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Commentary on Dinan's Hypothesis

  • Leslie L. Iversen (a1)

Extract

Dinan's paper seeks to question the validity of the now widely accepted hypothesis that neuroleptic drugs of various different chemical categories all act by a common mechanism, namely by blockade of dopamine receptors of the D2 type in brain (for review see Creese et al, 1978, 1983; Iversen, 1985). While it is always refreshing to re-examine existing scientific dogma, his criticisms did not appear to me to be very substantial. Having quite fairly reviewed the evidence in favour of the “dopamine hypothesis” for neuroleptic drug action, Dinan summarises his reasons for questioning it. He points out that many neuroleptic drugs have potent actions on a number of other targets, apart from the dopamine receptors in brain. This is indeed so, and the archetypal compound, chlorpromazine, has a particularly rich spectrum of pharmacological activity, being a potent antagonist of serotonin (5-HT2) receptors, ?-adrenoceptors, and histamine (HI) receptors in brain and other tissues. Other neuroleptics also have potent actions on a number of other systems. Indeed, if one were to have studied only chlorpromazine, it is doubtful whether the “dopamine hypothesis” could ever have been developed. The strength of this hypothesis lies in the fact that of all the diverse pharmacological actions which different neuroleptic drugs exhibit, this is the only action that is common to all neuroleptic compounds. Furthermore, in a large group of neuroleptics, which differ widely in potency (doses in man ranging from 1 mg/day to almost 1000 mg/day), the potencies of these drugs as dopamine (D2) antagonists correlate significantly with their clinical potencies. Attempts to make such correlations with any other known pharmacological properties of these drugs fail to show significance (Creese et al, 1978, 1983).

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References

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Creese, I., Burt, D. R. & Snyder, S. H. (1978) Biochemical actions of neuroleptic drugs. In Handbook of Psychopharmacology (eds L. L. Iversen, S. D. lversen & S. H. Snyder), vol. 10. New York: Plenum Press.
Creese, I., Burt, D. R. & Snyder, S. H. Hamblin, M. W., Leff, S. E. & Sibley, D. R. (1983) CNS dopamine receptors. In Handbook of Psychopharmacology (eds L. L. Iversen, S. D. Iversen & S. H. Snyder), vol. 17. New York: Plenum Press.
Iversen, L. L. (1985) Mechanism of action of antipsychotic drugs: retrospect and prospect. In Psychopharmacology: Recent Advances and Future Prospects (ed S. D. Iversen). Oxford University Press.

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Commentary on Dinan's Hypothesis

  • Leslie L. Iversen (a1)
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