Schizophrenia and L-745, 870, a novel dopamine D4 receptor antagonist

Bristow, Linda J.; Kramer, Mark S.; Kulagowski, Janusz J.; Patel, Smita S.; Ragan, C I; Seabrook, Guy R.

doi:10.1016/s0165-6147(97)01066-3

Cited by 91 publications

(62 citation statements)

References 7 publications

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“…We propose, on the basis of the functional properties and expression of ErbB4 and D4Rs in PV+ interneurons in the dorsal lateral prefrontal cortex (21,25) and hippocampus (this study), as well as their effects on KA-induced γ oscillations and plasticity (18,19), that these receptors are well situated to modulate network activity that impacts cognition. The fact that D4R-specific antagonists were found to be ineffective as antipsychotics for the treatment of schizophrenia (44,45) does not negate the potential use of D4R targeting drugs to treat cognitive deficits, as suggested by studies in primates and rodents (39,40,46,47). The colocalization of D4 and ErbB4 receptors on PV+ interneurons, activity of which is critically important for regulating excitatory/inhibitory balance and cognitive functions (31), perhaps by optimizing "signal-tonoise" ratio of cortical microcircuits (15), makes these receptor systems attractive targets for modulating network activities that underlie cognition.…”

Section: Significance Of Erbb4 and D4 Receptor Expression In Pv+ Gabamentioning

confidence: 99%

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

Andersson

Johnston

Herman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillationsa type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal γ oscillations. Using agonists for different D1-and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases γ oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for γ oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in γ oscillation power. This unique link between D4R and ErbB4 signaling on γ oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and γ oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.fast-spiking interneuron | attention-deficit/hyperactivity disorder | cognitive enhancers | excitatory/inhibitory balance G amma oscillations (30-80 Hz) are rhythmic local field potentials that synchronize local circuit activity and play an important role in higher brain processes, such as learning, memory, and cognition. Impairments in general synchronized network activity, in particular γ oscillations, are core features of several neurological and psychiatric disorders, such as schizophrenia, in which perception, cognition, and working memory are affected (1, 2). γ oscillation power is impaired during cognitive tasks in firstepisode schizophrenia independent of medication, indicating that these alterations are independent of disease history (3).Pharmacological studies in anesthetized rats and genetic studies in mutant mice emphasize the importance of recurrent excitatory and inhibitory interactions for the generation of γ oscillations in hippocampal networks (4). The development of methodologies to study neural network activity in acute hippocampal slices in vitro, whereby γ oscillations are induced by the activation of metabotropic glutamate receptors (5), muscarinic acetylcholine receptors (6), or kainate (KA) receptors (7), has been instrumental to identify cellular and molecular...

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Section: Significance Of Erbb4 and D4 Receptor Expression In Pv+ Gabamentioning

confidence: 99%

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

Andersson

Johnston

Herman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Clozapine is a preferential antagonist of the dopamine D 4 receptor (11), and several potent D 4 antagonists were discovered aiming to improve the therapeutic efficacy of the antipsychotic agents (19,39). However, the D 4 hypothesis has not been confirmed in the clinic as the mechanism of action of antipsychotic agents (40,41). Other hypotheses regarding the physiological or pathophysiological role of the D 4 receptor have been based on knock-out animals (42,43) or genetic association studies suggesting a potential role in noveltyseeking behavior, alcoholism, attention deficit, and depression; however, neither clinical nor preclinical research has confirmed these hypotheses (29).…”

Section: Figmentioning

confidence: 99%

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Brioni

Moreland

Cowart

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

105

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Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D 4 receptor agonist that activates human dopamine D 4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D 1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. P enile erection is the result of a complex series of integrated neuronal and vascular events that leads to accumulation of blood in the penis to achieve rigidity. The coordination of several neural events is required to release endogenous mediators (i.e., nitric oxide) at the level of the penile smooth muscle to induce relaxation, whereas a disruption of this series of events can lead to erectile dysfunction (ED) (1, 2). Traditionally, drugs used for the treatment of ED have had a peripheral site of action, including phosphodiesterase (PDE)-5 inhibitors like sildenafil, but the recent demonstration that apomorphine can facilitate penile erection in ED patients has introduced a new approach to treatment, because apomorphine acts on central dopaminergic systems (3,4). Dopamine is the main catecholamine in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward, hormonal regulation; abnormalities in dopaminergic neurotransmission have been implicated in Parkinson's disease, schizophrenia, attention-deficit disorder, depression, and drug abuse, among other disorders (5, 6). The regional distribution of the receptor subtypes, the recent generation of knock-out animals, and the availability of a large number of dopaminergic agents have aided researchers in clarifying the biological role of the dopamine receptors. Dopamine receptors in mammalian tissues have been classified as D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 , and D 4 ) based on their binding properties and their ability to activate or inhibit forskolin-induced adenylate cyclase activity, a classification supported by the cloning of the different subtypes during the last decade (7,8).Within the D 2 -like family, the D 2 receptor is highly expressed...

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“…An initial clinical study with the selective D4 antagonist L-745 870 did not demonstrate efficacy in the treatment of schizophrenia. 21,22 However, since only one small dose was tested, it is difficult to draw firm conclusions regarding the potential utility of D4 antagonists as antipsychotic agents. 23 Several other selective D4 antagonists have shown promise in preclinical pharmacological screens [24][25][26] and are currently being tested in patients with schizophrenia.…”

Section: Clinical Experience With Clozapine-inspired Putative Antipsymentioning

confidence: 99%

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

1999

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Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and serotonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer 'atypical' antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resistant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experience with the newer 'atypical' antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.Keywords: clozapine; olanzapine; risperidone; ziprasidone; quetiapine; antipsychotic; schizophrenia; dopamine; NMDA The introduction of clozapine for the pharmacotherapy of schizophrenia represented a significant advance in the treatment of this devastating mental illness. Clozapine is superior to typical neuroleptic drugs (eg haloperidol) in treating positive and negative symptoms, and is effective in many patients who are refractory to typical antipsychotics. [1][2][3] In addition, clozapine does not induce the extrapyramidal side effects (EPS) commonly caused by the typical agents. Because of these properties, clozapine was termed atypical and represents the prototype drug of this class. Although clozapine is the most efficacious antipsychotic currently available, serious side effects induced by the drug, including agranulocytosis, impose substantial limitations on its use. Concerted research and development efforts have been made to produce an antipsychotic drug with the therapeutic advantages of clozapine, without the properties contributing to its serious side effects. However, the specific pharmacological characteristics of clozapine that confer its therapeutic properties are poorly understood. Clozapine binds to a diverse number of neurotransmitter receptors (see Table 1) but it is unclear whether actions at specific serotonin, dopamine, or adrenergic receptors, alone or in combination, account for its clinical efficacy.A number of specific hypotheses concerning mechanisms of action of clozapine have directed drug discovery efforts and led to clinical trials of drugs with widely different receptor-binding characteristics. The clinical experience with drugs whose development was inspired by clozapine will be briefly reviewed and then actions of clozapine and other antip...

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Schizophrenia and L-745, 870, a novel dopamine D4 receptor antagonist

Cited by 91 publications

References 7 publications

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

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Schizophrenia and L-745, 870, a novel dopamine D4 receptor antagonist

Cited by 91 publications

References 7 publications

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

Activation of dopamine D 4 receptors by ABT-724 induces penile erection in rats

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

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Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats