Treatment of schizophrenia: A clinical and preclinical evaluation of neuroleptic drugs

Ellenbroek, Bart A.

doi:10.1016/0163-7258(93)90036-d

Cited by 122 publications

(65 citation statements)

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“…Even though, classical neuroleptics are clearly useful in the treatment of positive aspect of the disease, they have a limited efficacy on negative symptoms and cognitive deterioration (Meltzer 1991). Conversely, clozapine and the novel antipsychotics have been termed 'atypicals' because they have a lower incidence of extrapyramidal side effects and can be effective in the treatment of negative symptoms (Deutch et al 1991;Kinon and Lieberman 1996).The molecular basis of these differences has not been clearly established, but could be related to receptor profiles, regional specificity within the CNS and the possibility to produce adaptive changes in specific neurotransmitter systems whose function is altered in schizophrenia (Ellenbroek 1993). Among the others, dopamine, glutamate, and their reciprocal interactions within discrete neuronal circuitry, can be viewed as major players in schizophrenia imbalance (Weinberger 1987;Carlsson and Carlsson 1990;DiChiara et al 1994).…”

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confidence: 99%

“…The molecular basis of these differences has not been clearly established, but could be related to receptor profiles, regional specificity within the CNS and the possibility to produce adaptive changes in specific neurotransmitter systems whose function is altered in schizophrenia (Ellenbroek 1993). Among the others, dopamine, glutamate, and their reciprocal interactions within discrete neuronal circuitry, can be viewed as major players in schizophrenia imbalance (Weinberger 1987;Carlsson and Carlsson 1990;DiChiara et al 1994).…”

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confidence: 99%

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Regulation of Ionotropic Glutamate Receptors in the Rat Brain in Response to the Atypical Antipsychotic Seroquel (Quetiapine Fumarate)

Tascedda

Lovati

Blom

et al. 1999

Neuropsychopharmacology

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In light of the knowledge accumulated during the past couple of decades, it is apparent that schizophrenia is a complex and heterogeneous disease (Lieberman and Koreen 1993). Even though, classical neuroleptics are clearly useful in the treatment of positive aspect of the disease, they have a limited efficacy on negative symptoms and cognitive deterioration (Meltzer 1991). Conversely, clozapine and the novel antipsychotics have been termed 'atypicals' because they have a lower incidence of extrapyramidal side effects and can be effective in the treatment of negative symptoms (Deutch et al. 1991;Kinon and Lieberman 1996).The molecular basis of these differences has not been clearly established, but could be related to receptor profiles, regional specificity within the CNS and the possibility to produce adaptive changes in specific neurotransmitter systems whose function is altered in schizophrenia (Ellenbroek 1993). Among the others, dopamine, glutamate, and their reciprocal interactions within discrete neuronal circuitry, can be viewed as major players in schizophrenia imbalance (Weinberger 1987;Carlsson and Carlsson 1990;DiChiara et al. 1994). Hyperdopaminergic activity is thought to be relevant for positive symptoms of the disease, whereas alterations in glutamatergic system could explain several features of the disorder including negative symptoms and cognitive dysfunctions (Olney and Farber 1995;Weinberger and Lipska 1995). Hence, on the basis of its functional interaction with dopamine, glutamate and Received September 15, 1998; revised February 15, 1999; accepted February 25, 1999. Recently, a number of different laboratories, including our own, have examined the regulation of glutamate receptors in response to treatment with haloperidol and clozapine (Fitzgerald et al. 1995;Riva et al. 1997;Healy and Meador-Woodruff 1997;Brené et al. 1998). In the present study, we investigated the modulation of the mRNA encoding for NMDA and AMPA glutamate receptor subunits in response to the atypical antipsychotic drug "Seroquel (quetiapine fumarate, quetiapine)" (Goldstein 1996).In order to gain insight in the possible relationships between the changes in glutamate receptor expression and the clinical properties of the drug, we have compared the effects elicited by quetiapine to those observed with haloperidol and clozapine, the prototypes for classical and atypical antipsychotics. MATERIALS AND METHODMale Sprague Dawley rats (Charles River, Calco, Italy) weighing 250-350 g were used throughout the experiments. The animals were maintained under a 12 hr light/12 hr dark cycle with food and water available ad libitum. Animals received daily subcutaneous injections with saline, haloperidol (1 mg/kg), clozapine (30 mg/ kg), or quetiapine (25 mg/kg) for 21 days. Rats were sacrificed by decapitation 6 hr after the last injection. The brain regions were rapidly dissected, frozen in liquid nitrogen, and stored at Ϫ 70 Њ C for further analysis. All animal manipulations have been carried out in accordance with the Guide for...

