Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy

Richtand, Neil M.; Welge, Jeffrey A.; Logue, Aaron D; Keck, Paul E.; Strakowski, Stephen M.; McNamara, Robert K.

doi:10.1038/sj.npp.1301305

Cited by 114 publications

(77 citation statements)

References 49 publications

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“…Clozapine is a multireceptor acting AP; it has antagonistic activity on dopaminergic receptors, with a higher affinity at the D1 and D4 receptors than at the D2 receptors, also binding to the extra-striatal D3 receptors. Clozapine has also antagonistic activity at the 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3 receptors [75]. Our results are in agreement with previous reports indicating that clozapine is the atypical AP that more frequently is associated with seizures [17], or involving seizures/lowered seizure threshold associated with its use [78,79].…”

Section: Clozapinesupporting

confidence: 83%

“…Compared with typical APs, it also binds with a lower affinity at the adrenergic (α1 and α2) and H1 histaminergic receptors [75,76]. We found that risperidone increases the incidence and the severity of the audiogenic seizures (Figs.…”

Section: Risperidonementioning

confidence: 84%

“…Furthermore, haloperidol binds with a low affinity to the adrenergic (α1 and α2) and histaminergic H1 receptors [75,76]. We investigated the effects of haloperidol on audiogenic seizure in epileptic rats, demonstrating that this drug did not significantly increase seizure incidence and/or severity (Figs.…”

Section: Haloperidolmentioning

confidence: 99%

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Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

et al. 2015

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Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

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Section: Clozapinesupporting

confidence: 83%

Section: Risperidonementioning

confidence: 84%

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Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

et al. 2015

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“…Mesoridazine has also been used as a drug itself. Mesoridazine and thioridazine possess affinity for the dopamine D 2 , D 3 , and D 4 receptors (Richtand et al, 2007), with mesoridazine showing somewhat greater affinity. After administration of thioridazine, total exposure to thioridazine is about 6-fold greater than the mesoridazine; however, it has been shown that the parent drug is vastly more protein-bound than the metabolite.…”

Section: Procainamidementioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

137

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“…All approved antipsychotic medicines act, with respect to G-protein coupling, either as antagonists, inverse agonists or low efficacious partial agonists at the D2-like receptors. Moreover, their therapeutic active dose correlates with the occupancy at the D2 receptor (Akam and Strange, 2004;Burstein et al, 2005;Richtand et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

et al. 2008

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Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through β-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human β-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying β-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating β-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced β-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most antipsychotics are incapable of stimulating β-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling.

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Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy

Cited by 114 publications

References 49 publications

Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

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