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Titolo:
Dopamine D-2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats
Autore:
Wadenberg, MLG; Kapur, S; Soliman, A; Jones, C; Vaccarino, F;
Indirizzi:
Univ Toronto, Sect Biopsychol, CAMH, Toronto, ON, Canada Univ Toronto Toronto ON Canada ect Biopsychol, CAMH, Toronto, ON, Canada Univ Toronto, CAMH, Schizophrenia Div, PET Ctr, Toronto, ON, Canada Univ Toronto Toronto ON Canada phrenia Div, PET Ctr, Toronto, ON, Canada Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada Univ Toronto Toronto ON Canada M5S 1A1 ychol, Toronto, ON M5S 1A1, Canada Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada Univ Toronto Toronto ON Canada M5S 1A1 chiat, Toronto, ON M5S 1A1, Canada
Titolo Testata:
PSYCHOPHARMACOLOGY
fascicolo: 4, volume: 150, anno: 2000,
pagine: 422 - 429
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEUROLEPTIC-INDUCED CATALEPSY; ANTIPSYCHOTIC-DRUGS; SCHIZOPHRENIC-PATIENTS; CLOZAPINE; RACLOPRIDE; PET; BINDING; RISPERIDONE; HALOPERIDOL; INHIBITION;
Keywords:
[C-11]-raclopride; [H-3]-raclopride; in vivo; D-2 receptor occupancy; catalepsy; conditioned avoidance response; rat;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Wadenberg, MLG Univ Toronto, Sect Biopsychol, CAMH, 250 Coll St, Toronto, ON, Canada Univ Toronto 250 Coll St Toronto ON Canada nto, ON, Canada
Citazione:
M.L.G. Wadenberg et al., "Dopamine D-2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats", PSYCHOPHAR, 150(4), 2000, pp. 422-429

Abstract

Rationale: Human positron emission tomography (PET) shows that striatal dopamine D-2 receptor occupancy predicts extrapyramidal side effects (EPS). Patients showed a clinical response with greater than or equal to 65% D-2 occupancy, but EPS only when D-2 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 D-2 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 D-2receptor blockade using a method of evaluating D-2 receptor occupancy similar in principle to that used in patients. Methods: In vivo binding of [C-11]-raclopride and [H-3]-raclopride was compared. Doses of cold raclopride were chosen to provide a D-2 occupancy from 0 to 95%. The relationship between dose/time course of catalepsy and D-2 occupancy was assessed. Effects ofraclopride on conditioned avoidance response (CAR) behavior were tested. Results In vivo binding of [C-11]-raclopride compared to [H-3]-raclopride was virtually the same. Using [H-3]-raclopride, cold raclopride (0.01-0.2 mg/kg) produced 16-77% D-2 receptor occupancy and no catalepsy. Raclopride (0.5-2 mg/kg) produced 83-95% D-2 occupancy and significant catalepsy. Raclopride (2 mg/kg) produced on average 95% and 87% D-2 receptor occupancy 1 and 2 h after administration, respectively, and maximum catalepsy. D-2 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% D-2 occupancy, produced suppression of CAR. Conclusions: In vivo D-2 occupancy measurements in rats using [H-3]-raclopride is analogous to using [C-11]-raclopride in human PET scanning. Suppression of CAR occurred at a D-2 occupancy of around 70-75%, and catalepsy at D-2 occupancy greater than or equal to 80%. Results closely resembled human studies where 65-70% D-2 occupancy was required for antipsychotic response, while >80% D-2 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% D-2 receptor blockade.

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Documento generato il 25/01/20 alle ore 19:34:52