Efficacy, Safety and Tolerability of Raclopride, a Specific D2 Receptor Blocker, in Acute Schizophrenia

Jc, Cookson; Natorf, B; Hunt, Nicholas; Silverstone, Trevor; Uppfeldt, Gunilla

doi:10.1097/00004850-198901000-00007

Cited by 25 publications

(13 citation statements)

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“…Although raclopride is currently not used as an antipsychotic in the clinic, it clearly displays antipsychotic activity. Thus, open label clinical trials have reported that raclopride (4-16 mg/day) showed good antipsychotic efficacy (patients were rated "very much", or "much", improved), was well tolerated, and had a relatively safe side effect profile (Farde et al 1988b;Cookson et al 1989). Furthermore, in addition to its antipsychotic-like effects in the CAR test, raclopride (0.1-0.3 mg/kg) also dose-dependently reverses apomorphine-induced disruption of the prepulse inhibition of the acoustic startle reflex, PPI, in rats (Swerdlow et al 1991;Varty and Higgins 1995;Wadenberg and Pais, unpublished data), another screening test for antipsychotic activity (see Swerdlow and Geyer 1998).…”

Section: Discussionmentioning

confidence: 99%

Dopamine D 2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats

et al. 2000

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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 > or = 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.

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Section: Discussionmentioning

confidence: 99%

Dopamine D 2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats

et al. 2000

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“…Risperidone and the three benzamides, compounds with established clinical e¦cacy as antipsychotics (risperidone: Borison et al 1992;amisulpride: Delcker et al 1990;raclopride: Farde et al 1988;Cookson et al 1989;remoxipride: Den Boer et al 1990;Hebenstreit et al 1991) failed to potentiate PPI, whereas prazosin, an antihypertensive drug (Reid and Vincent 1986) with no demonstrated antipsychotic activity, enhanced PPI. These four false negatives (risperidone and the benzamides) and the false positive (prazosin) indicate that this PPI-potentiation test does not possess a very good predictive validity to screen for antipsychotics.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of prepulse inhibition of the startle reflex in rats: pharmacological evaluation of the procedure as a model for detecting antipsychotic activity

Depoortère¹,

Perrault²,

Sanger³

1997

Psychopharmacology

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Prepulse inhibition (PPI) of the startle reflex-whereby presentation of a weak prepulse preceding a startling pulse diminishes the amplitude of the startle reflex-is disrupted by dopamine (DA) agonists; this disruption can be reversed by antipsychotics. There are also some indications in the literature that a few antipsychotics (most notably clozapine and haloperidol) may, on their own, have effects opposite to those of DA agonists, i.e. may enhance PPI. In order to explore these antipsychotic-induced potentiations of PPI more thoroughly, we assessed, in Sprague-Dawley rats, the effects of IP administration of various clinically effective antipsychotics in a PPI procedure with levels of PPI (ranging from 5 to about 40%) low enough to facilitate detection of PPI-potentiating effects of drugs. Both clozapine (5-20 mg/kg) and haloperidol (0.25-1 mg/kg) robustly and dose-dependently potentiated PPI. A similar effect was not seen with risperidone (0.1-1 mg/kg) or with the three substituted benzamides amisulpride (10-60 mg/kg), raclopride (0.1-3 mg/kg) and remoxipride (1-10 mg/kg). As risperidone is known to have prominent 5-HT2 antagonistic activity, these results do not indicate a role for 5-HT2 receptors in the clozapine and haloperidol PPI-enhancing effects. The absence of effects with the benzamides and with risperidone, at doses with known anti-dopaminergic activity, suggests that DA antagonist activity is not involved. The demonstration that prazosin (3-20 mg/kg), a non-antipsychotic with alpha 1 adrenoceptor antagonistic properties, dose-dependently potentiated PPI indicates that alpha 1 receptors might mediate the clozapine and haloperidol PPI-enhancing activity. Additionally, the finding that diazepam (1-10 mg/kg) did not enhance, but on the contrary reduced PPI, argues against a sedation- or general depressant-mediated effect of clozapine, haloperidol and prazosin. The negative results with four clinically active antipsychotics (risperidone and the benzamides), and the positive result with the non-antipsychotic prazosin indicate that this PPI-enhancing procedure has poor predictive validity as a screening tool for potential antipsychotics.

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“…This study has two specific goals: (1) to determine the effects of subchronic and chronic treatment with a typical antipsychotic (haloperidol) on the three ionotropic glutamate receptor subtypes and (2) to compare the changes in glutamate receptor subtype binding induced by haloperidol to any possible changes in the same receptor subtype following subchronic and chronic treatment with the atypical antipsychotic (clozapine), the dopamine D 2 /D 3 receptor antagonist (raclopride) which exhibits antipsychotic activity (Farde et al 1988;Cookson et al 1989), or the dopamine D 1 (D 1 /D 5 ) receptor antagonist (SCH23390). Similar changes in a specific glutamate receptor level, as quantified by in vitro receptor autoradiography, within a specific brain region during chronic treatment with both typical and atypical antipsychotics may indicate it as a locus for the drug's antipsychotic action.…”

Section: Introductionmentioning

confidence: 99%

Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics

1996

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Quantitative in vitro receptor autoradiography was used to examine changes in three ionotropic glutamate receptor subtypes using 3H-MK801 (NMDA-R antagonist), 3H-CNQX (AMPA-R antagonist) and 3H-kainic acid (kainate-R agonist) following subchronic (28 days) and chronic (8 months) treatment of rats with a typical antipsychotic, haloperidol (1.5 mg/kg per day), atypical antipsychotic, clozapine (25 mg/kg per day), the dopamine D2/D3 receptor antagonist, raclopride (10 mg/kg per day), and the dopamine D1 (D1/D5) receptor antagonist SCH23390 (0.5 mg/kg per day). Subchronic and chronic drug treatments did not significantly alter 3H-CNQX or 3H-kainate binding in any of brain regions examined. Subchronic SCH23390 treatment elevated 3H-MK801 binding in the hippocampal formation with significant increases in the CA1 and dentate gyrus, suggesting a specific role for dopamine D1 receptors in the regulation of hippocampal NMDA receptor function. Subchronic, but not chronic, haloperidol and clozapine treatment significantly reduced 3H-MK801 binding in the medial prefrontal cortex. This suggests that typical and atypical antipsychotics may exert some of their clinical effects by affecting NMDA receptors in the medial prefrontal cortex. Both subchronic and chronic clozapine treatment decreased 3H-MK801 binding in the caudate putamen. The minimal extrapyramidal side effects produced by clozapine may result, in part, from the reduction in NMDA receptor binding in the caudate putamen.

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Efficacy, Safety and Tolerability of Raclopride, a Specific D2 Receptor Blocker, in Acute Schizophrenia

Cited by 25 publications

References 0 publications

Dopamine D 2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats

Dopamine D 2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats

Potentiation of prepulse inhibition of the startle reflex in rats: pharmacological evaluation of the procedure as a model for detecting antipsychotic activity

Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics

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