Neuroscience
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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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Comparative Study
Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments.
The nucleus accumbens septi is the major target of mesolimbic dopamine neurons originating in the ventral tegmental area of the mesencephalon. Studies involving experimental manipulation of dopamine transmission by drugs and by lesions, as well as in vivo monitoring of extracellular dopamine concentrations, have provided evidence that the dopamine transmission of the nucleus accumbens plays an important role in behaviour motivated by conventional (e.g., food, sex) and drug reinforcers. Motivated behaviour is distinguished into an appetitive (preparatory/anticipatory) phase consisting of flexible response patterns intended to search and approach the reward itself, and a consummatory phase, consisting of fixed response patterns (eating, drinking, copulating, etc.) finalized to the utilization of the biological resources of the reward (caloric, metabolic, genetic, etc.). ⋯ Unpredicted consumption of Fonzies preferentially stimulated dopamine transmission in the shell as compared to the core. Appetitive food stimuli (perforated Fonzies-filled boxes) phasically stimulated dopamine transmission in the core but not in the shell and sensitized the dopamine response to feeding in the core but inhibited that in the shell. These clear-cut differences between nucleus accumbens shell and core suggest that phasic dopamine transmission in each compartment of the nucleus accumbens subserves different roles in motivated behaviour.
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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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Comparative Study
Transgenic mice over-expressing substance P exhibit allodynia and hyperalgesia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists.
A transgenic mouse has been developed which, during development, over-expresses nerve growth factor under the control of a myelin basic protein promoter. These animals display an ectopic network of substance P-containing sensory fibers in the white matter of the spinal cord. To study the functional significance of this model to nociception, these mice were studied in a test measuring the latency to tail withdrawal from a noxious radiant heat stimulus. ⋯ The neurokinin-1 receptor antagonist CP-96,345, but not the inactive stereoisomer CP-96,344, administered subcutaneously 30 min before the 450 g stimulus, blocked the stimulation-induced allodynia in transgenic mice, and revealed a transient antinociception in transgenic and control mice. Ketamine, an N-methyl-D-aspartate receptor antagonist, given intraperitoneally 10 min before 450 g stimulation, blocked the allodynia in transgenic mice. These results indicate that these transgenic mice display hyperalgesia and allodynia, and that these nociceptive responses are reversed by substance P and N-methyl-D-aspartate receptor antagonists.
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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.