Clinical improvements in
Parkinson's disease produced by
dopamine D3 receptor-preferring agonists have been related to their neuroprotective actions and, more recently, to their neuroregenerative properties. However, it is unclear whether
dopamine agonists produce their neurotrophic effects by acting directly on receptors expressed by the mesencephalic dopaminergic neurons or indirectly on receptors expressed by astrocytes, via release of
neurotrophic factors. In this study, we investigated the effects of the
dopamine D3 receptor-preferring agonists
quinpirole and 7-hydroxy-N,N-di-propyl-2-aminotetralin (7-OH-DPAT), as well as of the indirect agonist
amphetamine, on dopaminergic neurons identified by
tyrosine hydroxylase immunoreactivity (TH-IR). Experiments were performed on neuronal-enriched primary cultures containing less than 0.5% of astrocytes prepared from the mouse embryo mesencephalon. After 3 days of incubation, both
quinpirole (1-10 microm) and
7-OH-DPAT (5-500 nm) dose-dependently increased the maximal dendrite length (P < 0.001), number of primary dendrites (P < 0.01) and [3H]
dopamine uptake (P < 0.01) of TH-IR-positive mesencephalic neurons. Similar effects were observed with 10 microm
amphetamine. All neurotrophic effects were blocked by the unselective D2/D3 receptor antagonist
sulpiride (5 microm) and by the selective D3 receptor antagonist
SB-277011-A at a low dose (50 nm).
Quinpirole and
7-OH-DPAT also increased the phosphorylation of
extracellular signal-regulated kinase (ERK) within minutes, an effect blocked by pretreatment with
SB-277011-A. Inhibition of the D2/D3 receptor signalling pathway to ERK was obtained with
PD98059, GF109203 or
LY294002, resulting in blockade of neurotrophic effects. These data suggest that
dopamine agonists increase dendritic arborizations of mesencephalic dopaminergic neurons via a direct effect on D2/D3 receptors, preferentially involving D3 receptor-dependent neurotransmission.