Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm

Carvey, Paul M.; Nath, Sarah T.; Kao, Li Chiung; Zhang, Tien J.; Lin, Dong Hui; Singh, Rekha; Amdur, Rachel L.; Klawans, Harold L.

doi:10.1016/0014-2999(90)90665-s

Cited by 9 publications

(1 citation statement)

References 34 publications

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“…These recent results are in agreement with previous findings, including animal studies, showing that by combining haloperidol with anticholinergic drugs, a clozapine-like pharmacologic profile was only partly duplicated (Coward et al 1989). Furthermore, in contrast with anticholinergics, coadministration of clozapine with haloperidol failed to attenuate the enhancement in striatal turnover induced by haloperidol alone (Carvey et al 1990) and to prevent development of haloperidol-induced behavioral hypersensitivity and proliferation of D2 receptor binding sites (Carvey et al 1988). Finally, it has been reported that both haloperidol and clozapine, chronically administered for 1 year, did not alter the carbachol-increasing effect on phosphoinositide hydrolysis in rats (Rubinstein et al 1989), suggesting that effects on cholinergic mechanisms do not completely account for the difference between clozapine and typical antipsychotics.…”

Section: Anticholinergic Mechanismssupporting

confidence: 92%

New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine

Brunello

Masotto

Steardo

et al. 1995

Neuropsychopharmacology

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Many studies have detected in the brain of schizophrenic patients various morphological and structural abnormalities in various regions and in particular in the cortical and limbic areas. These abnormalities might in part result from neurodevelopmental disturbances suggesting that schizophrenia might have organic causes. These abnormalities may be the primary event in schizophrenia and be responsible for altered dopaminergic, but not only dopaminergic, neurotransmission in these regions. If schizophrenia is in some way strictly related to brain morphological abnormalities it becomes hard to believe that a curative treatment will ever be possible. Considering this scenario, treatment of schizophrenia will be restricted to symptomatic and preventive therapy and therefore, more effective and better tolerated antipsychotics are necessary. The widely used classical antipsychotic drugs present some disadvantages. They do not improve all symptoms of schizophrenia, are not effective in all patients, produce a number of unpleasant and serious, and partly irreversible, motor side effects. The atypical antipsychotic clozapine constitutes a major advance in particular for patients not responding to conventional neuroleptics. To explain the unique therapeutic effect of clozapine many hypothesis have been proposed. Most of the explanations given so far assume that the D2 blockade is the basis for the antipsychotic activity of clozapine and that the difference in respect to other antipsychotics is due to the contribution of other receptor interactions. Considering the dopaminergic receptor, in particular the recently discovered D4 receptor subtype, it has been observed that even if several classical neuroleptics exhibit high affinity to the D4 receptor, clozapine is more selective for this subtype compared to D2 receptors. Moreover clozapine, differently from all other conventional neuroleptics, is a mixed but weak D1/D2 antagonist. This observation has prompted speculation that the synergism between D1 and D2 receptors might allow antipsychotic effects to be achieved below the threshold for unwanted motor side effects. Probably the D1 antagonistic activity exerted by clozapine at low doses enhances preferentially the extracellular concentration of dopamine in specific areas of the brain, such as the prefrontal cortex, where a dopaminergic hypoactivity has been suggested to be in part responsible for negative symptoms of schizophrenia. The clozapine enhancement of dopaminergic activity in this brain area might explain its efficacy against schizophrenia negative symptoms. However, it cannot be excluded that the affinities displayed by clozapine for other nondopaminergic receptors also contribute to its unique therapeutic profile. The various hypotheses mentioned in this review need to be further validated or disproved. The only way to do that is developing new drugs where the postulated mechanistic profile is specifically realized and to clinically test these compounds.

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Section: Anticholinergic Mechanismssupporting

confidence: 92%

New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine

Brunello

Masotto

Steardo

et al. 1995

Neuropsychopharmacology

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Mechanism of action of clozapine‐induced modification of motor behavior in an animal model of the “super‐off” phenomenon

et al. 1997

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We tested the effects of clozapine, and "atypical" neuroleptic with high affinity for the D4 (dopaminergic), and the 5-HT1c and 5-HT2 (serotonergic) receptor subtypes on locomotor activity in an animal model of Parkinson's disease showing a bimodal response curve to increasing doses of a D2 agonist. Sulpiride (D2 antagonist) and ritanserin (5-HT1c and 5-HT2 antagonist) were used for comparison. The D1 agonist SKF 38393 at a dose of 8 mg/kg significantly reversed the akinesia induced by chronic reserpine treatment (1 mg/kg for 5 days) and alpha-methyl-p-tyrosine pretreatment (300 mg/kg). In this model, the addition of a low dose of a D2 agonist, LY 171555 (quinpirole, 1 microgram/kg), inhibited the effects of SKF 38393, whereas the same drug at higher doses (5-50 microgram/kg) restored and potentiated the stimulatory response to D1 stimulation. Clozapine inhibited the inhibitory phase and potentiated the stimulatory phase of the curve. Sulpiride inhibited both phases of the dose-response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomenon possible mediated by the blockade by clozapine of a subpopulation of inhibitory, dopamine (DA) receptors belonging to the D2 "family."

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Alterations in striatal neurotrophic activity induced by dopaminergic drugs

Carvey

Ptak

Lin

et al. 1993

Pharmacology Biochemistry and Behavior

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Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm

Cited by 9 publications

References 34 publications

New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine

New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine

Mechanism of action of clozapine‐induced modification of motor behavior in an animal model of the “super‐off” phenomenon

Alterations in striatal neurotrophic activity induced by dopaminergic drugs

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