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


OBJECTIVE
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.
Turrone
Peter
P
Centre for Addiction and Mental Health, Schizophrenia and Continuing Care Program, 250 College Street, Room 745, Toronto, Ontario, Canada M5T 1R8. peter_turrone@camh.net
Remington
Gary
G
Kapur
Shitij
S
Nobrega
José N
JN
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008409:Mastication / Q000187:drug effects* / Q000502:physiology; D020891:Raclopride / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology
D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D020891:Raclopride; C033563:haloperidol decanoate; D006220:Haloperidol