Comparisons of L-DOPA-Induced Dyskinesia in Unilateral 6-Hydroxydopamine Lesioned and in Dopamine-Depleted Mice

Dopamine (DA) transporter KO mice with their DA stores depleted with α-methyl-p-tyrosine (i.e., DDD mice) are a model to rapidly screen compounds for antiparkinsonian and L-DOPA-induced dyskinesia (LID) responses. DDD mice were sensitized with L-DOPA/benserazide (Benz) and effects of D1 receptor (D1R) agonists and amantadine were examined.  Behaviors in an open field and circular maze were compared for indices of LID-like responses.  In the open field, there was a progressive increase in vertical counts with emergence of climbing and oral stereotypies.  In the circular maze, supported rearing and oral stereotypy predominated. Amantadine reduced vertical activities in DDD mice in the open field but were increased in the maze.  Oral stereotypies decreased with amantadine.  As a comparison, 6-hydroxy-DA (6-OHDA)-lesioned wild-type (WT) and β-arrestin 2 KO (βArr2 KO) mice were sensitized with L-DOPA and tested.  With a low dose of L-DOPA or in its absence, 6-OHDA βArr2 KO mice displayed more dyskinesia than WTs to D1R agonists.  Amantadine reduced both stereotypies and postural dyskinesia promoted by L-DOPA.  Based on proposed criteria, oral stereotypies constitute LID-like behaviors in DDD mice. Postural abnormalities in 6-OHDA mice constitute a pathophysiological feature of parkinsonism absent in the DDD model.  In addition, βArr2 results suggest that biased D1R compounds may show promise in treating LID in PD patients.Dopamine (DA) transporter KO mice with their DA stores depleted with α-methyl-p-tyrosine (i.e., DDD mice) are a model to rapidly screen compounds for antiparkinsonian and L-DOPA-induced dyskinesia (LID) responses. DDD mice were sensitized with L-DOPA/benserazide (Benz) and effects of D1 receptor (D1R) agonists and amantadine were examined.  Behaviors in an open field and circular maze were compared for indices of LID-like responses.  In the open field, there was a progressive increase in vertical counts with emergence of climbing and oral stereotypies.  In the circular maze, supported rearing and oral stereotypy predominated. Amantadine reduced vertical activities in DDD mice in the open field but were increased in the maze.  Oral stereotypies decreased with amantadine.  As a comparison, 6-hydroxy-DA (6-OHDA)-lesioned wild-type (WT) and β-arrestin 2 KO (βArr2 KO) mice were sensitized with L-DOPA and tested.  With a low dose of L-DOPA or in its absence, 6-OHDA βArr2 KO mice displayed more dyskinesia than WTs to D1R agonists.  Amantadine reduced both stereotypies and postural dyskinesia promoted by L-DOPA.  Based on proposed criteria, oral stereotypies constitute LID-like behaviors in DDD mice. Postural abnormalities in 6-OHDA mice constitute a pathophysiological feature of parkinsonism absent in the DDD model.  In addition, βArr2 results suggest that biased D1R compounds may show promise in treating LID in PD patients.