Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein

Abstract

Overexpression of alpha-synuclein causes familial Parkinson's disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/L-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. l-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of alpha-synuclein led to abnormal pharmacological responses in mice.

Fig. 1

L-DOPA (25 mg/kg) effects in Thy1-aSyn (n=10) and wild-type (n=11) mice on the challenging beam. Errors per step (A), steps (B), and time to traverse (C) were measured. ** Indicates P<0.01 compared with similarly treated wild-type mice. ^Δ Indicates P<0.05 compared with vehicle-treated mice of the same genotype.

Fig. 2

L-DOPA (25 mg/kg) effects in Thy1-aSyn (n=10) and wild-type (n=11) mice on spontaneous activity. Rears (A), forelimb (B) and hindlimb (C) stepping, and grooming (D) were measured over three minutes. ** Indicates P<0.01 compared with similarly treated wild-type mice. ^Δ Indicates P<0.05 compared with vehicle-treated mice of the same genotype.

Fig. 3

Apomorphine (2 mg/kg) effects in Thy1-aSyn (n=10) and wild-type (n=11) mice on the challenging beam. Errors per step (A), steps (B), and time to traverse (C) were measured. ** Indicates P<0.01 compared with similarly treated wild-type mice. ^Δ Indicates P<0.05 compared with vehicle-treated mice of the same genotype.

Fig. 4

Apomorphine (2 mg/kg) effects in Thy1-aSyn (n=10) and wild-type (n=11) mice on spontaneous activity. Rears (A), forelimb (B) and hindlimb (C) stepping, and grooming (D) were measured over three minutes. ^Δ And ^ΔΔ indicate P<0.05 and 0.01 compared with vehicle-treated mice of the same genotype.

Fig. 5

Amphetamine (5 mg/kg) effects in Thy1-aSyn (n=10) and wild-type (n=11) mice on the challenging beam. Errors per step (A), steps (B), and time to traverse (C) were measured. * And ** indicate P<0.05 and 0.01 compared with similarly treated wild-type mice. ^Δ Indicates P<0.05 compared with vehicle-treated mice of the same genotype.

Fig. 6

Amphetamine (5 mg/kg) effects in Thy1-aSyn (n=10) and wild-type (n=11) mice on spontaneous activity. Rears (A), forelimb (B) and hindlimb (C) stepping, and grooming (D) were measured over three minutes. * Indicates P<0.05 compared with similarly treated wild-type mice. ^Δ And ^ΔΔ indicate P<0.05 and 0.01 compared with vehicle-treated mice of the same genotype.

Fig. 7

Amphetamine-induced stereotypies in Thy1-aSyn (n=10) and wild-type (n=11) mice. In the cylinder stereotyped behaviors such as licking, head bobbing, turning and jumping were measured in the cylinder following amphetamine (5 mg/kg). * And ** indicate P<0.05 and P<0.01, respectively compared with similarly treated wild-type mice. ^ΔΔ Indicates P<0.01 compared with vehicle-treated wild-type mice.