Page 453 - The Toxicology of Fishes

Toxic Responses of the Fish Nervous System 433

A B
Presynaptic Presynaptic

coA
ACh ACh
mAChR
nAChR
mAChR
nAChR
chol ACh
ACh
AChE ACh AChE
ACh ACh ACh ACh
ace
ACh ACh ACh
ACh ACh ACh
ACh
nAChR nAChR
mAChR mAChR

Postsynaptic Postsynaptic

FIGURE 9.5 Role of acetylcholinesterase at synaptic junctions. (A) Typical cholinergic synapse. Acetylcholine is secreted
by the presynaptic neuron into the synapse, where it binds to presynaptic and postsynaptic muscarinic and nicotinic receptors.
Acetylcholinesterase breaks down acetylcholine into cholinesterase and acetylcholine. Cholinesterase is transported to the
presynaptic neuron, where acetyl coenzyme A converts it into acetylcholine. (B) Effect of acetylcholinesterase inhibitors
on cholinergic synapses. Acetylcholine is secreted into the synapse but is not broken down by acetylcholinesterase, leading
to an excess amount of acetylcholine in the synapse. ACh, acetylcholine; AChE, acetylcholinesterase; mAChR, muscarinic
receptor; nAChR, nicotinic receptor; chol, cholinesterase; coA, acetyl coenzyme A; ace, acetate.

Interestingly, although anticholinesterase compounds all disrupt acetylcholine signaling, all anticho-
linesterase compounds do not produce identical responses to poisoning (reviewed in Pope, 1999).
Acetylcholine signaling disruption is the first step in the acute neurotoxic response but is not sufficient
to explain all manifestations of toxicity. Several secondary, non-acetylcholinesterase targets have been
recognized (Casida and Quisad, 2004; Pope, 1999) and are thought to play instrumental roles in the
ultimate effects of cholinergic neurotoxicants. Furthermore, disruption of acetylcholine signaling alone
may not fully explain the developmental neurotoxicity of these compounds. Careful consideration should
be given to the non-cholinergic targets of these compounds when assessing toxicity, particularly in the
developing embryo. As shown in Figure 9.5A, the biochemical mechanisms of acetylcholine production,
secretion, and transmission are known in great detail. For the purposes of this discussion, only acetyl-
choline pathway components targeted by cholinergic agonists are addressed.

Manifestations of Cholinesterase Inhibitor Neurotoxicity in Fish
Brief exposures to organophosphorus pesticides can produce long-lasting neurological effects because of
the irreversibility of AChE inhibition; in fact, depression of AChE activity is considered a primary indicator
of organophosphate pesticide exposure in fish. As a result, the extensive research in fish neurotoxicity
has sought to correlate acute toxicity in adult fish with level of acetylcholinesterase inhibition (Heath,
1995; Murty and Ramani, 1992; Zinkl et al., 1991). Based on work in several different fish species and
with several cholinergic poisons, it is generally accepted that 70 to 80% AChE inhibition is lethal.
Acute exposures to organophosphorus and carbamate insecticides, in a variety of species including
goldfish (Carassius auratus), fathead minnows (Pimephales promelas), medaka (Oryzias latipes), and
rainbow trout (Oncorhynchus mykiss), increased spontaneous locomotor activity with high incidences of