Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

Philibin, Scott D.; Walentiny, D. Matthew; Vunck, Sarah A.; Prus, Adam J.; Meltzer, Herbert Y.; Porter, Joseph H.

doi:10.1007/s00213-008-1385-3

Cited by 20 publications

(7 citation statements)

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“…Previous studies in C57BL/6 mice have shown that 5-HT 2A serotonergic and α1-adrenoceptor antagonism mediate clozapine’s discriminative stimulus. [ 69 ] It should be noted that the 10.0 mg/kg dose of nuciferine that substituted for clozapine also produced significant rate suppression compared to vehicle control rates; however, previous studies have shown that the doses of antipsychotics that produce full substitution for clozapine are often accompanied by significant rate suppression (in both rats [ 70 , 71 ] and mice[ 72 , 73 ]).…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

et al. 2016

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RationaleThe sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.MethodsNuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.ResultsNuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.ConclusionsThe molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

et al. 2016

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“…The actions of atypical antipsychotic drugs are probably mediated through different and more than one neuroregulatory system (Butini et al 2009;Meltzer, 2002), and may be slightly superior in the treatment of schizophrenia (Kronig et al 1995;Leucht et al 1999;Mö ller, 1993). Ginkgo can increase synaptosomal uptake of 5-HT (Ramassamy et al 1992) similar to some of the atypical antipsychotic medications (Philibin et al 2009). Antioxidant treatment of schizophrenia can reduce the damaging effects of free radicals .…”

Section: Background and Hypothesismentioning

confidence: 96%

Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia

Singh

Chan

2009

Int. J. Neuropsychopharm.

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This study aimed to review the roles of antioxidants in the pathophysiology of schizophrenia, whether the properties of ginkgo can ameliorate symptoms of this illness, and evaluate available literature to test this assumption. This review is based upon published works on antioxidants and ginkgo. A primary electronic search for meta-analysis on the usage of ginkgo or its derived products in schizophrenia was conducted using Pubmed, Cochrane Library, EMBASE, CINAHL, PsycINFO and AMED. Inclusion criteria were: criteria-based diagnosis of schizophrenia, randomized case assignment, use of ginkgo as an add-on therapy, and assessment using standardized rating scales to measure the state of psychopathology for negative and total symptoms of schizophrenia. Additionally, a detailed review was undertaken to investigate if antioxidants are involved in development of psychotic symptoms in schizophrenia. The six studies that fulfilled the selection criteria were constituted of 466 cases on ginkgo and 362 cases on placebo. They all used the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms, and the Scale for the Assessment of Positive Symptoms (SAPS) or the Brief Psychiatric Rating Scale (BPRS) to measure total symptoms. Difference between ginkgo and control groups from their pre- and post-trial scores and its pooled standard deviation were used to compute standardized mean difference (SMD). Ginkgo as an add-on therapy to antipsychotic medication produced statistically significant moderate improvement (SMD=-0.50) in total and negative symptoms of chronic schizophrenia. Ginkgo as add-on therapy ameliorates the symptoms of chronic schizophrenia. The role of antioxidants in pathogenesis of schizophrenia has also been explored.

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“…For example, ADRA2A, one of the predicted ARGs, encodes adrenoceptor alpha 2A receptor. ADRA2A is a potential target of clozapine (Philibin et al ., 2009), an atypical antipsychotic drugs. Long-term clozapine treatment reduces Aβ deposition and improves cognitive impairment in an AD transgenic mice model (Choi et al ., 2017).…”

Section: Resultsmentioning

confidence: 99%

Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease

Fang

Zhang

Wang

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS to identify high-confidence AD risk genes (ARGs) that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. To address this critical problem in the field, we have developed a genotype-informed, network-based methodology that interrogates pathogenesis to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and preclinical AD models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.895, 95% confidence interval [CI] 0.841-0.951, P = 3.97 x 10-4) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR =0.921, 95% CI 0.861-0.983, P = 0.0146), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. In summary, we present an integrated, network-based methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.

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Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

Cited by 20 publications

References 55 publications

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia

Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease

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