Neuroscience
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Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. ⋯ Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT-/- mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT-/- mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse.
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Comparative Study
Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures.
Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach in seizure disorders and to examine the differential mechanisms involved in opioid anti- (morphine at 0.5-3 mg/kg) versus pro-convulsant (20-100 mg/kg) effects. ⋯ However, ultra-low dose naltrexone could not increase the maximal anticonvulsant effect of morphine (1-3 mg/kg), possibly due to a ceiling effect. The proconvulsant effects of morphine on seizure threshold were minimally altered by ultra-low doses of naltrexone while being completely blocked by a higher dose (1 mg/kg) of the antagonist. The present data suggest that ultra-low doses of opioid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of opioids.
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It was recently reported that glia cell line-derived neurotrophic factor (GDNF) facilitates presynaptic axonal growth and neurotransmitter release at neuromuscular synapses. Little is known, however, whether GDNF can also act on the postsynaptic apparatus and its underlying mechanisms. Using biochemical cold blocking of existing membrane acetylcholine receptors (AchRs) and biotinylation of newly inserted receptors we demonstrate that GDNF increases the insertion of AChRs into the surface membrane of mouse primary cultured muscle cells and that this does not require protein synthesis. ⋯ GDNF may signal through c-Ret as well as NCAM-140 pathways since both the signaling receptors are expressed in the neuromuscular junction (NMJ). These data suggest that GDNF is an autocrine regulator of NMJ to promote the insertion and stabilization of postsynaptic AchRs. In vivo, GDNF may function as a synaptotrophic modulator for both pre- and postsynaptic differentiation to strengthen the functional and structural connections between nerve and muscle, and contribute to the synaptogenesis and plasticity of neuromuscular synapses.
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Previous work showed that isolation rearing produces remarkable changes in the dendritic pattern and soma of the principal neurons in the dentate gyrus and hippocampal fields CA3 and CA1 of the guinea-pig. The aim of the present study was to obtain information about the effects of early postnatal isolation on neuron morphology in field CA2, the "resistant sector" of the hippocampal formation. Male and female guinea-pigs were assigned at 6-7 days of age to either a control (social) or an isolated environment where they remained for 80-90 days. ⋯ The dendritic atrophy in field CA2 of isolated males is in line with previous evidence that males react to isolation mainly with dendritic atrophy, though field CA2 neurons appear to be less damaged than those of the other hippocampal fields. This is in line with the resistance of this field to neurodegeneration. The absence of structural changes in field CA2 of isolated females confirms, once again, that males are more liable to be endangered by early isolation than females.
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In seven freely moving squirrel monkeys (Saimiri sciureus), the neuronal activity in the periaqueductal gray (PAG) and bordering structures was registered during vocal communication, using a telemetric single-unit recording technique. In 9.3% of the PAG neurons, a vocalization-correlated activity was found. Four reaction types could be distinguished: a) neurons, showing an activity burst immediately before vocalization onset; b) neurons, firing during vocalization, and starting shortly before vocalization onset; c) neurons, firing exclusively during vocalization; d) neurons, firing in the interval between perceived vocalizations (i.e. vocalizations produced by group mates) and self-produced vocal response. ⋯ None of the neurons reflected simple acoustic parameters, such as fundamental frequency or amplitude, in its discharge rate. None of the neurons reacted to vocalizations of other animals not responded to by the experimental animal. All four reaction types found in the PAG were also found in the reticular formation bordering the PAG, though in lower density.