Neuroscience
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Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters 6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling. 6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens, olfactory tubercle and ventral tegmental area. ⋯ This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3.5 microliters of 2.5 micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induces a lesion characterized by robust drug-induced rotation, changes in binding consistent with approximately 70% dopamine denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic striatal damage and stability for at least 12 weeks. This study outlines a technique for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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This study evaluated the effect of surgical sympathectomy on pain-related behaviours in a well established model of peripheral mononeuropathy produced by loose ligatures around the common sciatic nerve in the rat. Behavioural abnormalities include spontaneous abnormal position of the hindpaw after the nerve constriction, indicative of "spontaneous pain", and changes in responses to mechanical or thermal stimuli applied to this paw. These changes are usually maximal at week 2 after the surgery, stable until weeks 3-4, and disappear between weeks 8 and 12. ⋯ In contrast, the abnormal reaction to mechanical pressure was not influenced, and the behavioural abnormalities indicating spontaneous pain were still present. Sympathectomy alone resulted in a reduction of the vocalization threshold to pressure on both hindpaws, but also a short-lasting increased tolerance to cold immersion. This study confirms the selective role of the sympathetic nervous system in affecting the development and maintenance of some abnormal pain-related behaviours to thermal stimuli in rats with a moderate, but persistent, constriction of one sciatic nerve.
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Syntaxin is a synapse-specific protein previously localized to the plasma membrane of axon terminals. Biochemical and molecular biological studies indicate a prominent role for syntaxin 1A and 1B in synaptic vesicle docking and/or fusion, suggesting that these proteins are localized to active zone regions of most terminal varicosities in the central nervous system. We sought to test this hypothesis by examining the cellular and subcellular immunocytochemical localization of syntaxin 1 proteins in the striatum and frontal cortex of rats. ⋯ These findings suggest that syntaxin is primarily contained in a subpopulation of terminals that are associated with excitatory amino acid transmitters, but appears not to be ubiquitously expressed in all terminal classes. The results further indicate that syntaxin is localized to non-synaptic regions of axon and terminal membranes, but may not be enriched in presynaptic active zones. The apparent inconsistency between the subcellular localization of syntaxin and its proposed role in vesicle exocytosis is discussed in terms of possible technical limitations and alternative functions for syntaxin.
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Guanine nucleotide-binding regulatory protein stimulation of adenylyl cyclase has been shown to be an important second messenger system for many processes, including mechanical hyperalgesia. Recently, interactions between guanine nucleotide-binding regulatory protein subunits and adenylyl cyclase affecting the level of cyclic adenosine 3',5'-monophosphate accumulation have been demonstrated. In this study we evaluated such an interaction by measuring paw-withdrawal thresholds to mechanical stimuli in Sprague-Dawley rats in the presence of two direct-acting hyperalgesic agents, prostaglandin E2 and the adenosine A2-agonist, CGS21680. ⋯ On the other hand, injection of [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin 5 min after prostaglandin E2 or CGS21680 significantly enhanced the hyperalgesia observed. Injection of the adenosine A1-agonist N6-cyclopentyladenosine immediately before and 5 min after prostaglandin E2 or CGS21680 had a similar effect to [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. The decrease in sensitivity to prostaglandin E2- and CGS21680-induced hyperalgesia by preadministration of [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin or N6-cyclopentyladenosine and the enhancement by postadministration were all reversed by pertussis toxin, an inhibitor of inhibitory guanine nucleotide-binding regulatory protein, suggesting the involvement of an inhibitory guanine nucleotide-binding regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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Angiotensin II (250 pmol) infused into the cerebral ventricles of male rats induces the expression of c-fos in the subfornical organ, supraoptic and paraventricular nuclei of the hypothalamus, as well as in the lateral parabrachial nucleus, locus coeruleus and the nucleus of the solitary tract in the brainstem. Electrolytic lesions of the anteroventral third ventricle, principally the subcommissural (ventral) median preoptic nucleus, inhibited the dipsogenic response to i.c.v. angiotensin II and also suppressed c-fos expression in supraoptic nucleus, paraventricular nucleus, lateral parabrachial nucleus, locus coeruleus and nucleus of the solitary tract but not in the subfornical organ or dorsal median preoptic nucleus. The stimulating effect of i.c.v. angiotensin II on corticosterone was also reduced. ⋯ These experiments show that the ventral median preoptic nucleus (but not the subfornical organ), part of the anteroventral third ventricle, is critical for the expression of c-fos in more caudal areas of the brain following i.c.v. angiotensin II. c-fos expression in supraoptic nucleus and paraventricular nucleus following i.v. angiotensin II is also dependent on an intact median preoptic nucleus, suggesting that supraoptic nucleus and paraventricular nucleus activation may be dependent on the median preoptic nucleus, and that suppression following i.c.v. infusions is not due to mechanical obstruction to infused peptide. However, there is a clear separation of the effects of i.c.v. and i.v. angiotensin II on brainstem structures. The median preoptic nucleus (but not the subfornical organ) seems essential for activation following the former but not the latter, suggesting alternative mechanisms for the effect of i.v. angiotension II on the brainstem.(ABSTRACT TRUNCATED AT 400 WORDS)