Recent results in animal models suggest that thrombin may modulate brain injury in Parkinson's disease (PD). High doses of thrombin ( approximately 20U) can damage dopaminergic neurons, while we have found that low dose thrombin (1U), given several days before a brain insult (thrombin preconditioning), is protective in models of PD and stroke. However, the effects of such low levels of thrombin at the time of, or after, exposure to the dopamine neurotoxin 6-hydroxydopamine (6-OHDA) have not been examined and are the focus of this study. In the first set of experiments, rats received co-administration of thrombin (1U) or saline and 6-OHDA (5microg) into the medial forebrain bundle. 6-OHDA+thrombin resulted in striking increases in behavioral deficits, compared to 6-OHDA+saline. Similarly, co-administration of an agonist to protease-activated receptor (PAR)-1, a thrombin receptor, also resulted in significantly greater behavioral deficits. In a second set of experiments, thrombin (1U) or saline was administered 1 or 7 days after 6-OHDA to determine the effects of thrombin after 6-OHDA. Surprisingly, the rats that received saline had strikingly increased behavioral and neurochemical deficits resulting from the 6-OHDA lesion, while delayed thrombin administration prevented this effect. The results indicate that thrombin has differential effects in the 6-OHDA model, dependent on the time of administration. The ability of a second cannula insertion with saline infusion to increase dramatically deficits raises questions as to what role physical injury to already susceptible cells might play in the pathogenesis of some cases of PD.