Neuroscience
-
Functional loss after spinal cord injuries is originated by primary and secondary injury phases whose underlying mechanisms include massive release of excitatory amino acids to cytotoxic levels that contribute to neural death. Attenuation of this excitotoxicity is a key point for improving the functional outcome after injury. One of the drugs with potential neuroprotective actions is FK506, a molecule widely used as an immunosuppressant. ⋯ In contrast, the combination of both agents led to a transient reduction in Hsp70 levels in parallel to a marked reduction in IL-1beta precursor production by glial cells. The use of geldanamycin, which promotes persistent induction of Hsp70 in these cells as well as in motoneurons, did not produce tissue neuroprotection. These observations suggest that FK506 might protect spinal cord tissue by targeting on microglial cells and that transient downregulation of Hsp70 on these cells after excitotoxicity is a relevant mechanism of action of FK506.
-
Dysfunction of basal ganglia circuits underlies a variety of movement disorders and neuropsychiatric conditions. Selective control of the electrical activity of striatal outflow pathways by manipulation of ion channel function presents a novel therapeutic approach. Toward this end, we have constructed and studied in vitro an adenoviral gene transfer vector that employs the promoter region of the dopamine-1 receptor to drive expression of the inward rectifier K(+) channel Kir2.3. ⋯ Current clamp studies of transduced striatal neurons demonstrated an increase in the firing threshold, latency to first action potential and decrease in neuronal excitability. Neurotoxin-induced activation of c-Fos, a marker of neuronal activity, was blocked in transduced neurons indicating that the decrease in electrical excitability was physiologically significant. When used in vivo, this strategy may have the potential to positively impact movement disorders by selectively changing activity of neurons belonging to the direct striatal pathway, characterized by the expression of dopamine-1 receptors.
-
Comparative Study
Cortical dopaminergic innervation among humans, chimpanzees, and macaque monkeys: a comparative study.
In this study, we assessed the possibility that humans differ from other primate species in the supply of dopamine to the frontal cortex. To this end, quantitative comparative analyses were performed among humans, chimpanzees, and macaques using immunohistochemical methods to visualize tyrosine hydroxylase-immunoreactive axons within the cerebral cortex. Axon densities and neuron densities were quantified using computer-assisted stereology. ⋯ Analysis of axon length density to neuron density among species revealed that humans and chimpanzees together deviated from macaques in having increased dopaminergic afferents in layers III and V/VI of areas 9 and 32, but there were no phylogenetic differences in area 4. Finally, morphological specializations of axon coils that may be indicative of cortical plasticity events were observed in humans and chimpanzees, but not macaques. Our findings suggest significant modifications of dopamine's role in cortical organization occurred in the evolution of the apes, with further changes in the descent of humans.
-
Previous investigations with 3,4-methylenedioxymethamphetamine (MDMA) have suggested that administration of this drug results in a degeneration of 5-HT nerve terminals and subsequent alterations in 5-HT neurotransmission. However, only limited investigations have examined the effects of MDMA on the dorsal raphe nucleus. The present study was designed to assess the effect of MDMA on the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), by measuring TPH2 protein and mRNA levels in rat dorsal raphe (DR) nucleus. ⋯ MDMA treatment significantly decreased (125)I-RTI-55 labeled SERT binding sites in the striatum, nucleus accumbens and cingulate cortex demonstrating a loss of 5-HT terminals. The increase in TPH2 mRNA levels in both the mid DR and caudal DR of MDMA-treated rats may reflect a compensatory mechanism in the injured 5-HT neurons to increase TPH2 protein synthesis. Taken together, our results suggest that a serious defect occurs in the biosynthesis of TPH2 in the DR following MDMA administration.
-
The rewarding effects of cocaine have been reported to occur within seconds of administration. Extensive evidence suggests that these actions involve the ability of cocaine to inhibit the dopamine (DA) transporter. We recently showed that 1.5 mg/kg i.v. cocaine inhibits DA uptake within 5 s. ⋯ Further, the blood-brain barrier impermeant cocaine-methiodide had no effect on DA uptake or peak height, indicating that the generalized peripheral effects of cocaine do not contribute to the CNS alterations measured here. Finally, we show that GBR-12909 (0.75, 1.5, and 3.0 mg/kg) also significantly inhibited DA uptake within 5 s post-injection, although the peak effect and return to baseline were markedly delayed compared with cocaine, particularly at the highest dose. Combined, these observations indicate that the central effects of dopamine uptake inhibitors occur extremely rapidly following i.v. drug delivery.