Lack of apparent antipsychotic effect of the D1-dopamine recepotr antagonist SCH39166 in acutely ill schizophrenic patients

Karlsson, Per; Smith, Lance A.; Farde, Lars; Härnryd, C; Sedvall, Göran; Wiesel, Frits‐Axel

doi:10.1007/bf02246068

Cited by 144 publications

(70 citation statements)

References 34 publications

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“…The notion that the action of antipsychotic drugs might be mediated through increasing DARPP-32 phosphorylation is made more interesting by a recent report showing that treatment with a D1 antagonist (SCH39166) does not improve but actually worsens the symptoms of schizophrenia (Karlsson et al, 1995). D1 antagonists, like D2 agonists, would be expected to inhibit increases in DARPP-32 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional Regulation of DARPP-32 Phosphorylation by Dopamine

1997

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Dopamine has been shown to stimulate phosphorylation of DARPP-32, a phosphoprotein highly enriched in medium-sized spiny neurons of the neostriatum. Here, we investigated the contribution of D1-like and D2-like dopamine receptors in the regulation of DARPP-32 phosphorylation in mouse striatal slices. D1-like and D2-like receptors had opposing effects on the state of DARPP-32 phosphorylation. The D1 receptor agonist SKF82526 increased DARPP-32 phosphorylation. In contrast, the D2 receptor agonist quinpirole decreased basal as well as D1 agonist-, forskolin-, and 8-bromo-cAMP-stimulated phosphorylation of DARPP-32. The ability of quinpirole to decrease D1-stimulated DARPP-32 phosphorylation was calcium-dependent and was blocked by the calcineurin inhibitor cyclosporin A, suggesting that the D2 effect involved an increase in intracellular calcium and activation of calcineurin. In support of this interpretation, Ca 2ϩ -free/EGTA medium induced a greater than 60-fold increase in DARPP-32 phosphorylation and abolished the ability of quinpirole to dephosphorylate DARPP-32. The antipsychotic drug raclopride, a selective D2 receptor antagonist, increased phosphorylation of DARPP-32 under basal conditions and in D2 agonist-treated slices. The results of this study demonstrate that dopamine exerts a bidirectional control on the state of phosphorylation of DARPP-32.Key words: DARPP-32; dopamine; D2 receptor; phosphorylation; neostriatum; calcineurin; raclopride DARPP-32, a dopamine-and cAM P-regulated phosphoprotein of M r 32,000, is a cytosolic protein that is selectively enriched in medium-sized spiny neurons in neostriatum (Ouimet et al., 1984;Walaas and Greengard, 1984). DARPP-32 is phosphorylated by cAM P-dependent protein kinase (PK A) on a single threonine residue, thr 34 , resulting in its conversion into a potent inhibitor of protein phosphatase-1 . DARPP-32 can be dephosphorylated and inactivated in vitro by the calcium/ calmodulin-dependent protein phosphatase calcineurin (King et al., 1984). Dopamine has been shown to stimulate the phosphorylation of DARPP-32 in neostriatum by activation of a biochemical cascade involving stimulation of D1 receptors, activation of adenylyl cyclase, increased cAM P formation, and increased activity of PK A . The selective enrichment of DARPP-32 in dopaminoceptive neurons and its regulation by dopamine strongly indicate that DARPP-32, by regulating protein phosphatase-1 activity, plays a key role in mediating the effects of dopamine on these cells. The control of protein phosphatase-1 activity by DARPP-32 is likely to have a significant role in the regulation of neuronal excitability. For instance, in neostriatum, dopamine-mediated effects on the function of calcium channels (Surmeier et al., 1994), voltagedependent sodium channels (Surmeier et al., 1992;Schiffman et al., 1994), and Na ϩ ,K ϩ -ATPase (Aperia et al., 1991) are regulated directly or indirectly by protein phosphatase-1.Medium-sized spiny neurons of the neostriatum and nucleus accumbens receive dopaminergic input fro...

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Section: Discussionmentioning

confidence: 99%

Bidirectional Regulation of DARPP-32 Phosphorylation by Dopamine

1997

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“…Unfortunately, such drugs were not effective and there were indications that selective D1 antagonists may have even exacerbated symptoms of schizophrenia and induced extrapyramidal side effects. 6,7 Although selective D1 antagonists were not effective, it is possible that D1 antagonistic properties of clozapine, in combination with other actions of the drug, contribute to, but are not sufficient for, its therapeutic effects. Clozapine has relatively high affinity for 5HT2A receptors and is a potent antagonist of 5HT2A receptormediated responses in vivo.…”

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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“…23 However, the latter agents elicit various side effects, limiting their clinical use. 24,25 The effects of drug-associated cues are crucial for relapse in humans and probably reflect the progressive acquisition by these cues of an affective valence, often thought to be associated with incentive motivational properties. 26 Our study therefore suggests that D 3 receptor ligands, previously proposed in the treatment of cocaine addiction, 1,27 could be novel therapeutic tools to help smoking cessation by disrupting conditioning to environmental stimuli.…”

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confidence: 99%

Disruption of nicotine conditioning by dopamine D3 receptor ligands

Foll

Sokoloff

2003

Mol Psychiatry

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Tobacco smoking is the first cause of preventable death in modern countries. Nicotine replacement therapy or sustained release bupropion helps smoking cessation, but relapse rates are still very high. Nicotine, like other drugs of abuse, activates the dopamine mesolimbic system, which originates in the ventral tegmental area and projects notably to the nucleus accumbens. Situations or environmental stimuli previously associated with cigarette smoking, for example, smell of cigarette smoke, can elicit craving in abstinent smokers and promote relapse. Reducing the effects of nicotineassociated cues might therefore have potential therapeutic utility for smoking cessation. Such an approach has been validated for cocaine in animals, by using the dopamine D 3 receptor-selective partial agonist BP 897, which inhibits cocaine cue-induced drug-seeking behavior. Here we show that rats repeatedly injected with nicotine in a particular environment develop nicotineconditioned locomotor responses, accompanied by an increase in D 3 receptor expression in the nucleus accumbens. This conditioned behavior was inhibited by BP 897 or a selective D 3 receptor antagonist, suggesting that antagonizing dopamine selectively at the D 3 receptor disrupts nicotine-conditioned effects and might represent a novel therapeutic approach for smoking cessation.

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Lack of apparent antipsychotic effect of the D1-dopamine recepotr antagonist SCH39166 in acutely ill schizophrenic patients

Cited by 144 publications

References 34 publications

Bidirectional Regulation of DARPP-32 Phosphorylation by Dopamine

Bidirectional Regulation of DARPP-32 Phosphorylation by Dopamine

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

Disruption of nicotine conditioning by dopamine D3 receptor ligands

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