The relationship between dopamine D2 receptor occupancy and the vacuous chewing movement syndrome in rats

Abstract

Rationale: A dose-response relationship between dopamine D(2) occupancy and acute extrapyramidal symptoms (EPS) has been well established. However, the link with the induction of tardive dyskinesia (TD) is less clear.

Objectives: To ascertain the nature and extent of D(2) receptor occupancy effects on haloperidol-induced vacuous chewing movements (VCMs) in a rat model of TD.

Methods: Groups of eight rats received haloperidol decanoate injections corresponding to daily doses of 0, 0.08, 0.17, 0.33, or 1 mg/kg for 10-12 weeks. VCMs were measured on a weekly basis and D(2) occupancy levels were measured in vivo using [(3)H]-raclopride at the end of the experiment.

Results: Final VCM scores were significantly different between haloperidol doses ( P=0.001). Moderate but significant correlations were found between dose and average VCM scores (r=0.69, P<0.001) and between D(2) occupancy and average VCM scores (r=0.65, P<0.001). The rats that developed the VCM syndrome (>/=8 VCMs) had higher occupancies than rats that did not. Of the rats with an occupancy above 70%, 63% developed VCMs, compared with 37% of the rats with D(2) occupancy below that.

Conclusions: These results indicate that chronic haloperidol induces VCMs in a dose-dependent manner, with doses leading to high D(2) occupancy increasing the likelihood of emergence of the VCM syndrome. While a certain level of D(2) occupancy may be necessary for inducing VCMs, it is not sufficient in and of itself to induce the VCM syndrome.