Trends in Neurosciences
Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it?
Introduction
The neurotransmitter dopamine is synthesized by mesencephalic neurons of the substantia nigra and ventral tegmental area, and by hypothalamic neurons of the arcuate and periventricular nuclei [1]. Dopaminergic neurons located in these areas project their axons to the striatum (nigrostriatal pathway), neocortex (mesocortical pathway), limbic system (mesolimbic pathway) and hypophysis (tuberoinfundibular pathway), thereby controlling a large series of physiological functions, such as voluntary movements, motivated behaviours, learning and hormone production. The effects of dopamine are mediated through its interaction with G-protein-coupled membrane receptors. The dopamine receptor family contains five members that, according to structural and pharmacological similarities, are divided into two subfamilies: the D1-like family, comprising D1 and D5 receptors; and the D2-like family, which includes D2, D3 and D4 receptors 1, 2. The complexity generated by the presence of multiple dopaminergic pathways, dopamine receptors and transduction mechanisms means that picture of the participation of the different elements of the dopaminergic system in regulation of physiological functions is still incomplete.
Animal studies using the knockout technology are helping to reveal the role of each receptor in dopamine-mediated functions [3]. From these studies, it emerges that D1 and D2 receptors are the key components of this system, because their concurrent absence in the early postnatal period is lethal [4]. Nonetheless, ablation of single receptors results in animals that can survive and reproduce. An in-depth analysis of these mutants is thus still required to elucidate the eventual contribution of each of these receptors to human disorders.
Clinical evidence suggest that dopaminergic pathways are altered in several neurological and psychiatric diseases (Box 1). For example, reduced levels of dopamine, and thereby blunted postsynaptic dopamine signalling, are implicated in Parkinson's disease (PD), which is characterised by bradykinesia, rigidity, resting tremors and postural instability. Striatal dopamine depletion in PD is caused by degeneration of nigral neurons. Similarly, degeneration of selected neuronal populations in severe human illnesses, such as Huntington's disease, ischaemia and epilepsy, are also associated with dysfunctions of the dopaminergic system 5, 6, 7. Interestingly, whether in a receptor-dependent or -independent fashion, dopamine has been reported to have both neurotoxic and neuroprotective effects on selected neuronal populations and under different pathological conditions. We will focus on the receptor mechanisms involved in the neurotoxic and neuroprotective actions of dopamine.
Section snippets
Neurotoxic action of dopamine
Large series of studies have demonstrated that dopamine can have neurotoxic effects. In rodents, repeated systemic administration of methamphetamine, which results in a massive increase of dopamine levels in the striatum and inhibits dopamine uptake, results in extensive neurodegeneration of dopaminergic nerve terminals 8, 9. Thus, high dopamine levels might be detrimental to neurons, suggesting that defective mechanisms regulating dopamine homeostasis are likely to participate in the
D2-receptor-mediated neuroprotection
Dopamine can also exert a neuroprotective role through receptor-dependent mechanisms 40, 41 (Table 1). For example, it can protect cultured striatal neurons against glutamate-induced cell death, possibly through D1-mediated signalling [42]. Further studies support a putative neuroprotective role of dopamine, and implicate D2 receptors, more than D1 receptors, as mediators of this action. Indeed, activation of D2 receptors by quinpirole reduces the toxicity of both NMDA and kainic acid in
Future perspectives: unravelling the role of presynaptic and postsynaptic D2 receptors in dopamine-mediated neuroprotection
Results discussed in this review clearly indicate that dopamine can be both neurotoxic and neuroprotective in different experimental settings. From these studies emerges a predominant role for D2-receptor-mediated signalling in dopamine neuroprotection, as indicated by results obtained in experimental animal models and in humans. Two different D2 receptor isoforms arise from alternative splicing: D2L (long) and D2S (short). D2L and D2S are identical, except for the insertion of 29 amino acids
Acknowledgements
We apologize to authors whose studies have not been cited in this review owing to the large amount of bibliographic material available on this subject. Our research was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique and Fondation de France (E.B.), and by Fondazione Mariani (Y.B.).
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