Fibroblast growth factor-1 within the ventral tegmental area participates in motor sensitizing effects of morphine.

Drug addiction is viewed as a form of neural plasticity, and neurotrophic factors have been implicated in many forms of plasticity in the adult nervous system. Here we show that the fibroblast growth factor-1 (FGF-1), that is expressed on dopamine and GABA neurons of the ventral tegmental area (VTA), is involved in the sensitizing effects of morphine. The receptor FGFR-1 is expressed on VTA astrocytes, as well as dopamine and GABA neurons. FGF-1 or anti-FGF-1 infusions into the VTA during the induction (not expression) phase of sensitization advanced or blocked morphine's activating motor effects respectively, in a dose-dependent manner. Infusions into the adjacent substantia nigra, whose neurons also express FGF-1 and FGFR-1, did not modify normal morphine-induced sensitization. Biochemical traits related to morphine's sensitizing effects were altered by intra-VTA anti-FGF-1 because morphine-induced upregulation of both tyrosine hydroxylase (TH) and N-methyl d-aspartate glutamate receptor 1 (NMDAR1) in the VTA was blocked after anti-FGF-1. Changes in the activation state of VTA calcium/calmodulin-dependent kinase type II seem to participate in FGF-1-induced effects as well. We conclude that the FGF-1 system of the ventral tegmental area is required for biochemical and behavioral sensitization to this drug.

Morphophysiology of the Zuckerkandl's paraganglion: effects of dexamethasone and aging.

The extra-adrenal Zuckerkandl's paraganglion is used as a source of chromaffin cells for transplantation in parkinsonian animals. Aging can affect its viability, and this tissue needs further characterization for improving grafting procedures. The objectives were: (i) to compare the main morpho-functional characteristics of prepubertal and old Zuckerkandl's paraganglion (ZP), and (ii) to discern phenotypic changes after sub-chronic dexamethasone treatment in extra-adrenal tissue of prepubertal rats. For these purposes, immunostaining methods, stereology, voltammetry, cell culture, Western blotting, and ELISA were employed. The findings revealed that all paraganglia were composed of mesenchymal tissue and chromaffin cells. In prepubertal rats, chromaffin cells are arranged as large or small clusters. Large clusters (also known as "cell nests") contain densely packed chromaffin cells, and they are seen as fascicles in longitudinal sections. In old paraganglia, cell nests disappear, and chromaffin cells are found to be arranged as small cell clusters or dispersed throughout the mesenchyma. Paraganglionic chromaffin cells possess a rounded morphology with diameter ranging from 12 to 15 µm, with intracytoplasmic granules (100-500 nm in diameter) containing catecholamines. Prepubertal and old ZP chromaffin cells are mostly noradrenergics, and a few of them are dopaminergics. Aging reduces the amount of chromaffin tissue (28% in adult rats vs. 11% in old animals, both in relation to total volume of the paraganglion), and induces the presence of adrenergic cells and adrenaline. Both prepubertal and old cells express the neurotrophic factors GDNF and TGF-ß1, aging leading to reduced levels of both growth factors. Dexamethasone (50 µg/kg daily, 5 days) leads to the expression of phenylethanolamine-N-methyl-transferase in prepubertal paraganglia, and to a higher content and release of adrenaline.

Oleoylethanolamide exerts partial and dose-dependent neuroprotection of substantia nigra dopamine neurons.

Oleoylethanolamide (OEA), agonist of nuclear PPAR-alpha receptors and antagonist of vanilloid TRPV1 receptors, has been reported to show cytoprotective properties. In this study, OEA-induced neuroprotection has been tested in vitro and in vivo models of 6-OHDA-induced degeneration of substantia nigra dopamine neurons. First, PPAR-alpha receptors were confirmed to be located in the nigrostriatal circuit, these receptors being expressed by dopamine neurons of the substantia nigra, and intrinsic neurons and fibers bundles of the dorsal striatum. In the substantia nigra, their location was confined to the ventral tier. The in vitro study showed that 1 microM OEA exerted a significantly neuroprotective effect on cultured nigral dopamine neurons, effects following U-shaped dose-response curves. Regarding the in vivo study, rats were locally injected with OEA into the right striatum and vehicle into the left striatum 30 min before 6-OHDA-induced striatal lesion. In the short term, signals of heme oxygenase-1 (oxidation marker, 24 and 48 h post-lesion) and OX6 (reactive microglia marker, 96 h post-lesion) were found to be significantly less intense in the striatum pretreated with 5 microM OEA. In the long term (1 month), reduction in striatal TH and synaptophysin was less intense whether the right striatum was pretreated with 5 microM OEA, and nigral TH+ neuron death was significantly reduced after pretreatment with 1 and 5 microM OEA. In vivo effects also followed U-shaped dose-response curves. In conclusion, OEA shows U-shaped partial and dose-dependent neuroprotective properties both in vitro and in vivo models of substantia nigra dopamine neuron degeneration. The occurrence of U-shaped dose-response relationships normally suggests toxicity due to high drug concentration or that opposing intracellular pathways are activated by different OEA doses.

Grafts of extra-adrenal chromaffin cells as aggregates show better survival rate and regenerative effects on parkinsonian rats than dispersed cell grafts.

The objective was to discern the neuroregenerative effect of grafts of extra-adrenal cells of the Zuckerkandl's paraganglion (ZP) in the nigrostriatal circuit, by using the retrograde model of parkinsonism in rats. The antiparkinsonian efficacy of two types of grafting procedures was studied (cell aggregates vs. dispersed cells), and GDNF and TGFbeta(1) (dopaminotrophic factors) as well as dopamine presence in extra-adrenal tissue was analyzed. Extra-adrenal chromaffin cells are noradrenergics, tissue dopamine is low, and they express both GDNF and TGFbeta(1). Grafts of cell aggregates, not of dispersed cells, exerted a trophic regeneration of the host striatum, leading to amelioration of motor deficits. Sprouting of spared dopaminergic fibers within the striatum, reduction of dopamine axon degeneration, and/or enhanced phenotypic expression of TH would explain striatal regeneration. Grafted cells as aggregates showed a better survival rate than dispersed cells, and they express higher levels of GDNF. Higher survivability and GDNF content together with the neurorestorative and dopaminotrophic action of both GDNF and TGFbeta(1) could account for striatal recovery and functional amelioration after grafting ZP cell aggregates. Finally, nigral degeneration and partial degeneration of ventral tegmental area were not precluded after transplantation, indicating that the trophic effect of grafts was local within the host striatum.