This study is the first to quantify in vivo the death of neurons in the SN due to an endogenous toxin naturally produced in dopaminergic neurons. It augments our in vitro data implicating DOPAL as a toxin and supports our contention that intracellular accumulations of DOPAL AZ 960 905586-69-8 trigger death in dopaminergic neurons in the SNpc and may be relevant to the pathogenesis of PD in humans. Measurable levels of DOPAL are found in post-mortem human brains and increased amounts of DOPAL are in autopsy brains of PD. We have shown previously that DOPAL is toxic to PC12 cells in vitro at dosages as low as 6.6 mM and triggers aggregation of a-synuclein in vitro at dosages as low as 1.5 mM. Previous studies with intracerebral injections of DOPAL used doses ranging between 0.05–0.75 mg/200 nl, with doses above 0.1 mg/200 nl destroying at least some of the DA neurons in the substantia nigra/ventral tegmental area of the midbrain. However, these studies did not exclude that loss of THir after DOPAL injections into SN was due to decreased TH synthesis. In the present study we made three injections of 200 nl-400 nl-200 nl along the rostrocaudal extent of the SN, hoping to include all the DA neurons in the presumed ellipsoid shape of the injection. The DOPAL injections caused neuronal loss only in the SNpc, while sparing neurons in the juxtaposed SNpr. This is of interest since between 71–80% of neurons in SNpc are dopaminergic while those in SNpr are approximately 70–80% GABAergic, suggesting that DOPAL may be selectively lethal to DA neurons. We elected unilateral injections since bilateral disruption often results in aphagia, adipsia and high mortality rates. Most studies on rats inducing hemi-Parkinson symptoms use rather large injections of 6-OHDA into their median forebrain bundles. Numerous dopamine neurons in the ipsilateral SNpc are killed after such injections, resulting in loss of dopamine in the ipsilateral striatum but also in the prefrontal cortex, nucleus accumbens, septum and olfactory tubercles. Injecting DOPAL unilaterally into the SN also resulted in the ipsilateral loss of striatal TH immunoreactivity, and perhaps DA in nerve terminals of the striatum. Unilateral depletion of striatal DA also allows for tests comparing the dopamine innervation on either side of the striatum. Tests such as rotational asymmetry determine imbalances in dopaminergic innervation and are easily evaluated. Rotational behavior after unilateral nigral lesions is hypothesized to be dependent on the balance between striatal dopamine release and hypersensitivity of striatal dopamine receptors on the two sides. We evaluated rotational asymmetry in rats injected with the endogenous toxin DOPAL into their SN, and show significant asymmetry with rats turning ipsilateral to the injection. Our rats turned to the same side as the lesion after apomorphine injection, similar to other studies after intranigral injections of toxins. This finding is consistent with the typical asymmetrical onset of PD in humans.