Abstract Title

Inhibition of tyrosine hydroxylase in substantia nigra, but not striatum, reduces locomotor activity in an open-field.

Presenter Name

Michael F. Salvatore

RAD Assignment Number

1520

Abstract

Background: The risk of locomotor impairment increases substantially during aging. There are two primary sources of locomotor impairment; aging-related Parkinsonism and Parkinson’s disease (PD). One of the three cardinal symptoms of PD is bradykinesia, which is also observed in aging-related Parkinsonism. The neurobiological basis for the manifestation of bradykinesia in PD is associated with >70% loss of dopamine (DA) in the striatum, the terminal field compartment of the nigrostriatal pathway. Coincident with bradykinesia onset in PD, others have reported 40-50% DA loss in the substantia nigra (SN), the somatodendritic compartment of this pathway. While this degree of DA loss occurs in SN in aging, DA loss in striatum has never been reported to reach 70%. We have previously shown in young male rats that DA tissue content can be specifically reduced in either DA compartment to levels previously reported in aging studies with direct delivery of the tyrosine hydroxylase (TH) inhibitor, α-methyl-p-tyrosine (AMPT) in either striatum or SN. Hypothesis: We tested the hypothesis that DA reduction in the SN alone would be sufficient to reduce locomotor activity. Methods: To ensure that locomotor function would be devoid of aging-related confounds to locomotor performance, 6 month old Brown-Norway Fischer 344 F1 rats were used. To selectively reduce DA tissue content in either striatum or SN, rats were first anesthetized to implant double guide cannula to target striatum (+1.0 AP, 2.5 ML, 5.0 DV) or the SN (-5.7 AP, 2.5 ML, 7.5 DV). Following recovery, rats were placed into an open-field for three hour sessions immediately following infusion of saline or AMPT on a different day. This was repeated 5 times to acquire locomotor activity following saline or AMPT infusion. Results: Infusion of a quantity of 1.4 nmole AMPT into the SN, but not striatum, produced a significant decrease in open-field locomotor activity out to 2 hours past infusion. Infusion of 14 nmole AMPT into striatum did not produce significant decreases in open-field locomotor activity. Conclusions: The inhibition of TH activity in the SN, but not striatum, reduces open-field locomotor activity in young rats. This inhibition has been previously reported to reduce DA in SN or striatum to levels comparable seen with aging. Therefore, TH function in the SN may be a molecular component in the ability to initiate locomotor activity.

Presentation Type

Poster

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Inhibition of tyrosine hydroxylase in substantia nigra, but not striatum, reduces locomotor activity in an open-field.

Background: The risk of locomotor impairment increases substantially during aging. There are two primary sources of locomotor impairment; aging-related Parkinsonism and Parkinson’s disease (PD). One of the three cardinal symptoms of PD is bradykinesia, which is also observed in aging-related Parkinsonism. The neurobiological basis for the manifestation of bradykinesia in PD is associated with >70% loss of dopamine (DA) in the striatum, the terminal field compartment of the nigrostriatal pathway. Coincident with bradykinesia onset in PD, others have reported 40-50% DA loss in the substantia nigra (SN), the somatodendritic compartment of this pathway. While this degree of DA loss occurs in SN in aging, DA loss in striatum has never been reported to reach 70%. We have previously shown in young male rats that DA tissue content can be specifically reduced in either DA compartment to levels previously reported in aging studies with direct delivery of the tyrosine hydroxylase (TH) inhibitor, α-methyl-p-tyrosine (AMPT) in either striatum or SN. Hypothesis: We tested the hypothesis that DA reduction in the SN alone would be sufficient to reduce locomotor activity. Methods: To ensure that locomotor function would be devoid of aging-related confounds to locomotor performance, 6 month old Brown-Norway Fischer 344 F1 rats were used. To selectively reduce DA tissue content in either striatum or SN, rats were first anesthetized to implant double guide cannula to target striatum (+1.0 AP, 2.5 ML, 5.0 DV) or the SN (-5.7 AP, 2.5 ML, 7.5 DV). Following recovery, rats were placed into an open-field for three hour sessions immediately following infusion of saline or AMPT on a different day. This was repeated 5 times to acquire locomotor activity following saline or AMPT infusion. Results: Infusion of a quantity of 1.4 nmole AMPT into the SN, but not striatum, produced a significant decrease in open-field locomotor activity out to 2 hours past infusion. Infusion of 14 nmole AMPT into striatum did not produce significant decreases in open-field locomotor activity. Conclusions: The inhibition of TH activity in the SN, but not striatum, reduces open-field locomotor activity in young rats. This inhibition has been previously reported to reduce DA in SN or striatum to levels comparable seen with aging. Therefore, TH function in the SN may be a molecular component in the ability to initiate locomotor activity.