D2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons

Dragunow, Michael; Robertson, G.S.; Faull, Richard L.M.; Robertson, Hugh A.; Jansen, Karl

doi:10.1016/0306-4522(90)90399-o

Cited by 336 publications

(145 citation statements)

References 19 publications

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“…It has been shown that all effective antipsychotics induce FOS in nucleus accumbens shell, while FOS induction in the core region of the nucleus accumbens as well as dorsolateral striatum is an indicator of EPS liability (Deutch et al, 1992;Dragunow et al, 1990;Oka et al, 2004;Robertson et al, 1994;Robertson and Fibiger, 1996). All three antipsychotics in our study induced FOS in the shell of the nucleus accumbens.…”

Section: Discussionsupporting

confidence: 55%

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

180

116

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The novel antipsychotic aripiprazole requires high (490%) striatal D 2 receptor occupancy (D 2 RO) to be clinically active, but despite its high D 2 RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D 2 RO, they show motor side effects when D 2 RO exceeds 80%. We investigated this discrepancy between D 2 RO, 5HT 2 receptor occupancy (5-HT 2 RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D 2 RO. While risperidone clearly showed higher 5-HT 2 RO than D 2 RO, aripiprazole and haloperidol showed higher D 2 RO than 5-HT 2 RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing 480% D 2 RO, while aripiprazole despite higher D 2 RO (490%) induced no catalepsy. Haloperidol and risperidone's ED 50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to B60% D 2 RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D 2 RO, a 23-fold higher dose (86% D 2 RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D 2 ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D 2 RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D 2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D 2 agonist antipsychotics.

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Section: Discussionsupporting

confidence: 55%

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

180

116

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“…However, as rats received intracerebral injections while under anesthesia, it is possible that residual effects of the anesthetic reduced EMG activity up to the 1h time point. Nevertheless, the delay is consistent with the maximal cataleptic response observed 90 min after injection of dopamine antagonists (Ogren et al 1993) and may relate to the timing of post receptor events, such as transcription of immediate early genes (Dragunow et al 1990). …”

supporting

confidence: 72%

Changes in Muscle Tone Are Regulated by D1 and D2 Dopamine Receptors in the Ventral Striatum and D1 Receptors in the Substantia Nigra

Hemsley

Crocker

2001

Neuropsychopharmacology

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Muscle rigidity associated with antipsychotic drug treatment is believed to result from reduced striatal dopamine neurotransmission. In the current study the regulatory roles of dopamine D1 and D2 receptor subfamilies in the dorsal (DSTR) and ventral striatum (VSTR) and substantia nigra (SN) were investigated on muscle tone, assessed as increases in tonic electromyographic (EMG) activity. Rats were injected with the irreversible The use of antipsychotic drugs to treat the symptoms of schizophrenia can be associated with extrapyramidal side effects, which resemble the symptoms of Parkinson's disease and include increased muscle rigidity in up to 40% of patients (Baldessarini and Tarsy 1980). Further, it has been estimated that up to 30% of patients stop taking their medication because of these motor side effects (Hoge et al. 1990). It is not fully understood why antipsychotic drugs, all antagonists at the dopamine D2 receptor (Creese et al. 1976;Seeman et al. 1976; Peroutka and Snyder 1980) produce motor side effects, although there is some early experimental evidence supporting the view that antagonism of D2 receptors in the striatum is important (Chiodo and Bunney 1983;Creese 1983). Findings from studies in humans using positron emission tomography (PET) have led to the concept that a "threshold" of D2 antagonism by antipsychotic drugs of approximately 70%, exists in the striatum, above which patients experience motor side effects (Farde et al. 1992;Nordstrom et al. 1995). Additional support for the striatal D2 threshold hypothesis has N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 4 Dopamine D1 & D2 Receptors Regulate Muscle Tone 515 been provided by studies using experimental animals Ogren et al. 1994;Alcock and Crocker 1999;Hemsley and Crocker 1999a) and other imaging techniques in humans (Scherer et al. 1994). Further, it has been reported that clozapine, which does not produce motor side effects in humans or animals (Claghorn et al. 1987;Casey 1989), occupies sub-threshold levels of D2 receptors in the striatum (Farde et al. 1992;Hemsley and Crocker 1999a) and substantia nigra (Hemsley and Crocker 1999a). The role of dopamine D1 receptors in the production of motor side effects is unclear, and no relationship to D1 receptor occupancy was shown in PET studies (Farde et al. 1992). However, there is evidence that antagonism of D1 receptors may result in motor side effects Sedvall et al. 1995) and elicit such motor behaviors as catalepsy in rats (Ogren and Fuxe 1988). As many commonly used antipsychotic drugs, such as chlorpromazine, fluphenazine, and clozapine, are also potent dopamine D1 antagonists (Hacksell et al. 1995), it would be useful to understand the contribution that antagonism of the D1 receptor subfamily makes to the production of muscle rigidity.Experimental research investigating the mechanisms underlying the motor side effects associated with the use of antipsychotic drugs has been handicapped by the lack of a relevant, objective, and quantifiable endpoint of extrapyramidal side effects ...

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“…The degree of increase, however, differs depending on the drug examined. Typical antipsychotic drugs usually induce more Fos expression in the DLSt than in the NAc, whereas atypical antipsychotic drugs preferentially affect the NAc, having either no effect or less effect in the DLSt (Dragunow et al, 1990;Miller, 1990;Robertson et al, 1994). Thus, a reduced effect in the DLSt may predict a low propensity of a drug to cause the extrapyramidal side effects.…”

Section: Discussionmentioning

confidence: 99%

Effects of l-Stepholidine on Forebrain Fos Expression: Comparison with Clozapine and Haloperidol

Jin

Chen

et al. 2004

Neuropsychopharmacol

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l-Stepholidine (SPD) is a tetrahydroprotoberberine alkaloid and a mixed dopamine D1 agonist/D2 antagonist. Preliminary clinical trials suggest that SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. Here, we report that SPD mimics the effect of the atypical antipsychotic drug clozapine, preferentially increasing Fos expression in corticolimbic areas. Thus, at 10 mg/kg (i.p.), SPD induced Fos expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral septal nucleus (LSN) without significantly affecting the dorsolateral striatum (DLSt). At higher doses (20-40 mg/kg), SPD also increased Fos expression in the DLSt. The increase, however, was less pronounced than the increase seen in the NAc. Within the NAc, SPD also induced more Fos expression in the shell than in the core. In all subcortical areas examined, the Fos expression induced by SPD was mimicked by the D2 antagonist sulpiride and reversed by the D2 agonist quinpirole, suggesting that the effect is due to blockade of D2-like receptors by SPD. In the mPFC, however, the effect was not mimicked by sulpride or reversed by quinpirole. It was also not mimicked by the D1 agonist SKF38393 or SKF38393 plus sulpride, and not reversed by the D1 antagonist SCH23390. These results suggest that, in the mPFC, SPD may induce Fos expression through a non-DA mechanism. Whether the mechanism involves an interaction of SPD with other neurotransmitters such as 5-HT and norepinephrine remains to be determined.

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D2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons

Cited by 336 publications

References 19 publications

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Changes in Muscle Tone Are Regulated by D1 and D2 Dopamine Receptors in the Ventral Striatum and D1 Receptors in the Substantia Nigra

Effects of l-Stepholidine on Forebrain Fos Expression: Comparison with Clozapine and Haloperidol

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