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

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.

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates

“…These drugs also inhibited neuronal migration, and it is unclear to what extent the effects on axons were direct or reflected abnormal positioning. In rats, haloperidol reduced the density of dopaminergic axon terminals when administered immediately after a lesion to the substantia nigra, but improved dopamine terminal sprouting when administered after a delay (Tripanichkul et al, 2003), suggesting that the growth response of neurons to haloperidol can vary dramatically under slightly different circumstances. This parallels our observations that PhAPs can have either no effect or a robust growth-promoting effect when added to cells that are growing under permissive versus inhibitory conditions, respectively.…”

Chronic activation of the D2 autoreceptor inhibits both glutamate and dopamine synapse formation and alters the intrinsic properties of mesencephalic dopamine neurons in vitro

“…, 2001, 2002) whereas pharmacological blockade or genetic deletion of the D2R induced an increase in the terminal arbour volume (Parish et al. , 2002; Tripanichkul et al. , 2003).…”

“…In vivo studies in rats and mice have shown that the chronic blockade of D2R regulates the size of the terminal arbor in DA neurons of the substantia nigra (Parish et al. , 2002; Tripanichkul et al. , 2003).…”

Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro

“…In an opposite manner, pharmacological blockade or genetic deletion of the D2R induced an increase in the terminal arbor volume (Parish et al. , 2002; Tripanichkul et al. , 2003).…”