Robin Lester
University of Alabama at Birmingham, Neurobiology, Faculty Member
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It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing a4b2... more
It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing a4b2 receptors were chronically incubated (24-48 hr) in nicotine, and the resulting changes in specific ( 3H)nicotine binding to surface receptors on intact oocytes were compared with functional receptor desen- sitization.
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ABSTRACT
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Much of the addictive power of nicotine in humans may be attributable to learned contextual associations, such that these secondary cues become potent predictive incentives for both maintaining and driving relapse to drug use, even after... more
Much of the addictive power of nicotine in humans may be attributable to learned contextual associations, such that these secondary cues become potent predictive incentives for both maintaining and driving relapse to drug use, even after long periods of abstinence. Here, I review the evidence that chronic nicotine in vivo can induce persistent neuronal changes in excitability within the hippocampal circuitry, with a specific emphasis on the dentate gyrus as an initiator of drug use. The relevance of these early homeostatic (can be fully reversed by acute application of nicotine) neuroadaptations on withdrawal from nicotine is then related to known cognitive deficits also produced following chronic nicotine. I briefly discuss how the hippocampus may influence other parts of the reward circuitry to affect chronic drug use and how periods of drug cessation and/or withdrawal may convert these short-term changes into permanent alterations within the brain that may drive craving and/or re...
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We have compared the kinetic properties of NMDA receptor channels activated by exogenous agonists with those activated synaptically. Short (4 msec) applications of L-glutamate to outside-out patches from hippocampal neurons evoked... more
We have compared the kinetic properties of NMDA receptor channels activated by exogenous agonists with those activated synaptically. Short (4 msec) applications of L-glutamate to outside-out patches from hippocampal neurons evoked currents that decayed with a double exponential time course that was controlled by both the unbinding rate of agonist and receptor desensitization. Lower-affinity agonists evoked NMDA receptor-activated currents that had faster rates of decay and recovered from desensitization more quickly, consistent with the idea that agonists which dissociate faster allow the receptor to reach a desensitized state less often. Both synaptic and patch responses could be well fitted with a simple kinetic model comprised of two independent but identical binding sites, one open state, one closed state, and one desensitized state, all doubly liganded. Provided that the agonist has a slow unbinding rate relative to the rates into the open and desensitized states (e.g., L-gluta...
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Alterations in nicotinic acetylcholine (nAChR) receptor number can be induced by chronic exposure to nicotine possibly by stabilization of the desensitized state(s) of the receptor. Since within the central nervous system (CNS), many... more
Alterations in nicotinic acetylcholine (nAChR) receptor number can be induced by chronic exposure to nicotine possibly by stabilization of the desensitized state(s) of the receptor. Since within the central nervous system (CNS), many nAChRs are localized presynaptically, we have investigated the physiological consequences of prolonged nicotine applications on spontaneous transmitter release. In the presence of glutamate receptor antagonists, bicuculline-sensitive spontaneous GABA inhibitory synaptic currents (IPSCs) could be readily resolved in whole-cell recordings from neurons in the interpeduncular nucleus (IPN) maintained as brain slices. Nicotine (300nM) caused a marked enhancement in the frequency of spontaneous events. During a 15min exposure to nicotine, the time course of changes in IPSC frequency could be divided into two groups. In most neurons, there was a fast increase in event frequency followed by a decline to a lower steady-state level that remained above baseline. I...
Research Interests: Cognitive Science, Addiction, Developmental neuroscience, Information Processing, Nicotine, and 15 moreAnimals, Central Nervous System, Acetylcholine, Synaptic Transmission, Developmental, Steady state, Rats, Tetrodotoxin, Desensitization, Neurosciences, Glutamic Acid, Time Course, Glutamate Receptor, Mesencephalon, and Tobacco use disorder
The interactions between the glycine and glutamate binding sites of the NMDA receptor have been studied in outside-out patches and synapses from hippocampal neurons in culture using rapid drug application techniques. Desensitization of... more
The interactions between the glycine and glutamate binding sites of the NMDA receptor have been studied in outside-out patches and synapses from hippocampal neurons in culture using rapid drug application techniques. Desensitization of NMDA receptor-mediated currents elicited by glutamate in newly excised outside-out patches was reduced in the presence of saturating concentrations of glycine. This suggests that the glutamate and glycine binding sites of the NMDA receptor are allosterically coupled as has been reported in whole-cell preparations. A glycine-insensitive form of desensitization increased rapidly over the first few minutes of recording and largely occluded the glycine concentration-sensitive desensitization in outside-out patches. However, even in old patches that displayed no glycine-sensitive desensitization, the unbinding rate of glycine was increased fourfold by the presence of glutamate, suggesting that the two binding sites were still allosterically coupled. These ...
