Top of pageAbstract We have previously demonstrated focal synaptic inhibition through neuronal expression of the light chain (LC) fragment of tetanus toxin in vivo. The transient effects are spatially discrete lending them to application in deep brain nuclei. This experiment examines feasibility in creating a rat model for Parkinsons disease through gene-based synaptic inhibition of the substantia nigra. The present experiment examined the impact of nigral LC expression on apomorphine induced rotations. Methods: Tetanus light chain (LC) was cloned into an adenoviral vector under control of the CMV promoter containing a GFP marker. Next, the impact of unilateral nigral 6-OHDA on striatal dopamine and glutamate synapses was compared to unilateral nigral LC expression. Rats received medial forebrain bundle (MFB) injections of either 4 or 8|[mu]|L of AdTeTxLC, 4|[mu]|L of 6-OHDA or PBS. Apomorphine-induced rotational behavior was assessed using a rotometer weekly for up to 4 weeks. Results: A significant increase in contralateral rotation was observed in the 6-OHDA positive control group and the 8|[mu]|L TeTxLC group, in comparison to the 4|[mu]|L TeTxLC and PBS groups. 6-OHDA animals demonstrated an average of 7.84 rotations per minute (+/|[minus]|0.45 SEM) and rats receiving 8|[mu]|L TeTxLC demonstrated an average of 4.39 rotations per minute (+/|[minus]|0.41 SEM). PBS rats demonstrated an average of 0.325 rotations per minute and rats receiving 4|[mu]|L TeTxLC demonstrated an average of 0.708 rotations per minute. Significance: This initial model proves the feasibility of dopamine depletion through nigral LC expression. Because LC expression inhibits synaptic activity without killing neurons, this approach represents a strategy for transient dopamine depletion. A subsequent experiment will apply an adeno-associated vector containing a Tet-on expression cassette (rAAV.Tet-on.LC). This latter vector will facilitate controlled, transient nigral suppression and will facilitate the study of behavioral recovery and normalization of striatal receptors following the recovery of striatal dopaminergic input. Transient and controlled nigral inhibition may provide a superior model for studying striatal recovery and dopaminergic re-innervation.