Adenosinergic Protection of Dopaminergic and GABAergic Neurons against Mitochondrial Inhibition through Receptors Located in the Substantia Nigra and Striatum, Respectively

Mitochondrial dysfunction may contribute to dopaminergic (DAergic) cell death in Parkinson's disease and GABAergic cell death in Huntington's disease. In the present work, we tested whether blocking A₁ receptors could enhance the damage to DAergic and GABAergic neurons caused by mitochondrial inhibition, and whether blocking A_2a receptors could protect against damage in this model. Animals received an intraperitoneal injection of 8-cyclopentyl-1,3-dipropylxanthine (CPX) (A₁ antagonist) or 3,7-dimethyl-1-propargylxanthine (DMPX) (A_2a antagonist) 30 min before intrastriatal infusion of malonate (mitochondrial complex II inhibitor). Damage was assessed 1 week later by measuring striatal dopamine, tyrosine hydroxylase (TH), and GABA content. In mice and rats, malonate-induced depletion of striatal dopamine, TH, or GABA was potentiated by pretreatment with 1 mg/kg CPX and attenuated by pretreatment with 5 mg/kg DMPX. To determine the location of the A₁ and A_2a receptors mediating these effects, CPX or DMPX was infused directly into the striatum or substantia nigra of rats 30 min before intrastriatal infusion of malonate. When infused into the striatum, CPX (20 ng) potentiated, whereas DMPX (50 ng) prevented malonate-induced GABA loss, but up to 100 ng of CPX or 500 ng of DMPX did not alter malonate-induced striatal dopamine loss. Intranigral infusion of CPX (100 ng) or DMPX (500 ng), however, did exacerbate and protect, respectively, against malonate-induced striatal dopamine loss. Thus A₁ receptor blockade enhances and A_2a receptor blockade protects against damage to DAergic and GABAergic neurons caused by mitochondrial inhibition. Interestingly, these effects are mediated by A₁ and A_2a receptors located in the substantia nigra for DAergic neurons and in the striatum for GABAergic neurons.