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NEUROTRANSMITTERS IN PLATYHELMINTHS 389
Uredofos and metriphonate
The cholinesterases of cestode and trematode
parasites may be antagonized selectively with
less effect on the host. The partial selectivity of
the organophosphorus drugs like uredofos
and metriphonate has led to the use of these
compounds for treatment. Uredofos was introduced
in dogs and cats for the treatment of
Dipylidium caninum but the compound has
now been withdrawn because of toxicity. The
design and use of more selective cholinesterases
may be one approach for the development of
novel anthelmintic agents.
Glutamate
A number of lines of evidence suggest a role for
glutamate as a neurotransmitter in flatworms.
Glutamate is one of the most abundant free
amino acids in parasitic flatworms, and glutamate
immunoreactivity has been described in
the cephalic ganglia and longitudinal nerves,
as well as in the peripheral nerve nets of the
peripheral tissues, including somatic muscle.
In addition to the immunocytochemistry,
there is convincing physiological evidence
supporting a role for glutamate as a neurotransmitter.
Tissue slices of the tapeworm
H. diminuta take up glutamate through two
distinct Na -dependent transport systems, and
depolarization elicits a calcium-dependent
release of glutamate. Exogenous glutamate
elicits powerful rhythmic contractions of
longitudinal muscle preparations, and it has
biphasic effects on cAMP levels in H. diminuta
homogenates. Glutamate or aspartate
increase electrical activity in the nerve cords
of the cestodarian Gyrocotyle fimbriata. The
non-selective glutamate receptor antagonist
2-amino-4-phosphonobutyric acid antagonized
the effect of the excitatory amino acids,
suggesting an excitatory role for glutamate in
these flatworms. In schistosomes, exogenous
glutamate is also myoexcitatory. Surprisingly,
at least some of the myoexcitation is mediated
by electrogenic glutamate transporters located
on the muscle membranes. The application of
glutamate to isolated muscle fibers induces
contraction. These contractions are not blocked
by glutamate receptor antagonists, but they
are blocked by glutamate transport inhibitors
such as trans-pyrollidine-dicarboxcylic acid.
Like some glutamate transporters, the contractions
are dependent on extracellular Na .
GABA
GABA (and glycine) have inhibitory effects on
the discharges of the lateral nerve cords of
Gyrocotyle fimbriata. This effect is reversed by
the GABA antagonists picrotoxin and bicuculline.
However, these observations are only
suggestive of a possible general role of GABA,
since other authors have reported no effect of
GABA in intact S. mansoni. Thus the role of
GABA as a neurotransmitter in trematodes
and cestodes remains to be established.
5-HT
Bennett and Bueding showed that 5-HT is
present in the nervous system of both trematodes
and cestodes, and in both classes the
distribution is widespread throughout the
central nervous system and the peripheral
plexuses. One broad theme observed in flatworms
is that 5-HT distribution is often distinct
from the largely overlapping cholinergic
and peptidergic staining patterns. 5-HT is the
most studied of the flatworm neurotransmitter
candidates, and a number of biochemical
and physiological actions have been reported.
5-HT stimulates adenylate cyclase activity in
homogenates of trematodes and cestodes,
leading to the phosphorylation of a number of
proteins. In trematodes, phosphofructokinase
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS