Depolarisation block

Figure 17.5 Possible scheme for the initiation of depolarisation block of DA neurons. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. At5q)ical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. 17.7)...

Two features require some comment. The induction of depolarisation block in DA neurons needs afferent input to the nuclei, since prior lesion of the striatum and nucleus... 

Second, although typical neuroleptics produce depolarisation block of both A9 and AlO neurons, the atypical neuroleptics only induce it in AlO neurons (Chiodi and Bunney 1983). So after an atypical neuroleptic the A9 neurons of the nigrostriatal tract remain functional, which would explain why EPSs are not seen. Another difference is seen with the expression of an immediate-early gene, c-fos, and although its functional significance is not clear, typical neuroleptics induce its protein production in both the striatum and nucleus accumbens while the atypicals only achieve it in the accumbens. 

The slow time-course of depolarisation block not only offers an explanation for the latency of action of neuroleptic drugs but its occurrence may explain how they actually reduce DA function. Whether it explains their antischizophrenic effect is less certain since it is not possible to determine if such depolarisation occurs in patients on neuroleptic drugs. Certainly if this is how neuroleptics work it cannot be claimed that they have returned brain function to normal. 

Suxamethonium produces a typical depolarising block that is characterised by the appearance of fasciculations before the onset of block, absence of fade in response to tetanic and TOP stimulations, and potentiation of block by anticholinesterase drugs. 

Studies were carried out on the possible neuromuscular blocking actions of chloroquine diorotate in animals, because it was noticed that when it was used in the peritoneal cavity to prevent adhesions following abdominal surgery in man, it caused respiratory insufficiency during the recovery period. These studies found that it had a non-depolarising blocking action at the neuromuscular junction, which was opposed by neostigmine. It... 

The demonstration of GABA receptors coupled to Cl channels in the posterior pituitary (Zhang and Jackson 1993) prevailed Zhang and Jackson (1995) by activation of these receptors and gating the Cl channels to alter membrane potential, action potentials, and the status of voltage-gated channels. Their results supported a depolarisation block mechanism in the inhibition of secretion by GABA. 

Fig. 6.6 Characteristics of neuromuscular response following repeated nerve stimulation. Depolarisation block, with no fade, is characteristic of failure of neuromuscular transmission in the cholinergic syndrome produced by antichohnesterase compounds such as sarin...

Clinically, IMS resembles the syndrome of incomplete reversal of neuromuscular paralysis by non-depolarising blocking agents sometimes seen following general anaesthesia. Patients will recover after a week or 10 days if intensive care facilities are available with intermediate positive pressure variation. Unfortunately, OP pesticide poisoning often occurs in countries that have the least available resources in terms of intensive care. 

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