Central D2-Dopamine Receptor Occupancy in Schizophrenic Patients Treated With Antipsychotic Drugs

Farde, Lars; Wiesel, F.-A.; Halldin, Christer; Sedvall, Göran

doi:10.1001/archpsyc.1988.01800250087012

Cited by 660 publications

(269 citation statements)

References 28 publications

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“…The clinical effect of many antipsychotics emerge when 60-70% of striatal dopamine D 2 receptors are blocked, and motor side effects become prominent when the receptor blockade exceeds 80% (Farde et al, 1988;Kapur et al, 2000a). This pattern of relationship between striatal D 2 receptor occupancy (D 2 RO) and clinical efficacy has also been shown in animal occupancy studies using conditioned avoidance response (CAR) as a surrogate for antipsychotic efficacy and catalepsy (CAT) as a surrogate for motor side effects (Wadenberg et al, 2000).…”

Section: Introductionmentioning

confidence: 88%

“…In the case of 5-HT 2 RO, prefrontal cortex was used. This method is based on clinical occupancy experimentation and has been validated in experimental animals (Farde et al, 1988;Kapur et al, 1999;Wadenberg et al, 2000). The occupancy induced by the drug was calculated using the formula: %Occupan-cy ¼ 100 Â (BP controls ÀBP drug /BP controls ); where BP controls is the pooled D 2 or 5-HT 2 binding potential of all the control animals and BP drug is the D 2 or 5-HT 2 binding potential of a drug-treated animal.…”

Section: Drugsmentioning

confidence: 99%

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Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

180

116

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The novel antipsychotic aripiprazole requires high (490%) striatal D 2 receptor occupancy (D 2 RO) to be clinically active, but despite its high D 2 RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D 2 RO, they show motor side effects when D 2 RO exceeds 80%. We investigated this discrepancy between D 2 RO, 5HT 2 receptor occupancy (5-HT 2 RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D 2 RO. While risperidone clearly showed higher 5-HT 2 RO than D 2 RO, aripiprazole and haloperidol showed higher D 2 RO than 5-HT 2 RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing 480% D 2 RO, while aripiprazole despite higher D 2 RO (490%) induced no catalepsy. Haloperidol and risperidone's ED 50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to B60% D 2 RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D 2 RO, a 23-fold higher dose (86% D 2 RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D 2 ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D 2 RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D 2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D 2 agonist antipsychotics.

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Section: Introductionmentioning

confidence: 88%

Section: Drugsmentioning

confidence: 99%

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

180

116

View full text Add to dashboard Cite

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“…Striatal, prefrontal, and cerebellar counts expressed as disintegrations per minute/mg (DPM/mg) of tissue were used for calculations. The ratio of striatum minus cerebellum (index of specific binding)/cerebellum (index of free and nonspecific binding) was used to obtain an index of the binding potential (BP) of dopamine D 2 receptors and in case of 5-HT 2 receptors, prefrontal cortex was used instead of striatal tissue (Farde et al, 1988;Kapur et al, 1999;Wadenberg et al, 2000b). The occupancy induced by the drug was calculated using the formula: %Occupancy ¼ 100 Â (BP controls ÀBP drug / BP controls ); where BP controls is the pooled D 2 or 5-HT 2 binding potential of all the control animals and BP drug is the D 2 or 5-HT 2 binding potential of a drug-treated animal.…”

Section: Occupancy and Catalepsy Experimentsmentioning

confidence: 99%

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Natesan

Reckless

Barlow

et al. 2006

Neuropsychopharmacol

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There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

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“…We did not examine the effects of traditional neuroleptic treatment on amphetamine-induced raclopride binding to determine if classical antipsychotic agents and atypical drugs have differential striatal dopamine effects. Therapeutic doses of traditional antipsychotic agents show a steep dose-occupancy curve with apparent near-maximal binding of striatal D-2 receptors (i.e., у 80% estimated occupancy) (Farde et al 1988(Farde et al , 1992Wiesel et al 1990;Pilowsky et al 1993;Wolkin et al 1989;Coppens et al 1991;Karbe et al 1991) which could lead to baseline raclopride binding ratios that are too low to adequately assess amphetamine-related reductions in ligand binding. Another important issue is the lack of dopamine release data from A-10 dopamine neurons in limbic and cortical areas.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the new antipsychotic agents reverse amphetamine-induced effects on A-10 dopamine neurons to a greater degree than A-9 neurons (Stockton and Rasmussen, 1996b), whereas traditional neuroleptics reverse amphetamine effects on both A-9 and A-10 neurons (Bunney andAghajanian 1973, 1976;Goldstein et al 1986;Skarsfeldt 1992). Furthermore, previous brain imaging studies have shown that traditional neuroleptics have higher striatal dopamine D-2 receptor occupancy levels than the atypical agents (Pickar et al 1996;Nyberg et al 1997;Farde et al 1988Farde et al , 1989Kerwin et al 1993;Nordstrom et al 1993;Wiesel et al 1990). Taken together, these data suggest that the relative lack of effects on dorsal striatal dopamine neurons may contribute to the atypical profile of the new antipsychotic agents.…”

mentioning

confidence: 99%

Effects of Atypical Antipsychotic Drug Treatment on Amphetamine-Induced Striatal Dopamine Release in Patients with Psychotic Disorders

Breier

Su²,

Malhotra³

et al. 1999

Neuropsychopharmacology

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Central D2-Dopamine Receptor Occupancy in Schizophrenic Patients Treated With Antipsychotic Drugs

Cited by 660 publications

References 28 publications

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Effects of Atypical Antipsychotic Drug Treatment on Amphetamine-Induced Striatal Dopamine Release in Patients with Psychotic Disorders

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