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Regulation of Ionotropic Glutamate Receptors in the Rat Brain in Response to the Atypical Antipsychotic Seroquel (Quetiapine Fumarate)

Tascedda

Lovati

Blom

et al. 1999

Neuropsychopharmacology

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“…While a large number of different preclinical behavioral tests have been used for screening drugs in the development of new atypical antipsychotics (see Ellenbroek 1993;Arnt and Skarsfeldt 1998;Geyer and Ellenbroek 2003 for reviews), the focus of the present review is on drug discrimination. In particular, this review will focus on studies in which antipsychotic drugs have been used as the training drug.…”

Section: Introductionmentioning

confidence: 99%

“…Clozapine is referred to as an atypical or novel antipsychotic drug because it produces few, if any, extrapyramidal motor effects and is usually tolerated better than typical antipsychotic drugs (Claghorn et al 1987;Kane et al 1988;Meltzer 1992;Ellenbroek 1993;Arnt and Skarsfeldt 1998). Chronic treatment with clozapine does not appear to cause tardive dyskinesia (Casey 1989) or prolonged elevations in serum prolactin levels (Meltzer 1992).…”

Section: Introductionmentioning

confidence: 99%

“…These and similar acting drugs, now classified as "typical" or "classical" antipsychotic drugs, are relatively effective in relieving the positive symptoms of schizophrenia (e.g., hallucinations, delusions, excited motor behaviors, thought disorders), but offer little efficacy for the negative symptoms (e.g., emotional and social withdrawal, flat affect, slowness, impoverishment of thought and speech; see Crow 1987) or cognitive deficits in schizophrenia (Meltzer and McGurk 1999;Woodward et al 2005). In addition, typical antipsychotic drugs produce extrapyramidal motor side effects at therapeutic doses and long-term treatment may result in tardive dyskinesia (see review by Ellenbroek 1993).…”

Section: Introductionmentioning

confidence: 99%

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Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Porter

Prus

2008

Psychopharmacology

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Background Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the "prototypical" or "gold standard" atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years. Objectives Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed. Results Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine's cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine's cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs. Conclusions There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While lowdose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine's discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.

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Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum

Hiroi

Graybiel

1996

J. Comp. Neurol.

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Atypical and typical neuroleptics, when administered chronically, can bring about profound but contrasting changes in schizophrenic symptoms and motor activation and dramatically modulate brain neurochemistry. To explore the transcriptional events that might be involved in this neurochemical regulation, we used immunohistochemistry and immunoblotting to examine the expression patterns of two bZip transcription factors, c-Fos and FosB, in the striatum of rats treated acutely and chronically with neuroleptic drugs of different classes. Typical and atypical neuroleptic drugs produced contrasting regulatory effects on a FosB-like protein of ca. 36-39 kDa, the molecular weight of truncated FosB (delta FosB). Chronic treatments with two typical neuroleptics, haloperidol and metoclopramide, but not with the atypical neuroleptic clozapine, led to markedly enhanced FosB-like immunoreactivity in the caudoputamen. Further, c-Fos-like protein in the striatum, considered a marker for the induction of antipsychotic actions by neuroleptic treatments, was downregulated by chronic treatment with the two potent antipsychotic drugs tested, but not by chronic treatment with metoclopramide, which has low antipsychotic efficacy but induces extrapyramidal side effects. These results suggest that chronic treatments with neuroleptics having different effects on cognitive and motor behavior induce different long-term changes in transcription factor expression in the striatum. Nevertheless, we found that neuroleptics of both classes regulated transcription factor expression in overlapping populations of striatal neurons expressing enkephalin or DARPP-32. Contrasting patterns of transcriptional regulation in these neurons may thus contribute to the distinct neurochemical and behavioral effects that characterize neuroleptics of different classes.

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Treatment of schizophrenia: A clinical and preclinical evaluation of neuroleptic drugs

Cited by 122 publications

References 462 publications

Regulation of Ionotropic Glutamate Receptors in the Rat Brain in Response to the Atypical Antipsychotic Seroquel (Quetiapine Fumarate)

Regulation of Ionotropic Glutamate Receptors in the Rat Brain in Response to the Atypical Antipsychotic Seroquel (Quetiapine Fumarate)

Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum

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