Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography

Schotte, A.; Janssen, P.F.M.; Megens, Anton; Leysen, Josée E.

doi:10.1016/0006-8993(93)91535-z

Cited by 217 publications

(131 citation statements)

References 22 publications

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“…It thus complements the findings from PET studies in humans (Farde and Nördström 1992a;Farde et al 1992bFarde et al , 1992c and occupancy studies in experimental animals Schotte et al 1993;Sumiyoshi et al 1993Sumiyoshi et al , 1995. The current findings show that there are dose-related increases in EMG activity which are associated with dose-related increases in D 2 dopamine receptor occupancy in the striatum and substantia nigra.…”

Section: Discussionsupporting

confidence: 84%

“…The findings of the current study support the view that clozapine did not produce increased EMG activity because its maximum D 2 occupancy was below the occupancy threshold associated with the onset of EMG increases observed with raclopride and chlorpromazine. However, clozapine also interacts strongly with muscarinic and 5HT 2 receptors and has been shown to exhibit high 5HT 2 occupancy at the doses we used Schotte et al 1993), so that a role of non-dopamine receptors in the regulation of EMG activity cannot be ruled out and is the subject of ongoing studies. (5), 10 mg/kg ᭡ (7), 2.5 mg/kg ᭢ (4), and control ᮀ (8).…”

Section: Discussionmentioning

confidence: 99%

“…The effects of the three drugs were investigated on EMG activity and related to their D 2 receptor occupancy in the striatum and substantia nigra, using the ex vivo method of Schotte et al (1993). Pilot experiments were conducted to establish the feasibility of the experimental approach and a preliminary report of some of these findings has been published Crocker 1996, 1997).…”

mentioning

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: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…30 Spontaneous hyperlocomotion is considered a behavior mediated by increased DAergic tone in the nigrostriatal and mesolimbic DA system. 31 The observation that the classical antipsychotic drug haloperidol 32 fully blocked the hyperactivity in Nurr1 ( þ /À) heterozygous mice supports the notion that the hyperactivity could be mediated via increased DA transmission and stimulation of DA D 2 receptors.…”

Section: Discussionmentioning

confidence: 64%

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

et al. 2007

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The transcription factor Nurr1 (NR4A2) has been found to play a critical role in the development of midbrain dopaminergic neurons. Nurr1 heterozygous ( þ /À) male and female mice expressing 35-40% of normal levels of Nurr1 were generated and examined in animal models related to symptoms of schizophrenia. The Nurr1 ( þ /À) mice displayed hyperactivity in a novel environment, which persisted after administration of the dopamine-mimetic amphetamine and the N-methyl-D-aspartate receptor antagonist phencyclidine. The Nurr1 ( þ /À) mice were deficient in the retention of emotional memory and showed an enhanced response to swim stress. In addition, Nurr1 ( þ /À) male mice displayed a reduced dopamine turnover in the striatum and an enhanced dopamine turnover in the prefrontal cortex, while female mice showed an opposite pattern. These results show that Nurr1 ( þ /À) mice display a pattern of behaviors indicative of potential relevance for symptoms of schizophrenia combined with a gender-specific abnormal dopamine transmission in the striatum and prefrontal cortex, respectively. This suggests that the Nurr1 mutant mouse may be a potential animal model for studies on some of the behavioral and molecular mechanisms underlying schizophrenia.

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“…Even though both agents have a high serotonin 5HT 2A -to-dopamine D 2 binding ratio (a characteristic shared by most atypicals), risperidone has two orders of magnitude higher affinity for both of these receptors than does clozapine; it also has a substantially higher affinity for ␣ 1 and ␣ 2 adrenoceptors than does clozapine (Schotte et al 1993;Breier et al 1999;Richelson 1999). Also, among atypical APDs, risperidone has the simplest binding profile and clozapine has the most broad-spectrum one (Stahl 2000).…”

Section: Risperidone Is An Atypical Antipsychotic Drug That Increasesmentioning

confidence: 99%

Effects of Risperidone on the Peripheral Noradrenegic System in Patients with Schizophrenia A Comparison with Clozapine and Placebo

Elman

Goldstein

Green

et al. 2002

Neuropsychopharmacology

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Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE ( 3 H-NE) in risperidone-Clozapine is an atypical antipsychotic drug (APD) with efficacy superior to that of conventional agents and with little or no extrapyramidal signs or symptoms (EPS) (Kane et al. 1988;Lieberman et al. 1989;Breier et al. 1994a;Meltzer 1995;Meltzer et al. 1996). Because these advantageous therapeutic properties are accompanied by unusually severe side effects, scientists have been searching for clozapine-like APDs that would share its beneficial features but not induce bone marrow toxicity, seizures, or hypotension. This search has resulted in the introduction of four "newer atypical APDs" (i.e., risperidone, olanzapine, quetiapine, and ziprasidone), all of which have important effects on both dopaminergic and serotonergic neurotransmitter systems. Because none of these compounds has been proven as efficacious as the prototype, clozapine, in the treatment of resistant cases, continued research is focusing on other neurotransmitter systems affected by clozapine.Clozapine profoundly increases norepinephrine (NE) levels in both CSF (Ackenheil 1989;Lieberman et al. 1989;Lieberman et al. 1991;Pickar et al. 1992) and plasma (Pickar et al. 1992;Green et al. 1993;Davidson et al. 1993;Breier 1994;Breier et al. 1994b;Schulz et al. 1996;Schulz et al. 1997;Brown et al. 1997;Fleischhaker et al. 1998;Elman et al. 1999), an effect not seen with typical APDs. In some (Breier et al. 1994b;Schulz et al. 1997;Fleischhaker et al. 1998), but not all (Brown et al. 1997) studies, plasma NE increases have been related to clinical improvement, suggesting that this pharmacological effect may play a role in clozapine's beneficial central actions. In this context, findings implicating noradrenergic dysregulation in the pathophysiology of schizophrenia (Stein and Wise 1971;Sternberg 1984;Breier et al. 1990;Rao and Moller 1994;Breier 1994;Yamamoto et al. 1994;Litman et al. 1996;Breier et al. 1998;Goff and Evins 1998;Friedman et al. 1999a;Friedman et al. 1999b;Klimek et al. 1999) further support inquiry into the relevance of noradrenergic mechanisms in the action of APDs.We have reported previous data suggesting that high plasma NE levels in clozapine-treated patients result from increases in the appearance rate of the endogenously released NE in the plasma (spillover) rather than from decreased neuronal uptake of NE, inhibition of intraneuronal monoamine oxidase (MAO), or adrenoceptor antagonism . Risperidone, the next atypical antipsychotic drug marketed in the United States after clozapine, is associated with a low incidence of EPS and may have improved efficacy compared with conventional agents (Kane and McGlashan 1995;Pickar 1995;Campbell et al. 1999). Interestingly, risperidone has also recently been observed in a clinical study to produce a modest (i.e., 58%) inc...

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Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography

Cited by 217 publications

References 22 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

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

Effects of Risperidone on the Peripheral Noradrenegic System in Patients with Schizophrenia A Comparison with Clozapine and Placebo

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