Drugs and Toxins

The foregoing models are sufficient to piece together a crude model of synaptic transmission. However, many features were ignored, and there are many situations that can change the behavior of this system. Primary among these are drugs and toxins that affect specific events in the neurotransmission process. For example, the influx of calcium is reduced by divalent metal ions, such as Pb++, Cd++, Hg++, and Co++. By reducing the influx of calcium, these cations depress or abolish the action-potential-evoked transmitter release. Certain toxins, including tetanus and clostridial botulinus, are potent inhibitors of transmitter exocytosis, an action that is essentially irreversible. Botulinus neurotoxin is selective for cholinergic synapses and is one of the most potent neuroparalytic agents known. Tetanus toxin is taken up by spinal motor nerve terminals and transported retrogradely to the spinal cord, where it blocks release of glycine at inhibitory synapses. Spread of the toxin throughout the brain and spinal cord can lead to severe convulsions and death. The venom from black widow spider contains a toxin (a-latrotoxin) that causes massive transmitter exocytosis and depletion of synaptic vesicles from presynaptic nerve terminals.

Agents that compete with the transmitter for receptor binding sites, thereby preventing receptor activation, are called receptor antagonists. An example of an antagonist of the ACh receptors of the skeletal neuromuscular junction is curare. By inhibiting ACh binding at receptor sites, curare causes progressive decrease in amplitude and shortening of epps. In severe curare poisoning, transmission is blocked.

Selective antagonists exist for most transmitter receptors. For example, bicuculline is an antagonist of GABA receptors, and is a well-known convulsant.

Agents that mimic the action of natural transmitters are known as receptor agonists. A well-known agonist of ACh receptors in neuromuscular junction is nicotine. Nicotine binds to the ACh receptor and activates it in the same manner as ACh. However, nicotine causes persistent receptor activation because it is not degraded, as is ACh, by ACh-esterase. On the other hand, diisopropylphosphofluoridate (commonly known as nerve gas) is an example of an anticholinesterase, because it inhibits the activity of ACh-esterase, so that ACh persists in the synaptic cleft. Similarly, one effect of cocaine is to prolong the activity of dopamine, by blocking the uptake of dopamine from the synaptic cleft.

Other agents interfere with receptor-gated permeabilities by interfering with the channel itself. Thus, picrotoxin, which blocks GABA-activated Cl- channels, and strychnine, which blocks glycine-activated Cl- channels, are potent blockers of inhibitory synapses and known convulsants.

Gap junctions are small nonselective channels (with diameters of about 1.2 nm) that form direct intercellular connections through which ions or other small molecules can flow. They are formed by the joining of two connexons, hexagonal arrays of connexin protein molecules (Fig. 7.13). Despite being called electrical synapses, in this chapter we concentrate on models in which membrane potential plays no role, focusing instead on the interaction between intracellular diffusion and intercellular permeability. Electrical aspects of gap junctions are important for the function of cardiac cells and are discussed in that context in Chapter 11. An example of how gap junctions are used for intercellular signaling via second messengers is detailed in Chapter 12, where we discuss a model of intercellular calcium wave propagation.

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