Receptor subtype-specific modulation by dopamine of glutamatergic responses in striatal medium spiny neurons

Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92-019, Auckland, New Zealand.
Brain Research (Impact Factor: 2.84). 02/2003; 959(2):251-62. DOI: 10.1016/S0006-8993(02)03757-5
Source: PubMed


The output of GABAergic medium-sized spiny neurons in the dorsal striatum is controlled in part by glutamatergic input from the neocortex and the thalamus, and dopaminergic input from ventral midbrain. We acutely isolated these neurons from juvenile (P14-24) rats to study the consequences of the interaction between glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was used to identify the expression patterns of dopamine receptors. D1 and D2 dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons, respectively. Receptor mRNA co-expression was detected in 1/22 cells tested. Whole-cell voltage clamp recording (V(h)=-70 mV) was combined with local or bath application of dopaminergic and glutamatergic agonists to explore dopamine receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM) to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also attenuated by the D1 receptor agonist SKF 38393 (1 microM; n=28), while the D2/3 receptor agonist quinpirole (10 microM) had no effect. The currents evoked by application of AMPA (5 microM) displayed a steady rundown. Application of dopamine abolished or significantly reduced the rundown in the cells tested (n=17). A similar effect was observed after the application of SKF 38393 (1 microM), while quinpirole (10 microM) had no significant effect. Our results provide direct evidence for modulation by dopamine of glutamatergic responses of striatal medium spiny neurons, and demonstrate that the effects of this neuromodulator are receptor subtype specific. Disruption of this modulatory effect is likely to contribute to movement disorders associated with Parkinson's disease.

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    • "The effects of dopamine on glutamatergic neurotransmission have been previously studied. Some studies reported that the activation of D1 receptors enhanced NMDA receptor-mediated EPSCs in dorsal striatal slices ([35],[36],[37],[25],[38]), while others reported that D1 receptor agonists attenuated NMDA EPSCs in MS striatal neurons in culture ([24],[39]). In the nAcb, some investigators reported that DA or D1 receptor agonists potentiate NMDA receptor-mediated EPSCs in slices ([40],[41]), while others reported no significant modulatory effects of DA on NMDA receptor-mediated EPSCs ([42],[43]. "
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    ABSTRACT: Nucleus accumbens (nAcb), a major site of action of drugs of abuse and dopamine (DA) signalling in MSNs (medium spiny neurons), is critically involved in mediating behavioural responses of drug addiction. Most studies have evaluated the effects of DA on MSN firing properties but thus far, the effects of DA on a cellular circuit involving glutamatergic afferents to the nAcb have remained rather elusive. In this study we attempted to characterize the effects of dopamine (DA) on evoked glutamatergic excitatory postsynaptic currents (EPSCs) in nAcb medium spiny (MS) neurons in 1 to 21 day-old rat pups. The EPSCs evoked by local nAcb stimuli displayed both AMPA/KA and NMDA receptor-mediated components. The addition of DA to the superfusing medium produced a marked decrease of both components of the EPSCs that did not change during the postnatal period studied. Pharmacologically isolated AMPA/KA receptor-mediated response was inhibited on average by 40% whereas the isolated NMDA receptor-mediated EPSC was decreased by 90%. The effect of DA on evoked EPSCs were mimicked by the D1-like receptor agonist SKF 38393 and antagonized by the D1-like receptor antagonist SCH 23390 whereas D2-like receptor agonist or antagonist respectively failed to mimic or to block the action of DA. DA did not change the membrane input conductance of MS neurons or the characteristics of EPSCs produced by the local administration of glutamate in the presence of tetrodotoxin. In contrast, DA altered the paired-pulse ratio of evoked EPSCs. The present results show that the activation D1-like dopaminergic receptors modulate glutamatergic neurotransmission by preferentially inhibiting NMDA receptor-mediated EPSC through presynaptic mechanisms.
    PLoS ONE 05/2014; 9(5):e86970. DOI:10.1371/journal.pone.0086970 · 3.23 Impact Factor
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    • "Consistent with this, D1 receptors acting through PKA increase surface AMPA receptors in neuronal cultures prepared from nucleus accumbens (Sun et al., 2008) and PFC (Sun et al., 2005), whereas D2 receptor agonists decrease surface AMPA receptor levels (Sun et al., 2005). Moreover, membrane currents and potentials evoked by local application of AMPA receptor agonists in striatal and cortical neurons are depressed by D2 receptor stimulation (André et al., 2010; Herná ndez-Echeagaray et al., 2004; Levine et al., 1996a) and are either unaffected (Calabresi et al., 1995; Seamans et al., 2001a; Zheng et al., 1999) or potentiated (André et al., 2010; Levine et al., 1996a; Lin et al., 2003; Yan et al., 1999) by D1 receptor agonists. Importantly, DA receptor signaling is not sufficient to recruit AMPA receptors to postsynaptic terminals (Sun et al., 2005, 2008), probably because AMPA receptor surface expression and synaptic targeting by lateral diffusion constitute two independent and separately regulated trafficking steps (Shepherd and Huganir, 2007). "
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    ABSTRACT: Among the many neuromodulators used by the mammalian brain to regulate circuit function and plasticity, dopamine (DA) stands out as one of the most behaviorally powerful. Perturbations of DA signaling are implicated in the pathogenesis or exploited in the treatment of many neuropsychiatric diseases, including Parkinson's disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette's syndrome. Although the precise mechanisms employed by DA to exert its control over behavior are not fully understood, DA is known to regulate many electrical and biochemical aspects of neuronal function including excitability, synaptic transmission, integration and plasticity, protein trafficking, and gene transcription. In this Review, we discuss the actions of DA on ionic and synaptic signaling in neurons of the prefrontal cortex and striatum, brain areas in which dopaminergic dysfunction is thought to be central to disease.
    Neuron 10/2012; 76(1):33-50. DOI:10.1016/j.neuron.2012.09.023 · 15.05 Impact Factor
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    • "Regulation of striatal GLU transmission can be achieved at different compartments. Medium-sized spiny GABAergic neurons express both dopaminergic (D1 and D2) and glutamatergic (NMDA and AMPA) receptors as shown by single-cell reverse transcription (RT) PCR and physiological stimulations (Lin et al. 2007). Dopamine D2 receptors localized in presynaptic cortico-striatal GLU terminals take part in DA-mediated GLU release and are putatively involved in dampening striatal excitation (Bamford et al. 2004). "
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    ABSTRACT: Dopamine and L: -glutamate are important signals which guide the development of functional neural circuits within the striatal complex. Disequilibrium of these neurotransmitter systems is believed to be etiological for the genesis of neurological and psychiatric diseases. Since dopamine plays a crucial role for the early transmitter-regulated differentiation of striatal GABAergic neurons, we emphasized that dopaminergic transmission may also be involved in the fine tuning of intra-striatal glutamate action. In this study, we report that dopamine decreases the expression of the glutamate transporter GLT1 but not GLAST in striatal astrocytes by measuring gene and protein expression. Using glutamate-uptake approaches, we demonstrate an increase in glutamate clearance of externally added glutamate in dopamine-treated cultures compared to controls. Our findings imply that dopamine regulates the availability of L: -glutamate in the developing striatum. It is also suggested that the application of dopaminergic drugs can interfere with ontogenetic processes within the striatal complex.
    Journal of Molecular Neuroscience 09/2009; 39(3):372-9. DOI:10.1007/s12031-009-9273-9 · 2.34 Impact Factor
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