Partial depletion of dopamine in substantia nigra impairs motor performance without altering striatal dopamine neurotransmission

Abstract

Previous data indicate that the release of somatodendritic dopamine in substantia nigra influences motor activity and coordination, but the relative importance of somatodendritic dopamine release vs. terminal striatal dopamine release remains to be determined. We utilized simultaneous measurement of dopamine neurotransmission by microdialysis and motor performance assessment by rotarod test to investigate the effects of local dopamine depletion in rats. The vesicular monoamine transporter inhibitor tetrabenazine (100 microm) was administered locally in substantia nigra as well as in striatum. Nigral tetrabenazine administration decreased nigral dopamine dialysate concentrations to 7% of baseline and whole-tissue dopamine content by 60%. Nigral dopamine depletion was associated with a reduction in motor performance to 73 +/- 6% of pretreatment value, but did not alter dialysate dopamine concentrations in the ipsilateral striatum. Striatal tetrabenazine administration decreased striatal dopamine dialysate concentrations to 5% of baseline and doubled the somatodendritic dopamine response to motor activity, but it was not associated with changes in motor performance or dopamine content in striatal tissue. Simultaneous treatment of substantia nigra and striatum reduced motor performance to 58 +/- 5% of the pretreatment value. The results of this study indicate that partial depletion of nigral dopamine stores can significantly impair motor functions, and that increased nigral dopamine release can counteract minor impairments of striatal dopamine transmission.

Objective and quantitative evaluation of motor function in a monkey model of Parkinson's disease

“…Observations in 6-hydroxydopamine (6-OHDA)-treated rats showed that CFT binding in the striatum reflected the number of nigral DA neurons more directly than that in the SN (Forsback et al, 2004), suggesting that DAT in the SN might be associated with a compensatory response to DA cell injuries. In another rodent study, the effect of DA depletion on motor performance was more evident when toxins were locally applied to SN than when applied to the striatum (Andersson et al, 2006). Taken together, our results suggest that changes in somatodendritic DAT in SN have a pivotal plastic function in motor performance, and that this function is distinct from the nigro-striatal DA system.…”

“…The treatment of monkeys with MPTP has become the most successful primate model of human neurodegenerative disease. This treatment evokes a persistent syndrome in the monkey and produces virtually all of the cardinal behavioral, biochemical, and histological changes that occur within the DA system in PD (Andersson et al, 2006;Burns et al, 1983). Furthermore, most of the current anti-parkinsonism therapies were tested for efficacy and approved based on this model.…”

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

“…As dopamine released from the substantia nigra is critical for motor behaviors and striatally driven behaviors (Andersson et al, 2006), it may be difficult to completely dissociate motoric components of dopamine neurotransmission and D1/5 receptor activation from expression of the motor behaviors associated with aversive and reward learning (Chausmer and Katz, 2002;Diaz Heijtz and Castellanos, 2006). It is possible that even a subtle effect of D1/5 activation on locomotion could influence the effects on behavior.…”

Dendritic Release of Neurotransmitters

“…The action of dendritically released dopamine on D1 dopamine receptors in the terminals of the striatonigral direct pathway enhances GABA release from axons in the SNr, thereby amplifying inhibition of the principal cells of the SNr (149, 192, 239). Through these pathways, somatodendritic, as well as axonal dopamine release regulates motor behavior (3, 15, 45, 56, 141, 200, 212, 233). …”