Centre for Addiction and Mental Health, The University of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Xiberas et al (2001) report that atypical antipsychotics show a preferential cortical v. striatal dopamine D2 occupancy. This finding is not without controversy as Olsson & Farde (2001) failed to find such evidence and have suggested that an apparent corticalstriatal difference may be a methodological artefact. None the less, if the finding of Xiberas et al can be confirmed it prompts the question of why some drugs show a higher occupancy in one brain region compared with another.
Receptor occupancy by a drug is a function of its regional concentration and functional affinity for the receptor in that region. There are no data to suggest that the atypical antipsychotics show a higher regional concentration in the cortex; therefore, the difference is likely to arise because of higher functional affinity in the cortical regions. Functional affinity is determined by the receptor protein as well as local competition from endogenous neurotransmitters dopamine in this case. The protein structure of the D2 receptors throughout the brain is similar and so is their in vitro affinity in the absence of competition (Seeman & Ulpian, 1983). This leaves one plausible explanation that different concentrations of endogenous dopamine in cortical v. striatal regions may account for the difference in occupancies observed.
It has been suggested that a lower affinity and a faster off-rate (koff) may make atypical antipsychotics more susceptible to competition by the high levels of endogenous dopamine in the striatum compared with the low levels of endogenous dopamine in the cortex (Seeman et al, 1997; Kapur & Seeman, 2001). It is interesting that of the antipsychotics reported, the one with the lowest affinity, fastest dissociation from the D2 receptor and hence highest susceptibility to competition (clozapine) shows the greatest corticalstriatal difference, whereas the one with the highest affinity, slowest dissociation and least susceptibility (haloperidol) shows the least corticalstriatal difference. Furthermore, it seems that 5-HT2 blockade, or a multi-receptor profile, is not necessary to achieve this corticalstriatal difference since amisulpride, a relatively specific D2/3 antagonist, also shows this effect. Thus, a lower affinity and a faster koff of the atypical antipsychotics at the D2 receptor makes them more responsive to endogenous dopamine concentrations and may account for the corticalstriatal difference noted by Xiberas et al.
REFERENCES
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Olsson, H. & Farde, L. (2001) Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy a simulation study based on experimental data. Neuroimage, 14, 936-945.[CrossRef][Medline]
Seeman, P. & Ulpian, C. (1983) Neuroleptics have identical potencies in human brain limbic and putamen regions. European Journal of Pharmacology, 94, 145-148.[Medline]
Seeman, P., Corbett, R. & Van Tol, H. H. (1997) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology, 16, 93-110; discussion 111-135.[CrossRef][Medline]
Xiberas, X., Martinot, J. L., Mallet, L., et al
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