1,721,007 research outputs found
Neuronal nicotinic receptor alpha6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain.
No full textAlthough the neuronal nicotinic receptor alpha 6 subunit was cloned several years ago, its functional significance remains to be investigated. Here we describe an in situ hybridization study of the mRNA for this subunit in the adult rat central nervous system using oligonucleotide probes. Specific alpha 6 mRNA labelling was restricted to a few nuclei throughout the brain; it was particularly high in several catecholaminergic nuclei [the locus coeruleus (A6), the ventral tegmental area (A10) and the substantia nigra (A9)] at levels significantly higher than those found for any other known nicotinic receptor subunit mRNA. Labelling for alpha 6 mRNA was also detected at lower levels in the reticular thalamic nucleus, the supramammillary nucleus and the mesencephalic V nucleus. Some cells of the medial habenula (medioventral part) and of the interpeduncular nucleus (central and lateral parts) were also labelled. The distribution of alpha 6 mRNA was compared with the distribution of the other known nicotinic acetylcholine receptor subunit mRNAs. In several nuclei, the expression of alpha 6 was complementary to those of other alpha subunits. Moreover, some of the cell groups (such as the substantia nigra, the ventral tegmental area and the locus coeruleus) previously thought to contain mainly alpha 3 mRNA in fact were found to contain high levels of alpha 6 mRNA. Finally, we found extensive colocalization of alpha 6 and beta 3, indicating the possible existence of nicotinic receptor hetero-oligomers containing both subunits. The present results show that alpha 6 is the major nicotinic acetylcholine receptor alpha subunit expressed in dopaminergic cell groups of the mesencephalon and noradrenergic cells of the locus coeruleus. This suggests the involvement of the alpha 6 subunit in some of the major functions of central nicotinic circuits, including the modulation of locomotor behaviour and reward
Effects of nicotine injections on messenger RNAs encoding proteins involved in transmission in the mesostriatum dopaminergic system
No full textPromoter elements conferring neuron specific expression of the b2 subunit of the neuronal nicotinic acetylcholine receptor studied in vitro and in transgenic mice.
No full textSeveral genes encoding subunits of the neuronal nicotinic acetylcholine receptors have been cloned and regulatory elements involved in the transcription of the alpha 2 and alpha 7-subunit genes have been described. Yet, the detailed mechanisms governing the neuron-specific transcription and the spatio-temporal expression pattern of these genes remain largely uninvestigated. The beta 2-subunit is the most widely expressed neuronal nicotinic receptor subunit in the nervous system. We have studied the structural and regulatory properties of the 5' sequence of this gene. A fragment of 1163 bp of upstream sequence is sufficient to drive the cell-specific transcription of a reporter gene in both transient transfection assays and in transgenic mice. Deletion analysis and site-directed mutagenesis of this promoter reveal two negative elements and one positive element. The positively-acting sequence includes one functional E-box. One of the repressor elements is located in the transcribed region and is the NRSE/RE1 sequence already described in promoters of neuronal genes. In this paper, we describe the neuron-specific promoter of the gene encoding the neuronal nicotinic acetylcholine receptor beta 2-subunit
Developmental regulation of nicotinic receptor subunit mRNAs in the rat central and peripheral nervous systems.
No full textIn the present study we have investigated the anatomical distribution pattern of nAChR alpha 3, alpha 4, beta 2, and beta 4 subunit mRNAs during prenatal and perinatal development of the rat CNS and PNS. Three main developmental patterns have been recognized. (1) In the majority of cases studied (caudal brain, spinal cord, dorsal root ganglia, trigeminal and geniculate ganglia) all four subunit mRNAs are initially (E11-13) detected but, during subsequent prenatal development, the level of some of these subunit mRNAs (alpha 3 and beta 4 in the brain and spinal cord, alpha 4 and beta 4 in the dorsal root ganglia, alpha 4 in the visceral sensory ganglia, and alpha 3, alpha 4, and beta 4 in the somatic sensory ganglia) become undetectable. (2) In the case of the cerebral cortex a pair of subunit mRNAs (alpha 3-beta 2) is initially (E12-13) expressed followed by a repression of the alpha 3 subunit (E15) and the subsequent (E17-19) induction of the alpha 4 subunit. (3) Only some subunit mRNAs are initially (E13-15) expressed in the retina (alpha 3-alpha 4-beta 2-beta 4), parasympathetic or sympathetic motor ganglia (alpha 3-beta 2-beta 4), and vestibulo-cochlear ganglia (alpha 4-beta 2) and their level remains stable throughout prenatal and early postnatal development. Overall, in most central and peripheral structures the appearance of nAChR subunit mRNAs is precocious and temporally related to the timing of neuronal differentiation. In addition, in several structures the expression of certain subunits (alpha 3, alpha 4 or beta 4) is transient, although not beta 2. Finally, the comparison of the different regional distribution patterns suggests that a limited number of structure-specific receptor isoforms are functional during development of CNS and PNS
Involvement of alpha 6 nicotinic receptor subunit in nicotine-elicited locomotion, demonstrated by in vivo antisense oligonucleotide infusion
No full textENHANCED locomotion in a habituated environment is a well documented effect of nicotine mediated by the mesotelencephalic dopaminergic system. The nicotinic receptor subunit alpha 6 is, among other subunits, strongly expressed in the dopaminergic neurons of the mesencephalon. To examine the functional role of this subunit, we inhibited its expression in vivo using antisense oligonucleotides. lit vitro treatments of embryonic mesencephalic neuron cultures demonstrated that the alpha 6 antisense oligonucleotides caused a marked decrease in the level of alpha 6 subunit protein. In vivo, 1 week infusion of alpha 6 antisense oligonucleotides by osmotic mini-pump reduced the effect of nicotine on locomotor activity in habituated environment by 70%. These data support the notion that the effects of nicotine on the dopaminergic system involve alpha 6 subunit containing nAChRs
Localization of nAChR subunit mRNAs in the brain of Macaca mulatta.
