in the DD mice.
5.5. The D2 dopamine receptor knockout mouse
The D2 knockout mouse is one of two DA receptor
knockout mice for which a change in seizure susceptibility
has been identified. Bozzi et al. (2000) showed that D2
receptor knockout mice were more susceptible to KA-
induced seizures and the associated neurotoxicity than
wild-type mice. The increased hippocampal cell death in
the D2 DA receptor knockout mouse could be attributed to
the high level of this receptor subtype in the hippocampus.
 D. Weinshenker, P. Szot / Pharmacology & Therapeutics 94 (2002) 213–233
D2 DA receptors in the hippocampus are localized to the
CA1, CA3, and dentate gyrus regions, areas where cell death
was observed. This led the authors to hypothesize a neuro-
protective role of the D2 DA receptor in the hippocampus.
The observed increased sensitivity of D2 knockouts to
KA is consistent with the anticonvulsant activity demon-
strated by D2 agonists (see Section 3.4.3). The loss of this
inhibitory receptor could result in increased neuronal excit-
ability and sensitivity to convulsant stimuli.
5.6. The D4 dopamine receptor knockout mouse
Like the D2 knockout mouse, the D4 knockout also has
altered seizure susceptibility. The greatest density of the D4
DA receptor is in the frontal cortex (Meador-Woodruff et al.,
1996; Mrzljak et al., 1996; Ariano et al., 1997). D4 DA
receptor signaling is implicated in memory (Williams &
Goldman-Rakic, 1995), in response to novel stimuli (Tassin
et al., 1980; Roth et al., 1988; Bardo et al., 1996), and in the
site of action of atypical antipsychotics (Van Tol et al., 1991;
Roth et al., 1995). Removal of this receptor results in an
animal less responsive to novel stimuli (Dulawa et al., 1999)
and increased excitability of cortical neurons to bicuculline
(BIC) (Rubinstein et al., 2001). The increased number of
paroxysmal discharges induced by BIC in D4 DA receptor
knockout mice may be due to increased levels of glutamate
in the synapse. These animals also have increased seizure
activity and increased mortality in response to BIC than
wild-type mice (Rubinstein et al., 2001).
5.7. Other knockouts affecting dopaminergic signaling
Knockout mice also exist for the D1 (Drago et al., 1994;
Xu et al., 1994) and D2 (Accili et al., 1996) DA receptors, as
well as for the DAT (Giros et al., 1996). Seizure-suscep-
tibility experiments using these mice have not been
reported, but offer an elegant set of reagents to study
whether DA has a role in animal models of epilepsy,
especially since the pharmacological experiments performed
to date have not distinguished between DA receptors within
the D1 or D2 classes. Of particular interest are the D1 DA
receptor knockouts. D1 agonists are proconvulsant in some
seizure paradigms (see Section 3.4.2), which may be attrib-
uted to the potentiating action of the D1 receptor on N-
methyl-D-aspartate receptors (Levine et al., 1996).
6. Conclusion
There is little doubt that catecholamine signaling, espe-
cially 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 a2AR agonist
clonidine that can decrease LC firing and NE release had
227
proconvulsant effects on patients with intractable focal
epilepsies (Kirchberger et al., 1998) and a single patient
with intractable complex partial seizure disorder (Schmitt
et al., 1999). There is one intriguing report that stimulating
the LC of epileptic humans reduced the incidence and
severity of their seizures (Feinstein et al., 1989). a1AR
density was found to be decreased in foci from patients with
intractable partial epilepsy (Brière et al., 1986), and changes
in TH activity, NE levels, and noradrenergic innervation
have been documented in foci from a number of types of
human epilepsy (e.g., Sherwin et al., 1984; Goldstein et al.,
1988; Trottier et al., 1994). The strongest case to be made
so far comes from the studies described in this review
suggesting that the noradrenergic system is important for
mediating the effects of clinical anticonvulsant therapies.
One intriguing possibility is that a combination of typical
anticonvulsant drugs and drugs that boost noradrenergic
signaling may be effective in treating seizure disorders.
One interesting study found that NE reuptake blockers poten-
tiated the effect of typical anticonvulsants in mice (Kleinrok
et al., 1991). Experiments along these lines warrant further
investigation, perhaps including selective AR agonists and
using genetically engineered mice with altered NE or AR
levels to achieve specificity. Use of these mice and those
with altered dopaminergic signaling in various seizure
paradigms will advance our understanding of how catechol-
amines influence neuronal excitability and seizure suscep-
tibility. Brain region-specific transgenics and knockouts will
help pinpoint where the anticonvulsant activities of the
catecholaminergic systems are located. To our knowledge,
there are no ongoing or planned clinical trials testing the
anticonvulsant activity of noradrenergic drugs. However,
given that NE reuptake blockers and AR-acting drugs are
already approved for treatment of other human disorders,
such as depression, hypertension, and asthma (e.g., Ruffolo
et al., 1995), perhaps approval for such studies could be
obtained more readily than for completely novel drugs.
Taking advantage of endogenous anticonvulsant neurotrans-
mitters such as NE is a rationale step in new drug discovery
for the treatment of epilepsy.
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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