Sensitization versus tolerance to haloperidol-induced catalepsy: Multiple determinants

Barnes, Deborah E.; Robinson, B. R. H.; Csernansky, John; Bellows, Elisabeth P.

doi:10.1016/0091-3057(90)90094-x

Cited by 42 publications

(27 citation statements)

References 16 publications

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Section: Discussionmentioning

confidence: 99%

“…This might mean that the D 2 occupancy threshold for the 5-hour EMG response is less than the ‫%07ف‬ reported above and 70%-89% from PET studies. Alternatively, the apparent change in the relationship between occupancy and offset of drug effects may relate to changes in receptor-mediated mechanisms which might involve immediate early gene expression (Robertson and Fibiger 1992) or sensitization to D 2 receptor blockade (Barnes et al 1990).No significant increases in EMG activity were ever found with clozapine up to a dose of 40 mg/kg, which far exceeds the range used clinically (Kane et al 1988), and occupied only 54% of striatal and 63% of nigral receptors, values similar to those reported by Sumiyoshi et al (1995) who utilized an in vivo receptor binding technique. In PET studies the low incidence of EPS associated with the use of clozapine has been attributed to its reduced occupancy of striatal D 2 receptors, which ranged from 38%-63%, that is, less than the Ͼ70% occupancy threshold obtained with the typical antipsychotic drugs (Farde and Nördström 1992a;Farde et al 1992b Farde et al , 1992c Nördström et al 1993;Nyberg et al 1995).…”

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confidence: 99%

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Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Hemsley

Crocker

1999

Neuropsychopharmacology

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The aim of the present study was to investigate the relationship between effects on muscle tone and D 2 receptor occupancy of two typical antipsychotic drugs, raclopride and chlorpromazine, and the atypical drug, clozapine. Increased muscle tone (i.e., muscle rigidity), was measured as increases in tonic electromyographic (EMG) The introduction of antipsychotic drugs has revolutionized the treatment of schizophrenia, but their use has been limited by the appearance of extrapyramidal side effects (EPS). These include acute dystonic reactions which appear early in treatment and are characterized by intense contractions of antagonistic muscles, and Parkinson-like side effects which include muscle rigidity and hypokinesia (Ayd 1961). It has been reported that 35% of drug noncompliance is due to the unacceptability of the side effects associated with antipsychotic drug treatment (Hoge et al. 1990) and this has stimulated a search for effective antipsychotic drugs which do not produce extrapyramidal side effects.The likelihood of extrapyramidal side effects developing appears to be dependent on the affinity of the antipsychotic drug for D 2 dopamine receptors (Creese et al. 1976;Seeman et al. 1976) so that there is a greater incidence associated with the high-potency drugs such as haloperidol and a lesser incidence with low-potency drugs such as chlorpromazine. Support for the view that there may be an association between the appearance of extrapyramidal side effects and D 2 receptor occupancy has come from positron emission tomography (PET) studies in humans (Farde and Nördström 1992a;Farde et al. 1992b Farde et al. , 1992cNyberg et al. 1995). These studies showed that EPS were associated with high D 2 receptor occupancy of 70%-89% in the striatum obtained with conventional doses of typical antipsychotics, but showed no association with D 1 occupancy. Importantly, clozapine whose (Farde and Nörd-ström 1992a;Farde et al. 1992b Farde et al. , 1992cNyberg et al. 1995).Despite being the subject of intense research interest, the mechanisms underlying drug-induced EPS remain unknown. One of the main factors contributing to this situation has been the lack of an objective, quantifiable experimental endpoint relevant to a cardinal feature of EPS, muscle rigidity, or increased muscle tone. We have developed an objective and quantifiable measure of muscle rigidity, assessed as changes in tonic electromyographic (EMG) activity in the anterior tibialis and gastrocnemius muscles of the hindlimb of conscious, unrestrained rats. We reported that tonic EMG activity is significantly increased in both muscles in an animal model of Parkinson's disease, namely following lesions of the ascending nigrostriatal dopaminergic neurons by bilateral 6-hydroxydopamine injections (Double and Crocker 1993). These EMG increases were significantly reduced by subcutaneous injection of the mixed D 1 /D 2 dopamine receptor agonist, apomorphine. Further work showed that both D 1 and D 2 dopamine receptors in the substantia nigra were involved in th...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Hemsley

Crocker

1999

Neuropsychopharmacology

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“…For instance, several studies have shown that although tolerance develops when antipsychotics are administered continuously, reverse tolerance (sensitization) is observed when antipsychotics are administered intermittently so that the drug is allowed to wear off between repeated administrations (Ezrin-Waters and Seeman, 1977;Carey and DeVeaugh-Geiss, 1984;Barnes et al, 1990;Csernansky et al, 1990;See and Ellison, 1990;Ahlenius et al, 1991). The few studies that have aimed to assess the importance of antipsychotic treatment schedule on alteration of D 2 -receptor density gave conflicting results.…”

Section: Introductionmentioning

confidence: 93%

D2-Receptor Upregulation is Dependent upon Temporal Course of D2-Occupancy: A Longitudinal [11C]-Raclopride PET Study in Cats