No full textWe present here a systematic mapping of nAChR subunit mRNAs in Macaca mulatta brain. A fragment, from the transmembrane segments MIII to MIV of Macaca neuronal nAChR subunits was cloned, and shown to exhibit high identity (around 95%) to the corresponding human subunits. Then, specific oligodeoxynucleotides were synthesized for in situ hybridization experiments. Both alpha4 and beta2 mRNA signals were widely distributed in the brain, being stronger in the thalamus and in the dopaminergic cells of the mesencephalon. Most brain nuclei displayed both alpha4 and beta2 signals with the exception of some basal ganglia regions and the reticular thalamic nucleus which were devoid of alpha4 signal. alpha6 and beta3 mRNA signals were selectively concentrated in the substantia nigra and the medial habenula. The strongest signals for alpha3 or beta4 mRNAs were found in the epithalamus (medial habenula and pineal gland), whereas there were no specific alpha3 or beta4 signals in mesencephalic dopaminergic nuclei. alpha5 and alpha7 mRNA signals were found in several brain areas, including cerebral cortex, thalamus and substantia nigra, although at a lower level than alpha4 and beta2. The distribution of alpha3, alpha4, alpha5, alpha6, alpha7, beta2, beta3 and beta4 subunit mRNAs in the monkey is substantially similar to that observed in rodent brain. Surprisingly, alpha2 mRNA signal was largely distributed in the Macaca brain, at levels comparable with those of alpha4 and beta2. This observation represents the main difference between rodent and Macaca subunit mRNA distribution and suggests that, besides alpha4beta2*, alpha2beta2* nAChRs constitute a main nAChR isoform in primate brain
Neuronal nicotinic acetylcholine receptor: From gene to smoking addiction
No full textThe nicotinic acetylcholine receptor present in muscle is an allosteric pentameric protein and has been used as a model for the structure and function of the superfamily of ligand gated ion channels. A related family of receptors is localized in the nervous system. These receptors, which are composed of two alpha subunits that are chiefly responsible for the binding of acetylcholine and three non-alpha subunits, mediate neuronal nicotinic neurotransmission. To date, ten genes have been isolated encoding subunits of the neuronal nicotinic receptor expressed in various brain regions. The electrophysiological and pharmacological properties of the neuronal nicotinic receptors are dependent upon the subunit composition of the receptor, and can be modified by innervation as well as by agents such as calcium and cAMP. The expression of the receptor can be altered as a result of diverse neuronal pathologies
Facile: a command-line network compiler for systems biology
Full text linkA goal of systems biology is the quantitative modelling of biochemical networks. Yet for many biochemical systems, parameter values and even the existence of interactions between some chemical species are unknown. It is therefore important to be able to easily investigate the effects of adding or removing reactions and to easily perform a bifurcation analysis, which shows the qualitative dynamics of a model for a range of parameter values
Brain nicotinic receptors: structure and regulation, role in learning and reinforcement.
Full text linkThe introduction, in the late sixties, of the concepts and methods of molecular biology to the study of the nervous system had a profound impact on the field, primarily through the identification of its basic molecular components. These structures include, for example, the elementary units of the synapse: neurotransmitters, neuropeptides and their receptors, but also ionic channels, intracellular second messengers and the relevant enzymes, cell surface adhesion molecules, or growth and trophic factors [21,78,81, 52,79]. Attempts to establish appropriate causal relationships between these molecular components, the actual organisation of neural networks, and a defined behavior, nevertheless, still must overcome many difficulties. A first problem is the recognition of the minimum levels of organisation, from the molecular, cellular, or multicellular (circuit) to the higher cognitive levels, that determine the given physiological and/or behavioral performance under investigation. A common difficulty (and potential source of errors of interpretation) is to relate a cognitive function to a network organization which does not possess the required structural complexity and vice-versa. Another problem is to distinguish, among the components of the system, those which are actually necessary and those which, taken together, suffice for a given behavior to take place. Identification of such a minimal set of building blocks may receive decisive insights from the elaboration of neurally plausible formal models that bring together, within a single and coherent 'artificial organism', the neuronal network, the circulating activity, and the behavior they determine (see [42,43,45,72,30]). In this communication, we shall attempt, still in a preliminary fashion, to bring together: (1) our recent knowledge on the molecular biology of brain nicotinic receptors (nAChRs) and their allosteric properties and (2) integrated behaviors, such as cognitive learning, investigated for instance with delayed-response or passive avoidance tasks that are likely to involve nAChRs in particular at the level of reinforcement (or reward) mechanisms (see [18,29,135])
Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain
No full textNicotine affects many aspects of behaviour including learning and memory through its interaction with neuronal nicotinic acetylcholine receptors (nAChR). Functional nAChRs are pentameric proteins containing at least one type of alpha-subunit and one type of beta-subunit. The involvement of a particular neuronal nicotinic subunit in pharmacology and behaviour was examined using gene targeting to mutate beta 2, the most widely expressed nAChR subunit in the central nervous system. We report here that high-affinity binding sites for nicotine are absent from the brains of mice homozygous for the beta 2-subunit mutation. Further, electrophysiological recording from brain slices reveals that thalamic neurons from these mice do not respond to nicotine application. Finally, behavioural tests demonstrate that nicotine no longer augments the performance of beta 2-1- mice on passive avoidance, a test of associative memory. Paradoxically, mutant mice are able to perform better than their non-mutant siblings on this task
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