Typical and atypical antipsychotic drugs are similar in that both posses affinity for the dopamine D2 receptor; however, they differ in their propensity to induce extrapyramidal side effects and hyperprolactinemia. Despite additional activities at other dopamine receptor sub-types and transmitter systems, atypicals are less likely to induce EPS or hyperprolactinemia. The application of in vivo receptor occupancy coupled to neurochemical and behavioral measures from the same animals has led to increased predictive validation of an acute rodent model of EPS---the bar test. The clinical relationship of greater than 80% D2 occupancy resulting in EPS as determined by PET is similar to that assessed in rats utilizing LC/MS/MS to assess D 2 occupancy. In parallel, from the same set of animals, it was determined that 50% D2 receptor occupancy led to a doubling in rat striatal DOPAC levels---a traditional consequence of D2 antagonism. Additionally, it was observed that typical and atypical antipsychotics differ with atypical antipsychotics plateauing at a significantly lower dopamine D2 occupancy than the dopamine occupancy achieved by typical antipsychotics. The occupancy plateau achieved by typical antipsychotics was not significantly different from 100% whereas atypicals plateaued at an occupancy value significantly lower than 100%. Central serotonin 2a antagonism does not appear to be responsible for this observation since an atypical receptor occupancy profile was not seen after co-administration of MDL 100907 with haloperidol. Atypicals also displayed a wider dose range where high levels of D2 receptor occupancy at or above 80% were seen without appreciable catalepsy, despite the presence of increasing brain drug levels. This suggests that atypicals require additional compound in the brain as well as 80% dopamine D2 receptor occupancy to elicit EPS. These findings could be seen to support the dopamine fast off-rate hypothesis of atypicality, proposed by Kapur (2000), providing a possible explanation for the diverging profiles detected in the in vivo D2 occupancy assay.pages 109 and 110 for a diagram of the protocols for both the oral and intravenous antipsychotic receptor occupancy experiments. ... Raclopride was made up at 6 ug/ml in saline and dosed in 0.120.13 mls depending on the weight of the rat to achieve 3 ug/kg. ... The same parameters were maintained for both the radiolabeled raclopride as well as the cold ligand-based experiments to legitimizeanbsp;...
|Title||:||Typical and Atypical Antipsychotics: Relationships Between Rat in Vivo Dopamine D(2) Receptor Occupancy Assessed Using LC/MS and Changes in Neurochemistry and Catalepsy|
|Publisher||:||ProQuest - 2006|