An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET

Farde, Lars; Wiesel, Frits‐Axel; Jansson, Paul; Uppfeldt, Gunilla; Wahlén, A; Sedvall, Göran

doi:10.1007/bf00735871

Cited by 112 publications

(42 citation statements)

References 23 publications

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“…The results for the selective D 2 antagonist raclopride show an association between increased EMG activity and D 2 receptor occupancy which is similar to that reported for raclopride from PET studies (Farde et al 1988; Nördström et al 1993). PET studies have shown the level of striatal D 2 occupancy associated with EPS to be 70%-89% for a number of typical antipsychotic drugs (Farde and Nördström 1992a;Farde et al 1992b Farde et al , 1992cNyberg et al 1995).…”

Section: Discussionsupporting

confidence: 84%

“…It thus complements the findings from PET studies in humans (Farde and Nördström 1992a;Farde et al 1992b Farde et al , 1992c and occupancy studies in experimental animals Schotte et al 1993;Sumiyoshi et al 1993Sumiyoshi et al , 1995. The current findings show that there are dose-related increases in EMG activity which are associated with dose-related increases in D 2 dopamine receptor occupancy in the striatum and substantia nigra.The results for the selective D 2 antagonist raclopride show an association between increased EMG activity and D 2 receptor occupancy which is similar to that reported for raclopride from PET studies (Farde et al 1988; Nördström et al 1993). PET studies have shown the level of striatal D 2 occupancy associated with EPS to be 70%-89% for a number of typical antipsychotic drugs (Farde and Nördström 1992a;Farde et al 1992b Farde et al , 1992cNyberg et al 1995).…”

supporting

confidence: 84%

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Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Hemsley

Crocker

1999

Neuropsychopharmacology

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The aim of the present study was to investigate the relationship between effects on muscle tone and D 2 receptor occupancy of two typical antipsychotic drugs, raclopride and chlorpromazine, and the atypical drug, clozapine. Increased muscle tone (i.e., muscle rigidity), was measured as increases in tonic electromyographic (EMG) The introduction of antipsychotic drugs has revolutionized the treatment of schizophrenia, but their use has been limited by the appearance of extrapyramidal side effects (EPS). These include acute dystonic reactions which appear early in treatment and are characterized by intense contractions of antagonistic muscles, and Parkinson-like side effects which include muscle rigidity and hypokinesia (Ayd 1961). It has been reported that 35% of drug noncompliance is due to the unacceptability of the side effects associated with antipsychotic drug treatment (Hoge et al. 1990) and this has stimulated a search for effective antipsychotic drugs which do not produce extrapyramidal side effects.The likelihood of extrapyramidal side effects developing appears to be dependent on the affinity of the antipsychotic drug for D 2 dopamine receptors (Creese et al. 1976;Seeman et al. 1976) so that there is a greater incidence associated with the high-potency drugs such as haloperidol and a lesser incidence with low-potency drugs such as chlorpromazine. Support for the view that there may be an association between the appearance of extrapyramidal side effects and D 2 receptor occupancy has come from positron emission tomography (PET) studies in humans (Farde and Nördström 1992a;Farde et al. 1992b Farde et al. , 1992cNyberg et al. 1995). These studies showed that EPS were associated with high D 2 receptor occupancy of 70%-89% in the striatum obtained with conventional doses of typical antipsychotics, but showed no association with D 1 occupancy. Importantly, clozapine whose (Farde and Nörd-ström 1992a;Farde et al. 1992b Farde et al. , 1992cNyberg et al. 1995).Despite being the subject of intense research interest, the mechanisms underlying drug-induced EPS remain unknown. One of the main factors contributing to this situation has been the lack of an objective, quantifiable experimental endpoint relevant to a cardinal feature of EPS, muscle rigidity, or increased muscle tone. We have developed an objective and quantifiable measure of muscle rigidity, assessed as changes in tonic electromyographic (EMG) activity in the anterior tibialis and gastrocnemius muscles of the hindlimb of conscious, unrestrained rats. We reported that tonic EMG activity is significantly increased in both muscles in an animal model of Parkinson's disease, namely following lesions of the ascending nigrostriatal dopaminergic neurons by bilateral 6-hydroxydopamine injections (Double and Crocker 1993). These EMG increases were significantly reduced by subcutaneous injection of the mixed D 1 /D 2 dopamine receptor agonist, apomorphine. Further work showed that both D 1 and D 2 dopamine receptors in the substantia nigra were involved in th...

