Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary

Inoue, Atsuko; Seto, Mayumi; Sugita, Sayori; Hide, Izumi; Hirose, Tetsuro; Koga, Nobuyuki; Kikuchi, Tetsuro; Nakata, Yoshihiro

doi:10.1016/s0169-328x(98)00009-6

Cited by 36 publications

(18 citation statements)

References 28 publications

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“…The apparent preferential action of these compounds at peripheral over central D 2 receptors is consistent with results from ex vivo occupancy studies (Kapur et al, 2002). The aripiprazole-induced prolactin release measured in the present study is at variance with published data showing a smaller increase or even a decrease in prolactin levels in rats (Inoue et al, 1996(Inoue et al, , 1998. Although a D 2 agonistic component of aripiprazole would be expected to reduce the prolactin release originating from its D 2 receptor blockade (Marchese et al, 2002), we could not establish this.…”

Section: Discussionsupporting

confidence: 89%

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D₂ Antagonist for the Treatment of Schizophrenia

Langlois¹,

Megens²,

Lavreysen³

et al. 2012

J Pharmacol Exp Ther

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All marketed antipsychotics act by blocking dopamine D 2 receptors. Fast dissociation from D 2 receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D 2 receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D 2 ligand. Its D 2 receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [␣ 1 , ␣ 2 , H 1 , muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D 2 antagonism (D 1 , D 3 , and 5-HT 2A ). JNJ-37822681 occupied D 2 receptors in rat brain at relatively low doses (ED 50 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED 50 (0.17 mg/kg, peripheral D 2 receptors) close to the ED 50 required for apomorphine antagonism (0.19 mg/kg, central D 2 receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D 2 antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D 2 antagonism for the treatment of schizophrenia and bipolar disorder.

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Section: Discussionsupporting

confidence: 89%

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D₂ Antagonist for the Treatment of Schizophrenia

Langlois¹,

Megens²,

Lavreysen³

et al. 2012

J Pharmacol Exp Ther

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“…At the gene level, Jaber et al [1994] have shown, using quantitative in situ and Northern blot hybridizations, that repeated administration of haloperidol or sulpiride to rats induced significant increases in the mRNAs of both PRL and GH in the pituitary gland. Inoue et al [1998], using a quantitative ribonuclease protection assay for PRL mRNA, also found that oral treatment of rats with haloperidol for 21 days increased the pituitary level of prolactin mRNA. Such findings indicate that the upregulation of GH and PRL produced by EGb 761 may have some relationship to antipsychotic mechanisms (or to antipsychotic drug treatment).…”

Section: Effects Of Dietary Egb 761 On Gene Expression In Rodent Brainmentioning

confidence: 88%

Effects of Ginkgo biloba extract (EGb 761) on gene expression: Possible relevance to neurological disorders and age‐associated cognitive impairment

DeFeudis¹

2002

Drug Development Research

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Ginkgo biloba leaf extract (EGb 761), which contains many constituents, including flavonoid glycosides and terpenoids (ginkgolides, bilobalide), is used to treat cerebrovascular and peripheral vascular insufficiency, as well as cognitive impairment and other symptoms of dementia. Recent studies have indicated that these therapeutic effects of EGb 761 probably involve modification of the expression of many genes by actions involving several of its active constituents. As examples: EGb 761 and its ginkgolide B constituent inhibit the expression of the peripheral benzodiazepine receptor in the adrenal cortex and decrease circulating levels of corticosterone in the rat, effects that provide a mechanism for explaining the ''antistress'' action of the extract. Both the flavonoid and terpenoid constituents of EGb 761 decrease the expression of inducible nitric oxide synthase (iNOS), supporting an action of the extract of opposing the deleterious effects of excessive formation of NO. EGb 761 upregulates several genes that encode vital antioxidant enzymes, including heme oxygenase-1 and the regulatory and catalytic subunits of g-glutamyl-cysteinyl synthetase. Dietary treatment of mice with EGb 761 upregulates the expression of genes encoding neuronal tyrosine/threonine phosphatase 1 and microtubule-associated tau in the cerebral cortex, findings that are of interest since these proteins are associated with the intracellular neurofibrillary tangles found in the brain in Alzheimer's disease. Bilobalide upregulates two mitochondrial-DNA-encoded genes, subunit III of cytochrome c oxidase and subunit ND1 of NADH dehydrogenase, indicating a fundamental mechanism that may underlie EGb 761-induced neuroprotection. Collectively, such results indicate that the therapeutic effects of EGb 761 on cognitive impairment (dementia) may involve its action of altering gene expression. Drug Dev.

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“…The doses were extrapolated from the dose relationship between haloperidol and APZ as used in clinical practice and in previous animal trials with haloperidol and clozapine (Fitzgerald et al 1995;Schmitt et al 2003b). The low (10 mg/kg/day) and high (40 mg/kg/day) doses lie in the range of other animal trials with subcutaneaous (Li et al 2005), oral (Inoue et al 1998;Kalinichev et al 2005) (Dr. Kikutichi, personal communication), or intraperitoneal (Cheng et al 2008;Semba et al 1995;Semba et al 1996) routes of application. APZ treatment showed a tendency to induce weight loss in our system (Segnitz et al 2009) in contrast to the animal study of Kalinichev et al (2005) but quite in concert with clinical observations (Englisch et al 2009;Henderson et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

et al. 2011

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Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary

Cited by 36 publications

References 28 publications

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D₂ Antagonist for the Treatment of Schizophrenia

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D₂ Antagonist for the Treatment of Schizophrenia

Effects of Ginkgo biloba extract (EGb 761) on gene expression: Possible relevance to neurological disorders and age‐associated cognitive impairment

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

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Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary

Cited by 36 publications

References 28 publications

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D2 Antagonist for the Treatment of Schizophrenia

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D2 Antagonist for the Treatment of Schizophrenia

Effects of Ginkgo biloba extract (EGb 761) on gene expression: Possible relevance to neurological disorders and age‐associated cognitive impairment

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

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Resources

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Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D₂ Antagonist for the Treatment of Schizophrenia

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D₂ Antagonist for the Treatment of Schizophrenia