Regulation of polysynaptic subthalamonigral transmission by D2 D3 and D4 dopamine receptors in rat brain slices

摘要

Dopamine depletion in experimental models of Parkinson's disease promotes burst firing of neurons in the subthalamic nucleus (STN) and substantia nigra zona reticulata (SNR). A synaptically generated form of burst firing has been shown to arise from complex excitatory postsynaptic currents (EPSCs) that are evoked in SNR neurons by STN stimulation. The present experiments were designed to characterize actions of dopamine on complex EPSCs in slices of rat brain. Using patch pipettes to record whole-cell currents under voltage clamp, dopamine (30 μm) caused a reversible 64% reduction in complex EPSC charge. This effect was partially mimicked by D2, D3 and D4 receptor agonists, and the action of dopamine could be nearly completely blocked by the combined effects of the D2/3 antagonist sulpiride and the D4 antagonist L-745,870. Local application of dopamine to the STN caused a larger inhibition of the complex EPSC (55% reduction) than did dopamine application to the SNR (15% reduction). Simple, monophasic EPSCs, which were evoked in SNR neurons by stimulating the SNR close to the recording pipette, were inhibited to a smaller extent compared to complex EPSCs. Bursts of action potentials evoked in SNR neurons by STN stimulation were inhibited by dopamine to a greater extent than was spontaneous firing. These results show that dopamine D2-like receptors inhibit complex EPSCs and burst discharges in the SNR by acting within the STN to suppress transmission in the subthalamonigral pathway. Dopamine receptor-mediated inhibition of polysynaptic connections in the STN might be beneficial in the treatment of Parkinson's disease.