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The behavior of nicotinic acetylcholine receptor (nAChR) channels in acutely isolated habenula neurons was examined by rapidly applying nicotinic agonists to outside-out membrane patches. At negative membrane potentials, applications of... more
The behavior of nicotinic acetylcholine receptor (nAChR) channels in acutely isolated habenula neurons was examined by rapidly applying nicotinic agonists to outside-out membrane patches. At negative membrane potentials, applications of 100 microM nicotine routinely produced macroscopic currents due to the opening of a large number of channels. During the continuous application of the agonist, the number of open nAChR channels decreased exponentially, i.e. receptor desensitization. A progressive loss in the number of channels contributing to the peak current was observed with time following outside-out patch excision, i.e. receptor rundown. In addition to rundown there was a time-dependent increase in the rate of desensitization and a concomitant slowing in the rate of recovery from desensitization. The extent of rundown and the changes in desensitization were coupled to the time after patch excision and were not dependent on ligand activation of nicotinic channels.
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1. The involvement of N-methyl-D-aspartate (NMDA) receptors in the response to single-shock (0.033 Hz) stimulation of the Schaffer collateral-commissural pathway in hippocampal slices has been investigated using current- and voltage-clamp... more
1. The involvement of N-methyl-D-aspartate (NMDA) receptors in the response to single-shock (0.033 Hz) stimulation of the Schaffer collateral-commissural pathway in hippocampal slices has been investigated using current- and voltage-clamp techniques. 2. In the presence of Mg2+ (1 or 2 mM) at membrane potentials near rest, the selective NMDA antagonist D-2-amino-5-phosphonovalerate (APV) had no effect on the excitatory postsynaptic potential (EPSP) and the biphasic inhibitory postsynaptic potential (IPSP) evoked by Schaffer collateral-commissural stimulation. The recurrent IPSP evoked by antidromic stimulation of alvear fibres was also unaffected by APV. 3. The introduction of a Mg2+-free perfusate led, at high stimulus intensity, to an orthodromically evoked epileptiform discharge but little change in the recurrent IPSP. APV suppressed a large proportion of the enhanced response in Mg2+-free perfusate. 4. EPSPs and excitatory postsynaptic currents (EPSCs) evoked in Mg2+-free perfusa...
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Excitatory synaptic transmission in the central nervous system relies predominantly on stimulation of L-glutamate-gated ion channels in postsynaptic membranes. Activation of these channels not only mediates millisecond to millisecond... more
Excitatory synaptic transmission in the central nervous system relies predominantly on stimulation of L-glutamate-gated ion channels in postsynaptic membranes. Activation of these channels not only mediates millisecond to millisecond signalling but can also have long term influences on synaptogenesis and synaptic plasticity. Recent work has resolved some longstanding problems involving the identity of the transmitter, the postsynaptic localization of the receptor subtypes, and the time course of the transmitter in the synaptic cleft.
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... In the rat hippocampus, presynaptic 7-containing nAChRs were shown to initiate a calcium signal that increases glutamate release from presynaptic terminals (Gray et al., 1996; Dani, 2001). The calcium-sensitive dye, Fura-2, was... more
... In the rat hippocampus, presynaptic 7-containing nAChRs were shown to initiate a calcium signal that increases glutamate release from presynaptic terminals (Gray et al., 1996; Dani, 2001). The calcium-sensitive dye, Fura-2, was introduced into the presynaptic terminals in the ...
It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing a4b2... more
It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing a4b2 receptors were chronically incubated (24-48 hr) in nicotine, and the resulting changes in specific ( 3H)nicotine binding to surface receptors on intact oocytes were compared with functional receptor desen- sitization.
