Perspective

What is obvious from all the experimental evidence is that it is easier to unravel the cause of the undesirable than it is to explain the desirable effects of neuroleptic drugs. EPSs occur because such drugs all have some D2 antagonist activity and so reduce DA transmission in the striatum. The degree to which they achieve this and whether they are typical or atypical depends on their affinity for D2 striatal receptors, since EPSs

Figure 17.8 Comparison of the antagonist potencies of some neuroleptics on different NT receptors. Data are shown for haloperidol (HAL), chlorpromazine (CPZ), clozapine (CLOZ) and risperidone (RISP) acting on dopamine D1 and D2, 5-HT2 (S2), alpha (a2) adrenoceptors and cholinergic muscarinic receptors (M). The height of each column shows an average of the dissociation constants obtained from a number of publications (see Seeman 1990). The values, which can vary some fiftyfold, are expressed as the negative logarithms (i.e. 9 = 10~9 M,lnM) so that the higher the column, the more potent the compound. The order of potency of the four compounds at each receptor is shown alongside

Figure 17.8 Comparison of the antagonist potencies of some neuroleptics on different NT receptors. Data are shown for haloperidol (HAL), chlorpromazine (CPZ), clozapine (CLOZ) and risperidone (RISP) acting on dopamine D1 and D2, 5-HT2 (S2), alpha (a2) adrenoceptors and cholinergic muscarinic receptors (M). The height of each column shows an average of the dissociation constants obtained from a number of publications (see Seeman 1990). The values, which can vary some fiftyfold, are expressed as the negative logarithms (i.e. 9 = 10~9 M,lnM) so that the higher the column, the more potent the compound. The order of potency of the four compounds at each receptor is shown alongside diminish with low D2 affinity and their ability to block ACh muscarinic or 5-HT2 or other receptors. Trying to translate from in vitro binding studies to an explanation of antipsychotic effectiveness is also made more difficult by the fact that they do not readily distinguish between agonist and antagonist activity. More functional studies of neuroleptic activity in different brain areas is required.

Measuring the expression of the early-immediate gene c-fos supports the striatal role of neuroleptics in the induction of EPSs because although all neuroleptics induce such expression in both the nucleus accumbens and striatum, the atypical neuroleptics do so more in the accumbens while clozapine, but not risperidone, also achieve it in the prefrontal cortex (Robertson, Matsumura and Fibiger 1994). How this arises is uncertain but since risperidone is a more potent 5-HT2 antagonist than clozapine, it cannot be through that mechanism.

Establishing the possible site of action of a drug in vivo first and then trying to unravel what it actually does at the cellular or molecular level is an alternative approach to the analysis of drug action. In this respect much was, and is, hoped of PET (SPECT) studies in humans and non-human primates. Of course, these tell us primarily where drugs are not located and therefore certainly do not act. Locating their labelled form in particular brain regions does, however, indicate where they may act, although a high concentration in one area does not automatically make that the drug's primary site of action. Nevertheless, this approach does help to clarify the origin of EPSs since although both typical and atypical drugs appear to bind to limbic and cortical areas to a similar extent it is only the typical ones that show high striatal levels.

On this evidence one can confidently equate EPS with neuroleptic DA receptor (D2) antagonism in the striatum and possibly a reduction in the positive symptoms of schizophrenia through similar action in the limbic system (nucleus accumbens).

brain area prefrontal

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LIMBIC ^SYSTEM NUCLEUS ACCUMBENS

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REQUIRED EFFECT

DA INFLUENCE f ?

NEGATIVE SYMPTOMS

DA INFLUENCE J,

POSITIVE SYMPTOMS

DA INFLUENCE EPSs

TYPICAL

NEUROLEPTIC ATYPICAL

CLOZAPINE

DA INFLUENCE SYMPTOMS

INCREASED

DECREASED

PARTIAL EFFECT

EFFECT J

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum; the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal u> side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ^

Whether the amelioration of negative symptoms results from an action in the cortex and, in particular, the prefrontal cortex requires further study. The fact that clozapine, the atypical drug that is currently most effective in this respect, has actions there which are not shown by other compounds is encouraging even though the precise mechanism by which it works remains to be elucidated.

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug.

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