Ginovart

Wilson

Hussey

et al. 2008

Neuropsychopharmacol

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Long-term occupancy of dopamine D 2 -receptors, as achieved by chronic treatment with antipsychotics, leads to D 2 -receptor upregulation, and this upregulation is thought to be responsible for loss of efficacy and development of tardive dyskinesia. However, little is known about the parameters of D 2 -receptor blockade (duration and percentage of blockade) that lead to upregulation. In this study, we investigated the effects of different degrees (60 vs 480%) and durations (a transient peak vs 24 h/day) of D 2 -receptor blockade on inducing this upregulation. These different patterns of D 2 -receptor occupancy kinetics were produced in cats using bolus vs constant infusion of haloperidol for 4 weeks. D 2 -receptors were measured using positron emission tomography and Scatchard analyses of [ 11 C]raclopride binding, before and after withdrawal of treatment. Continuously high (80% for 24 h/day) D 2 -receptor blockade led to a robust upregulation of striatal D 2 -receptors that was maximal at 1-week withdrawal (35 ± 5%) and still detectable at 2-week withdrawal (20 ± 3%). This pattern of D 2 -receptor blockade also induced behavioral tolerance to the effect of haloperidol on spontaneous locomotor activity. Continuously moderate (60% for 24 h/day) or transiently high (80% for a few hours/day) D 2 -receptor blockade did not produce any of these effects. The long-term effect of haloperidol on D 2 -receptor density and behavioral tolerance thus appears to be dependent not only on a critical threshold of D 2 -receptor blockade but also on the daily duration of D 2 -receptors blockade. This suggests that as far as antipsychotics are concerned, not only dose but disbursment throughout the day have an impact on eventual pharmacodynamic and behavioral outcomes.

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“…In the present study, the increase in cataleptic behavior induced by repeated testing was observed later in mice treated with saline when compared to mice receiving SCH 23390. Interestingly, some studies have reported a repeated testing effect for the catalepsy bar test in haloperidol-treated mice or rats but not in animals receiving saline (Stanley and Glick 1976;Iwata et al 1989;Barnes et al 1990). Thus, one might be led to suspect that a pharmacological component of cataleptic behavior would be able to potentiate a learning component of this behavior.…”

Section: Discussionmentioning

confidence: 99%

Conditioning to Injection Procedures and Repeated Testing Increase SCH 23390-Induced Catalepsy in Mice

Chinen

Frussa‐Filho

1999

Neuropsychopharmacology

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The cataleptic behavior induced by the dopamine D 1 antagonist SCH 23390 (SCH) has proven to be a useful assay for investigating the sensitivity of D 1 -like dopamine receptor-mediated effects during chronic drug administration. A fundamental flaw in most of these studies may be the involvement of the "repeated measures effect," a behavioral phenomenon well demonstrated for neurolepticinduced catalepsy but not yet investigated for dopamineThe ability of chronic neuroleptic treatment to produce increasing or decreasing degrees of both Parkinsonism in humans (see Hansen and Hoffman 1997) and catalepsy in laboratory animals (Barnes et al. 1990) over time remains controversial. Specifically, concerning the evolution of catalepsy during chronic haloperidol treatment, tolerance (Asper et al. 1973;Ezrin-Waters and Seeman 1977;Campbell and Baldessarini 1981), sensitization (Antelman et al. 1986;Kinon and Kane 1989;Barnes et al. 1990), or no effects (György et al. 1969;Moller Nielsen et al. 1974;Frussa-Filho et al. 1992) have been reported. Although the patterns of change in catalepsy responses to chronic neuroleptic treatment are influenced by multiple determinants (Barnes et al. 1990), two specific biological mechanisms seem to be of particular importance in determining the development of tolerance or sensitization: dopamine receptor supersensitivity (Ezrin-Waters and Seeman 1977;Hoffman and Beninger 1988) and a learning process due to repeated testing in the catalepsy apparatus (Iwata et al. 1989;Ferré et al. 1990), respectively. In regards to the learning process, both repeated measures in a single session after acute haloperidol administration (Stanley and Glick 1976;Hillegaart et al. 1987 Received October 12, 1998; revised April 30, 1999; accepted May 17, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 5 Conditioning and SCH 23390-Induced Catalepsy 671 et al. 1990) have been reported to markedly enhance the cataleptic behavior presented by rodents.For many years, dopamine D 2 -like receptors were implicated as the only site mediating the cataleptic behavior of neuroleptics (Seeman 1980). However, in 1984, Christensen et al. (1984 first reported the cataleptogenic properties of SCH 23390, a selective antagonist of D 1 -like dopamine receptors (Hyttel 1983). Thus, besides providing a functional correlate of dopamine D 1 receptor antagonism (Mizuki et al. 1996), SCH 23390-induced catalepsy has proven to be a useful assay for investigating the functional interactions between D 1 -and D 2 -like dopamine receptors (see Klemm 1993). Catalepsy has also been used to investigate the sensitivity of D 1 -like dopamine receptor-mediated effects during chronic drug administration. In two landmark investigations, Hess et al. (1986Hess et al. ( , 1988 reported that although chronic treatment of rats with SCH 23390 resulted in an increase in D 1 -like striatal dopamine receptors as well as in spontaneous locomotion and D 1 -like and D 2 -like dopamine agonist-induced stereotypy, no tolerance to the cataleptic effect ...

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Sensitization versus tolerance to haloperidol-induced catalepsy: Multiple determinants

Cited by 42 publications

References 16 publications

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

D2-Receptor Upregulation is Dependent upon Temporal Course of D2-Occupancy: A Longitudinal [11C]-Raclopride PET Study in Cats

Conditioning to Injection Procedures and Repeated Testing Increase SCH 23390-Induced Catalepsy in Mice

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