No abstract

No abstract

Intrastriatal injections of the mitochondrial toxto cause damage to striatum. Systemic administration ins malonate and 3-nitropropionic acid produce selective of 3-nitropropionic acid, an inhibitor of succinate decell death similar to that seen in transient ischemia and hydrogenase (complex II of the mitochondrial respiraHuntington's disease. The extent of cell death can be tory chain), selectively destroys striatal GABAergic attenuated by pharmacological or surgical blockade of projection neurons in rats (Brouillet et al., 1993). In cortical glutamatergic input. It is not known, however, if dopamine contributes to toxicity caused by inhibition of primates the same treatment causes dystonia, dyskinemitochondrial function. Exposure of primary striatal culsia, and cognitive defects (Brouillet et a!., 1995; Palfi tures to dopamine resulted in dose-dependent death of et al. , 1996), whereas accidental ingestion of the cornneurons. Addition of medium supplement containing free pound by humans produces dystonia and striatal degenradical scavengers and antioxidants decreased neuronal eration, all of which are similar to symptoms observed loss. At high concentrations of the amine, cell death was in HD patients (Ludoiph et al., 1991). Intrastriatal predominantly apoptotic. Methyl malonate was used to injections of malonate or methyl malonate cause masinhibit activity of the mitochondrial respiratory chain. Neisive neuronal death and sparing of NADPH diaphother methyl malonate (50 1zM) nor dopamine (2.5~.tM) rase-positive cells, which is also observed in HD (Beal caused significant toxicity when added individuallyto culet al., 1993; Dutra et al., 1993; Greene et a!., 1993). tures, whereas simultaneous addition of both compoundsWe have demonstrated that exposure of striatal and killed 60% of neurons. Addition of antioxidants and free radical scavengers to the incubation medium prevented cortical neurons in culture to methylmalonate results in this cell death. Dopamine (up to 250 tiM) did not alter the rapid depolarization of the plasma membrane, calcium ATP/ADP ratio after a 6-h incubation. Methyl malonate, at influx, depletion of ATP, and dose-dependent cell 500 p~M, reduced the ATP/ADP ratio by~-~30% after 6 h; death in neurons (McLaughlin et al., 1998). This death this decrease was not augmented by coincubation with was predominately apoptotic and could be attenuated 25~iM dopamine. Our results suggest that dopamine by antioxidants and free radical scavengers. 3-Nitrocauses primarily apoptotic death of striatal neurons in propionic acid also causes loss of ATP, a rise in proculture without damaging cells by an early adverse action duction and external concentration of glutamate, and on oxidative phosphorylation. However, when combined substantial apoptotic demise in vitro (Ludolph et al., with minimal inhibition of mitochondrial function, dopa-1992; Ereciñska and Nelson, 1994; Behrens et al., mine neurotoxicity is markedly enhanced.

Like the hippocampus, the striatum receives excitatory afferents from the cerebral cortex but, in the case of the striatum, very little is known about the molecular events associated with plasticity after lesions of this pathway. Using immunohistochemical techniques, we have examined the effects of cortical lesions induced either by aspiration of the frontoparietal cortex or by thermocoagulation of pial blood vessels on axonal and glial molecules associated with neuronal plasticity in the striatum. The growth associated protein GAP-43, a molecule present in axons and growth cones, decreased in the dorsolateral striatum after aspiration but not after thermocoagulatory lesions. In contrast, synaptophysin, a marker of synaptic vesicles, remained unchanged in the denervated striatum after both types of lesions. Immunostaining for basic fibroblast growth factor (bFGF) markedly decreased in striatal astrocytes after both lesions, despite an increased staining for glial fibrillary acidic protein (GFAP). The adhesion molecules tenascin, chondroitin sulfate proteoglycans, highly polysialylated neural cell adhesion molecule (PSA-NCAM), and laminin did not change significantly in the gray matter of the dorsolateral striatum after either type of lesion. These effects differed from those observed after partial denervation of the hippocampus and spinal cord, revealing marked regional differences in the response of axonal and glial proteins to afferent lesions. In addition, the results further indicate that cortical lesions have both similar and distinct consequences, depending on the procedure by which the lesions are induced, suggesting that cortical lesions associated with different types of pathology may differentially affect subcortical structures.

The distribution of the serotonin (5-HT) receptor 5-HT2C mRNA was examined at the single-cell level with in situ hybridization histochemistry and emulsion autoradiography in the basal ganglia and mesolimbic system of adult rats, with focus on the pallidum and the substantia nigra, which receive striatal inputs and play a critical role in basal ganglia function. 5-HT2C receptor mRNA expression was always restricted to a subpopulation of neurons in the regions examined. In the neostriatum, labeled neurons were more numerous in the rostral nucleus accumbens than in the caudal nucleus accumbens and were more numerous in the ventral and ventrolateral caudate-putamen than in the dorsal caudate-putamen, where labeled neurons were restricted to isolated clusters. In striatal target areas, dense labeling in the entopeduncular nucleus (internal pallidum, direct striatal output pathway) contrasted with an absence of labeling in the globus pallidus (external pallidum, indirect striatal output pathway). Double-label in situ hybridization in the substantia nigra revealed coexpression of 5-HT2C receptor mRNA with glutamic acid decarboxylase but not with tyrosine hydroxylase mRNA, indicating that it was restricted to gamma-aminobutyric acid (GABA)ergic neurons. In this region, dense labeling for 5-HT2C mRNA was found in half of the neurons at middle and caudal levels of both the pars compacta and the pars reticulata, with little labeling rostrally. The data suggest that drugs acting on the 5-HT2C receptor could selectively affect discrete neuronal populations in the basal ganglia and mesolimbic systems and indicate a new level of neurochemical heterogeneity among GABAergic neurons of the substantia nigra.