Neuroleptics EPSs with

Reference has been made already to the shortcomings of the term neuroleptic . We now have a situation in which the drugs that are most useful in schizophrenia are regarded as atypical. While the term was introduced to cover those neuroleptics that do not cause EPSs, it has become synonymous with clozapine which has additional advantages over other neuroleptics (e.g. reduces negative symptoms, see text). Thus it is not always clear what is meant or covered by atypical. Hopefully this distinction between the neuroleptics will become unnecessary as better compounds are developed and the older ones become obsolete. 

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. 

Figure 17.7 Possible mechanism by which atypical neuroleptics with antimuscarinic activity produce few EPSs. Normally the inhibitory effects of DA released from nigrostriatal afferents on to striatal neuron D2 receptors is believed to balance the excitatory effect of ACh from intrinsic neurons acting on muscarinic (M2) receptors (a). Typical neuroleptics block the inhibitory effect of DA which leaves unopposed the excitatory effect of ACh (b) leading to the augmented activity of the striatal neurons and EPSs (see Fig. 15.2). An atypical neuroleptic with intrinsic antimuscarinic activity reduces this possibility by counteracting the excitatory effects of released ACh as well as the inhibitory effects of DA (c). Thus the control of striatal neurons remains balanced...

Unfortunately although much is known about the pathways and receptors involved in extrapyramidal activity and the mechanism of the EPSs that follow neuroleptic therapy and even the possible origin of negative symptoms in the prefrontal cortex, the precise site of origin and NT involvement in the overriding positive symptoms is less clear. Until that is corrected, permutations of NT antagonisms are likely to multiply with the neuroleptics. 

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