Equivalent Occupancy of Dopamine D<sub>1</sub> and D<sub>2</sub> Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics

Tauscher, Johannes; Hussain, Tabasum; Agid, Ofer; Verhoeff, Nicolaas Paul L.G.; Wilson, Alan A.; Houle, Sylvain; Remington, Gary; Zipursky, Robert B.; Kapur, Shitij

doi:10.1176/appi.ajp.161.9.1620

Cited by 147 publications

(102 citation statements)

References 48 publications

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“…Clozapine also has affinity for dopamine D 1 receptors, although it is still unclear whether the drug acts as an agonist or antagonist (Tauscher et al, 2004). D 1 receptor activation by other drugs has also been shown to promote NMDAR function (Flores-Hernandez et al, 2002;Morari et al, 1994).…”

Section: Effect Of Antipsychotic Drugsmentioning

confidence: 99%

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Gozzi

Large

Schwarz

et al. 2007

Neuropsychopharmacol

108

118

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Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D 2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D 2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.

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Section: Effect Of Antipsychotic Drugsmentioning

confidence: 99%

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Gozzi

Large

Schwarz

et al. 2007

Neuropsychopharmacol

108

118

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“…Since olanzapine is an antagonist of 5-HT2 and D1-D2 receptors [33], the block of these receptors could cause the lack of body temperature elevation due to orexin A [34,35]. Since olanzapine exerts also influences on cholinergic, adrenergic and histaminergic pathways, an involvement of these pathways cannot be excluded [36].…”

Section: Discussionmentioning

confidence: 99%

Neuroleptic Drugs Affect Sympathetic and Thermogenic Reactions to Orexin A

S¹

2014

J Psychiatry

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This review of our literature describes the effects of many neuroleptic drugs on the sympathetic and hyperthermic reactions due to orexin A, a neuropeptide affecting body temperature and food intake by an increase in sympathetic activity. Haloperidol reduces, while clozapine and olanzapine block the hyperthermia induced by orexin A. Risperidone enhances the elevation of body temperature due to orexin A. Quetiapine delays these hyperthermic effects. The implications on human therapeutic strategies are discussed, including the involvement of orexinergic pathway in the induction of obesity, induced by these neuroleptic substances. We summarize our published data in a unique report so to emphasize the influences of these neuroleptic drugs on the control of body temperature, exerted by orexinergic system. This large vision could be also useful to address therapeutic choices.Patients with serious mental illness are at higher risk of developing metabolic abnormalities (e.g., weight gain, increased blood pressure, and glucose or lipid levels) in comparison to general population. Since the risk increases following initiation of narcoleptic therapy, it must assess carefully risks and benefits when choosing a particular antipsychotic drug.

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“…[1][2][3][4][5][6][7] At therapeutic doses, clozapine displays dopamine D 2 receptor blockade ranging from 20 to 60% occupancy. 4 It has a heterogeneous receptor binding profile that includes affinity for dopamine D 1 , D 2 and D 4 , serotonin (5-HT) 5-HT 2A , 5-HT 2C and 5-HT 3 , muscarinic M 1 , histaminic H 1 and a-adrenergic a 1 and a 2 receptors.…”

Section: Introductionmentioning

confidence: 99%

“…4 It has a heterogeneous receptor binding profile that includes affinity for dopamine D 1 , D 2 and D 4 , serotonin (5-HT) 5-HT 2A , 5-HT 2C and 5-HT 3 , muscarinic M 1 , histaminic H 1 and a-adrenergic a 1 and a 2 receptors. [5][6][7] In addition to treating positive symptoms of schizophrenia, clozapine has been shown to effectively treat secondary negative symptoms and cognitive deficits. 8,9 Clozapine has been shown to be successful in the treatment of schizophrenia within suicidal patients.…”

Section: Introductionmentioning

confidence: 99%

cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects

et al. 2005

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Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.

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Equivalent Occupancy of Dopamine D₁ and D₂ Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics

Cited by 147 publications

References 48 publications

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Neuroleptic Drugs Affect Sympathetic and Thermogenic Reactions to Orexin A

cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects

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Equivalent Occupancy of Dopamine D1 and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics

Cited by 147 publications

References 48 publications

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Neuroleptic Drugs Affect Sympathetic and Thermogenic Reactions to Orexin A

cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects

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Product

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Equivalent Occupancy of Dopamine D₁ and D₂ Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics