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Psychopharmacology

, Volume 150, Issue 4, pp 422–429 | Cite as

Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats

  • Marie-Louise G. Wadenberg
  • Shitij Kapur
  • Alexandra Soliman
  • Corey Jones
  • Franco Vaccarino
Original Investigation

Abstract.

Rationale: Human positron emission tomography (PET) shows that striatal dopamine D2 receptor occupancy predicts extrapyramidal side effects (EPS). Patients showed a clinical response with ≥65% D2 occupancy, but EPS only when D2 occupancy >78%. Catalepsy and the selective suppression of conditioned avoidance response (CAR) are often used as animal models to predict EPS and antipsychotic effect, respectively. However, the quantitative relationship between striatal D2 occupancy and effects in these models is not known. Objectives: The present study intended to investigate the relationship between animal catalepsy, suppression of CAR, and D2 receptor blockade using a method of evaluating D2 receptor occupancy similar in principle to that used in patients. Methods: In vivo binding of [11C]-raclopride and [3H]-raclopride was compared. Doses of cold raclopride were chosen to provide a D2 occupancy from 0 to 95%. The relationship between dose/time course of catalepsy and D2 occupancy was assessed. Effects of raclopride on conditioned avoidance response (CAR) behavior were tested. Results: In vivo binding of [11C]-raclopride compared to [3H]-raclopride was virtually the same. Using [3H]-raclopride, cold raclopride (0.01–0.2 mg/kg) produced 16–77% D2 receptor occupancy and no catalepsy. Raclopride (0.5–2 mg/kg) produced 83–95% D2 occupancy and significant catalepsy. Raclopride (2 mg/kg) produced on average 95% and 87% D2 receptor occupancy 1 and 2 h after administration, respectively, and maximum catalepsy. D2 occupancy at 4, 8 and 24 h was on average 58%, 46%, and 4%, respectively. No catalepsy was observed. Raclopride (0.2 mg/kg), estimated at 70–75% D2 occupancy, produced suppression of CAR. Conclusions: In vivo D2 occupancy measurements in rats using [3H]-raclopride is analogous to using [11C]-raclopride in human PET scanning. Suppression of CAR occurred at a D2 occupancy of around 70–75%, and catalepsy at D2 occupancy >80%. Results closely resembled human studies where 65–70% D2 occupancy was required for antipsychotic response, while ≥80% D2 occupancy led to EPS. Brain mechanisms involved in mediation of catalepsy in rats and EPS in humans might indeed be similar. Both suppression of CAR in rats and antipsychotic response in humans might share an underlying construct, i.e. the need for around 70% D2 receptor blockade.

[11C]-Raclopride [3H]-Raclopride In vivo D2 receptor occupancy Catalepsy Conditioned avoidance response Rat 

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Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Marie-Louise G. Wadenberg
    • 1
  • Shitij Kapur
    • 2
  • Alexandra Soliman
    • 2
  • Corey Jones
    • 2
  • Franco Vaccarino
    • 3
  1. 1.Section of Biopsychology, CAMH, 250 College Street, University of Toronto, Toronto, Canada
  2. 2.Schizophrenia Division PET Centre, CAMH, University of Toronto, Toronto, Canada
  3. 3.Department of Psychology, University of Toronto, Toronto, Canada

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