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Section: Discussionsupporting

confidence: 84%

supporting

confidence: 84%

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Hemsley

Crocker

1999

Neuropsychopharmacology

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“…Clinical equivalence of drugs is particularly important to this experiment, because it is at these relative doses that the drugs have equivalent antipsychotic efficacy and are used clinically. The clinically equivalent dose of raclopride in this experiment would have been approximately 2.0mg/kg/day (Farde, 1988); but, a dose of 10 mg/kg/day raclopride was selected for other experimental reasons. Clozapine, being approximately 15-20 times less potent than haloperidol in treating psychosis, was administered at 25 mg/kg/day (Kane et al, 1988).…”

Section: Drug Administration and Dose Rationalementioning

confidence: 99%

Drug-induced oral dyskinesias in rats after traditional and new neuroleptics

Kakigi

Gao

Tamminga

1995

J. Neural Transmission

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Tardive dyskinesia (TD) is a serious human side effect of neuroleptic treatment in psychotic disorders. Although the etiology is clear (i.e. chronic neuroleptic drugs), its pathophysiology has not yet been satisfactorily explained. This is important not only theoretically but also to inform drug development, allowing the introduction of antipsychotic compounds without TD liability. The development of an animal condition which putatively models these delayed onset dyskinesias, has provided a technique to differentiate between neuroleptic drug effect and dyskinesia correlates. We report here the development of oral dyskinesias in rats in response to a number of different neuroleptics, which have a range of neurochemical and clinical characteristics. Traditional neuroleptics (e.g. haloperidol) produced rat oral dyskinesias, in an open-cage environment. Clozapine, while it produced an increased rate of oral movements, showed a significantly decreased potency in this model. SCH23390 (D1 antagonist) neither produced the oral movements nor modified their onset by coadministration with raclopride. These data replicate and extend other similar studies in the literature. They suggest that clozapine differs from traditional neuroleptics with respect to motor side effects.

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“…Studies conducted using sulpiride report either no change in striatal binding with advancing age (Memo et al, 1980) or a more subtle, subregion-specific age-related decline in caudate D2 binding (Morelli et al, 1990). These apparent differences in raclopride and sulpiride binding may in fact represent metabolic differences between in vivo and in vitro studies, as raclopride is the superior ligand for PET studies due to its greater bioavailability and brain penetration (Farde et al, 1988); considerations that are not relevant to postmortem work.…”

Section: Dat and D1 Receptor Binding In The Dorsal Striatum Decreasesmentioning

confidence: 99%

Dysregulation of Striatal Dopamine Receptor Binding in Suicide

Fitzgerald

Kassir

Underwood

et al. 2016

Neuropsychopharmacol

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]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R 2 = 0.31, po0.05) that was not present in suicides (R 2 = 0.00, p = 0.97). In suicides and controls with reported ELA, there was no correlation between striatal DAT and D1 receptor binding (R 2 = 0.07, p = 0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R 2 = 0.32, po0.05). After controlling for age, there were no significant ELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R 2 = 0.12, po0.05; DAT: R 2 = 0.36, po0.001). There appears to be an imbalance in dopaminergic receptor and transporter expression related to suicide that differs from that associated with ELA or age.

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An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET

Cited by 112 publications

References 23 publications

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Drug-induced oral dyskinesias in rats after traditional and new neuroleptics

Dysregulation of Striatal Dopamine Receptor Binding in Suicide

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