Neuroscience
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From a classical viewpoint, tolerance to analgesic effects of opiates refers to the decreased effectiveness of a given opiate following its repeated use. Despite much research, it has not been conclusively demonstrated in vivo that functional changes observed at the opioid receptor level in the responsiveness to opiates account for development of tolerance. An alternative hypothesis is that opioid receptors remain operative following repeated opiate administration but that opioid receptor activation rapidly induces a prolonged increase in pain sensitivity which opposes the predominant opiate analgesic effect following repeated opiate administration. ⋯ Herein we report that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold which progressively masked a sustained heroin analgesic functional effect. MK-801 prevented such opiate-induced allodynia and thereby prevented development of an apparent decrease in the effectiveness of heroin. These results indicate that intermittent heroin administration induced a persistent increase in the basal pain sensitivity which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance.
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Comparative Study
Sex and seasonal differences in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles.
In order to study the neurobiological basis of seasonal changes in hippocampal structure and function, the rate of cell proliferation was examined in male and female wild meadow voles captured during different seasons. We found that the number of [3H]thymidine-labeled cells varied across the seasons and across sex in the meadow vole. Non-breeding female meadow voles had a higher rate of cell proliferation and cell death than males captured during either season or breeding females. ⋯ Females captured during the non-breeding season had higher rates of cell proliferation in the granule cell layer than females captured during the breeding season. This seasonal fluctuation was related to hormone levels, with high levels of corticosterone and estradiol being related to lower levels of cell proliferation. These seasonal changes in cell proliferation may be related to known changes in spatial learning in the meadow vole and provide insights into changes in the hippocampus that occur in other species, including primates.
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The modulation of GABA-gated ion channel responses to GABA, pentobarbital and diazepam by muscarine was studied in freshly isolated rat dorsal root ganglion neurons using a whole-cell patch-clamp technique. Muscarine enhanced current activated by 5 microM GABA dose-dependently with an EC50 of 40 +/- 2 microM. This potentiation was not blocked by pirenzepine, gallamine and atropine, the specific and non-specific muscarinic receptor antagonists. ⋯ However, muscarine attenuated the facilitatory effect of saturating concentrations of diazepam (> 100 nM). The potentiating effect of muscarine was blocked by 1 nM ethyl-beta-carboline-3-carboxylate, the inverse agonist of benzodiazepine receptors. These results suggest that GABA-gated ion channel responses to GABA and pentobarbital were potentiated by muscarine and the binding site(s) for muscarine might be related to those for diazepam.
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Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. ⋯ Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways.
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The hippocampus has long been known to be important for memory function. However, the involvement of hippocampal dopamine systems with memory has received little attention. In the current study, dopamine D1 and D2 hippocampal receptor system involvement with memory was assessed in female Sprague-Dawley rats by local infusion of D1 and D2 agonists and antagonists into the ventral hippocampus. ⋯ This study provides clear evidence that hippocampal D2 activity is positively related to working memory performance, while evidence for D1 systems is less compelling. Dopamine D2 receptors in the ventral hippocampus were shown to have important influences on spatial working memory. In a consistent pattern of effects ventral hippocampal infusion of the D2 agonist quinpirole improved working memory performance in the radial-arm maze, while ventral hippocampal infusion of the D2 antagonist raclopride impaired performance.