The role of dopamine D(2) occupancy in the vacuous chewing movement (VCM) model of tardive dyskinesia
By: by Peter Turrone.
Published: 2004
Language: eng
Number of pages: 143
Description: Background. Dopamine D2 receptor occupancy has proven to be an important factor in understanding how antipsychotic medications exert their beneficial, as well as adverse, effects. However, little is known about the relationship between D2 occupancy and risk of tardive dyskinesia, a potentially irreversible motor side effect. Objectives . Using the vacuous chewing movement (VCM) animal model for tardive dyskinesia, we sought to determine (a) whether there is a relationship between antipsychotic dose and induction of VCMs; (b) the role of D 2 occupancy in the development of VCMs; (c) the differential effect of continuous (minipump) versus transient (subcutaneous) D2 occupancy on VCMs using haloperidol, a 'typical' antipsychotic; and, (d) whether continuous infusion of 'atypical' antipsychotics, in this case olanzapine and remoxipride, produces VCMs in a fashion similar to what occurs with the typical antipsychotic, haloperidol. Methods . A series of animal studies were carried out to address each of these objectives, with a similar treatment model forming the basis for each comparison. Other than haloperidol, where haloperidol decanoate was used, the model compared daily subcutaneous injections (transient D2 exposure) with minipump infusions (continuous D2 exposure). VCMs were measured over a 2-minute test period weekly for a period of 2 months. D2 occupancy levels were measured ex vivo using [3H]-raclopride.  Results. (a) There is a relationship between antipsychotic dose and VCMs; (b) the likelihood of developing VCMs is dependent upon the level of antipsychotic-induced dopamine D2 receptor occupancy; (c) antipsychotic-induced continuous D2 receptor occupancy via minipump is significantly more likely to lead to the VCM syndrome than transient D2 receptor occupancy via daily subcutaneous injections; and, (d) atypical antipsychotics such as olanzapine and remoxipride also lead to the VCM syndrome when administered via minipump. Conclusion . Collectively, these studies have underscored the important role of both continuous drug infusion and continuous dopamine D2 occupancy in the development of the VCM syndrome in rodents, which in turn has clinical implications related to the induction of tardive dyskinesia in humans.
Notes: Adviser:  Gary Remington.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5019.