The impact of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF-a (-/-) deficient mice and C57bL/6 mice were treated with MPTP (4 · 15mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF-a synthesis. Realtime RT-PCR revealed that the striatal mRNA levels of TNF-a, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex-1 (MAC-1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP-induced dopamine (DA) depletion, and TNF-a (-/-) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF-a deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild-type mice after acute MPTP treatment (4 · 20mg/kg, 2 h interval). HPLC measurement of MPP + levels revealed no differences in TNF-a (-/-), wild-type and thalidomide treated mice. This study demonstrates that TNF-a is involved in MPTP toxicity and that inhibition of TNF-a response may be a promising target for extending beyond symptomatic treatment and developing antiparkinsonian drugs for the treatment of the inflammatory processes in PD.

Recombinant adeno-associated viruses (rAAVs) can transduce several tissues, including the brain. However, in brain the duration of gene expression in different areas is variable, which has been ascribed to viral (CMV) promoter silencing in some regions over time. We have compared expression of enhanced green fluorescent protein (EGFP) in the nigrostriatal pathway of rats mediated by rAAVs containing the CMV or platelet-derived growth factor-␤ chain (PDGF-␤) promoter. In addition, we studied the effects of the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) on transgene expression in vivo. The rAAV vectors containing the neuron-specific PDGF-␤ chain promoter transduced significantly more dopaminergic neurons than

No abstract

Extracellular single-unit recordings were used to assess the effects of PCP and PCP-like drugs (MK-801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (+/-)CPP, and to BTCP, a PCP-derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK-801, and TCP produced dose-dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 197555 and (+/-)CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP-like drugs, and the resultant hyperdopaminergia within the mesolimbic-mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists.

We investigated spatial learning in rats with unilateral and bilateral lesions of the nigrostriatal dopaminergic system. We used the Morris water maze paradigm, which tests spatial forms of learning and memory and allows discrimination between sensory-motor and learning disabilities. Animals were trained preoperatively to learn the location of a spatially fixed hidden platform to escape from the swimming pool (acquisition training). A visual and a probe test were used before and after the acquisition training, respectively. Our results show that animals with unilateral lesions, although displaying longer escape latencies, have normal spatial memory abilities. Animals with bilateral lesions were able to swim as fast or even faster than animals with unilateral lesion. Despite the fact that these animals had learned the spatial navigation tasks preoperatively, bilateral dopaminergic lesions led to a profound deficit in ability to find a hidden platform during an acquisition task. In general, animals with bilateral lesions persisted in swimming along the pool walls and their spatial navigation performance during a probe test was very poor. These results suggest that deficit of the nigrostriatal dopaminergic system can affect the selection and maintenance of behavioral strategies in spatial navigation.