Atypical antipsychotics, cortical D₂ receptors and sensitivity to endogenous dopamine

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 cortical—striatal 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 (k_off) 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 cortical—striatal difference, whereas the one with the highest affinity, slowest dissociation and least susceptibility (haloperidol) shows the least cortical—striatal difference. Furthermore, it seems that 5-HT₂ blockade, or a multi-receptor profile, is not necessary to achieve this cortical—striatal difference since amisulpride, a relatively specific D_2/3 antagonist, also shows this effect. Thus, a lower affinity and a faster k_off of the atypical antipsychotics at the D₂ receptor makes them more responsive to endogenous dopamine concentrations and may account for the cortical—striatal difference noted by Xiberas et al.