D2 Dopamine receptor blockade results in sprouting of DA axons in the intact animal but prevents sprouting following nigral lesions

Authors

  • W. Tripanichkul,

    1. Neurosciences Group, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton 3168, Australia
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    • *

      W. T. and D. S. contributed equally to this work.

  • D. Stanic,

    1. Neurosciences Group, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton 3168, Australia
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    • *

      W. T. and D. S. contributed equally to this work.

  • J. Drago,

    1. Neurosciences Group, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton 3168, Australia
    2. Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, 3010, Australia
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  • D. I. Finkelstein,

    1. Neurosciences Group, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton 3168, Australia
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  • M. K. Horne

    1. Neurosciences Group, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton 3168, Australia
    2. Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, 3010, Australia
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: Professor M. Horne, 2Howard Florey Institute, as above.
E-mail: m.horne@hfi.unimelb.edu.au

Abstract

Recently it was demonstrated that sprouting of dopaminergic neurons and a microglial and astrocyte response follows both partial lesions of the substantia nigra pars compacta and blockade of the D2 dopamine receptor. We therefore studied the effects of the combination of these two treatments (lesioning and D2 dopamine receptor blockade). Haloperidol administration caused a 57% increase in dopaminergic terminal tree size (measured as terminal density per substantia nigra pars compacta neuron) and an increase of glia in the striatum. Following small to medium nigral lesions (less than 60%), terminal tree size increased by 51% on average and returned density of dopaminergic terminals to normal. In contrast, administration of haloperidol for 16 weeks following lesioning resulted in reduced dopaminergic terminal density and terminal tree size (13%), consistent with absent or impaired sprouting. Glial cell numbers increased but were less than with lesions alone. When haloperidol was administered after the striatum had been reinnervated through sprouting (16–32 weeks after lesioning), terminal tree size increased up to 150%, similar to the effect of haloperidol in normal animals. By examining the effect of administering haloperidol at varying times following a lesion, we concluded that a switch in the effect of D2 dopamine receptor blockade occurred after dopaminergic synapses began to form in the striatum. We postulate that when synapses are present, D2 dopamine receptor blockade results in increased terminal density, whereas prior to synapse formation D2 dopamine receptor blockade causes attenuation of a sprouting response. We speculate that D2 dopamine receptors located on growth cones ‘push’ neurites toward their targets, and blockade of these receptors could lead to attenuation of sprouting.

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