Dopamine receptor downregulation: an alternative strategy for schizophrenia treatment

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Abstract

Schizophrenia is a common and devastating illness. The cause of schizophrenia is still unknown and the simplest formulation of the “Dopamine hypothesis” posits that schizophrenia results from dopaminergic hyperactivity. Under the hypothesis of dopaminergic hyperactivity in schizophrenia, antipsychotics blocking the dopamine D2 receptor (DRD2) and other approaches to reduce dopamine (DA) transmission have been used to treat schizophrenia. I propose that dopamine receptor (DR) downregulation could be an alternative strategy to compromise dopaminergic overactivity implicated in the pathogenesis of schizophrenia. Agonist-induced receptor downregulation includes receptor proteolysis, modulation of receptor gene transcription and affecting of RNA stability. These processes cause a decrease of existing receptors and reduction of receptor synthesis. This hypothesis could explain the antipsychotic mechanisms of DA agonists or partial agonists, like aripiprazole. It is suggested that the development of agents that increase DR downregulation could be an alternative strategy for schizophrenia treatment.

Introduction

Antipsychotic medication, introduced in 1950s, has revolutionised the treatment of schizophrenia. It has been proposed, based on the fact that traditional (typical) antipsychotics selectively bind to and block the dopamine D2 receptor (DRD2), and the DRD2 affinity of typical antipsychotics is highly correlated with antipsychotic potency, that antipsychotics exert their effects against psychosis by blocking DRD2 [1]. With this finding and because drugs that increased dopaminergic activity (e.g., amphetamine) are psychomimetic, the `Dopamine (DA) hypothesis of schizophrenia' posits that schizophrenia results from dopaminergic hyperactivity. This hypothesis is further supported by evidence from brain neuroimage studies, which have shown increased DRD2 density (e.g. [2]), increased baseline DA levels (e.g. [3]) and increased DA synthesis (e.g. [4]) or release (e.g. [5]) in schizophrenic patients, although not all studies had similar findings.

Under the hypothesis of dopaminergic hyperactivity in schizophrenia, other approaches to reduce DA transmission have been used to treat schizophrenia. For example, blockade of DA synthesis by alpha-methyltyrosine [6], or depletion of presynaptic DA by reserpine [7], have been shown to improve psychotic symptoms in schizophrenia. Here, I propose that dopamine receptor (DR) downregulation could be an alternative strategy to compromise dopaminergic overactivity implicated in the pathogenesis of schizophrenia.

Long-term exposure to an agonist agent often induces receptor downregulation, referring to a decrease in the total number of receptors present in cells [8], [9]. The major mechanisms implicated in the agonist-induced receptor downregulation include receptor proteolysis [10], modulation of receptor gene transcription [11], or affecting of RNA stability [12]. Receptor proteolysis causes a decrease of existing receptors, while modulating receptor gene transcription or affecting RNA stability, which can reduce receptor synthesis. For the dopaminergic system, studies in cell-line or animals have demonstrated that repeat administration of DA [13], a DA agonist (quinpirole) [14] or an indirect DA agonist (L-dopa) [15] can reduce DRD2 receptor density.

Dopamine agonists have long been found to have a therapeutic effect on schizophrenia. In 1978, Tamminga et al. [16] found that a significant improvement in psychotic symptoms occurred after apomorphine (a DA agonist) treatment, in doses sufficient to stimulate postsynaptic DR, compared with placebo treatment of schizophrenic patients. In addition, a recent meta-analysis of 30 studies (716 patients), has shown that L-dopa administered concomitantly with antipsychotic drugs, provides a beneficial response in patients with schizophrenia, and that the percentage of improved patients had a central tendency of around 50% [17].

A new atypical antipsychotic and DA partial agonist, aripiprazole, has demonstrated efficacy in the treatment of schizophrenia. An animal study has shown that chronic administration of aripiprazole decreased DRD2 density and the DRD2 mRNA in the rat pituitary, suggesting that aripiprazole may downregulate DR [18].

The mechanisms underlying the antipsychotic effects of DA agonists or aripiprazole are still unknown. Several hypotheses have been proposed [19], [20]. For example, first, stimulation of the presynaptic DA autoreceptor by DA agonists or aripiprazole may decrease the synthesis and release of DA, thus depressing the dopaminergic neuronal activity. Second, aripiprazole may compete with endogenous DA and act as an antagonist on post-synaptic DR. Third, aripiprazole may act through selected other biogenic amine receptors (e.g., serotonin 1A (5HT1A), serotonin 2A (5HT2A)), to improve psychotic symptoms [21]. These possible mechanisms may act with DR downregulation to improve schizophrenic symptoms, which need further exploration.

Section snippets

Conclusion

In this report, it is proposed that DR downregulation may be an alternative strategy to compromise DA hyperactivity associated with schizophrenia. There are several recommendations for future research, namely:

  • 1.

    For G-protein-coupled receptors (GPCRs), receptors are internalised when exposed to agonist stimulation [22]. Such internalisation can then induce reversible sequestration of receptors in endosomes, or proteolytic downregulation of receptors in lysosomes [23]. It is likely, after DA

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