An animal model of extrapyramidal side effects induced by antipsychotic drugs: relationship with D2 dopamine receptor occupancy.
1. Muscle rigidity was assessed quantitatively and objectively as increases in electromyographic (EMG) activity (muscle rigidity) in the hindlimb muscles of the rat following subcutaneous administration of haloperidol, fluphenazine and thioridazine. 2. Behavioural changes were assessed as increases in the catalepsy score, defined as the time taken for an animal to move off an inclined grid. 3. Increased tonic EMG activity, or the presence of catalepsy was related to the level of occupancy of dopamine D2 receptors in the striatum and substantia nigra of the brain, measured using ex vivo quantitative autoradiography. 4. Increases in tonic EMG activity and the induction of catalepsy were associated with >80% occupancy of striatal and nigral D2 receptors by fluphenazine, while haloperidol increased tonic EMG activity at D2 occupancies of >57%. 5. Thioridazine at doses ranging from 1-15 mg/kg failed to increase EMG activity and occupied <61% of striatal D2 receptors. 6. Overall the findings support the hypothesis that muscle rigidity is observed when a threshold level of D2 receptors in the striatum and substantia nigra are occupied by antipsychotic drugs. 7. This conclusion is consistent with the results of positron emission tomography (PET) studies in humans, and those from our past studies in rats using raclopride, chlorpromazine and clozapine, in which a threshold of approximately 70% striatal and nigral D2 receptor occupancy has been demonstrated.
Crocker
A D
AD
Department of Clinical Pharmacology, The Flinders University of South Australia, Bedford Park, Australia. Ann.Crocker@flinders.edu.au
Hemsley
K M
KM
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004576:Electromyography / Q000187:drug effects; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009127:Muscle Rigidity / Q000139:chemically induced / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*; D013881:Thioridazine / Q000378:metabolism / Q000494:pharmacology
D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D006220:Haloperidol; D013881:Thioridazine