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Research Interests: Genetics, Drug interactions, Memory, Insecticides, Hippocampus, and 15 moreHumans, Insect Resistance, Nicotine, Animals, Ethanol, Nicotinic Acetylcholine Receptors, Animal Model, Neurons, Pest control, Mechanism of action, Anthelmintics, Point of View, Action Selection, Adverse effect, and Pharmacology and pharmaceutical sciences
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Alpha7 nicotinic acetylcholine receptors (nAChRs) modulate network activity in the CNS. Thus, functional regulation of alpha7 nAChRs could influence the flow of information through various brain nuclei. It is hypothesized here that these... more
Alpha7 nicotinic acetylcholine receptors (nAChRs) modulate network activity in the CNS. Thus, functional regulation of alpha7 nAChRs could influence the flow of information through various brain nuclei. It is hypothesized here that these receptors are amenable to modulation by tyrosine phosphorylation. In both Xenopus oocytes and rat hippocampal interneurons, brief exposure to a broad-spectrum protein tyrosine kinase inhibitor, genistein, specifically and reversibly potentiated alpha7 nAChR-mediated responses, whereas a protein tyrosine phosphatase inhibitor, pervanadate, caused depression. Potentiation was associated with an increased expression of surface alpha7 subunits and was not accompanied by detectable changes in receptor open probability, implying that the increased function results from an increased number of alpha7 nAChRs. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated exocytosis was shown to be a plausible mechanism for the rapid delivery of additional alpha7 nAChRs to the plasma membrane. Direct phosphorylation/dephosphorylation of alpha7 subunits was unlikely because mutation of all three cytoplasmic tyrosine residues did not prevent the genistein-mediated facilitation. Overall, these data are consistent with the hypothesis that the number of functional cell surface alpha7 nAChRs is controlled indirectly via processes involving tyrosine phosphorylation.
Research Interests: Neuroscience, Drug interactions, Enzyme Inhibitors, Hippocampus, Mutagenesis, and 15 moreInsulin, Animals, Nicotinic Acetylcholine Receptors, Acetylcholine, Phosphorylation, Rats, Radioligand Assay, Genistein, Oocytes, Choline, Interneurons, Biotinylation, Psychology and Cognitive Sciences, Protein tyrosine kinases, and Medical and Health Sciences
Research Interests: Neuroscience, Patch-clamp and imaging techniques, Hippocampus, Nicotine, Animals, and 11 moreMale, The, Rats, Time Factors, Tetrodotoxin, Action Potentials, Excitatory Postsynaptic Potentials, Psychology and Cognitive Sciences, Sodium channel blockers, Medical and Health Sciences, and In Vitro Techniques
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The peak concentration and rate of clearance of neurotransmitter from the synaptic cleft are important determinants of synaptic function, yet the neurotransmitter concentration time course is unknown at synapses in the brain. The time... more
The peak concentration and rate of clearance of neurotransmitter from the synaptic cleft are important determinants of synaptic function, yet the neurotransmitter concentration time course is unknown at synapses in the brain. The time course of free glutamate in the cleft was estimated by kinetic analysis of the displacement of a rapidly dissociating competitive antagonist from N-methyl-D-aspartate (NMDA) receptors during synaptic transmission. Glutamate peaked at 1.1 millimolar and decayed with a time constant of 1.2 milliseconds at cultured hippocampal synapses. This time course implies that transmitter saturates postsynaptic NMDA receptors. However, glutamate dissociates much more rapidly from alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Thus, the time course of free glutamate predicts that dissociation contributes to the decay of the AMPA receptor-mediated postsynaptic current.
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Research Interests: Psychology, Addiction, Neuropharmacology, Patch-clamp and imaging techniques, Compositional Analysis, and 12 moreLow Dose, Mice, Nicotine, Animals, Nicotinic Acetylcholine Receptors, Habenula, mRna expression levels, mRNA, Protein Binding, Neurosciences, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
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Synaptic release of glutamate results in a two component excitatory postsynaptic current (e.p.s.c.) at many vertebrate central synapses. Non-N-methyl-D-aspartate receptors mediate a component that has a rapid onset and decay while the... more
Synaptic release of glutamate results in a two component excitatory postsynaptic current (e.p.s.c.) at many vertebrate central synapses. Non-N-methyl-D-aspartate receptors mediate a component that has a rapid onset and decay while the component mediated by N-methyl-D-aspartate (NMDA) receptors has a slow rise-time and a decay of several hundred milliseconds, 100 times longer than the mean open time of NMDA channels. The slow decay of the NMDA-mediated e.p.s.c. could be due to residual glutamate in the synaptic cleft resulting in repeated binding and activation of NMDA receptors. However, in cultured hippocampal neurons, we find that the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate has no effect on the slow e.p.s.c. when rapidly applied after activation of the synapse, suggesting that rebinding of glutamate does not occur. In addition, a brief pulse of glutamate to an outside-out membrane patch results in openings of NMDA channels that persist for hundreds of milliseconds, indicating that glutamate can remain bound for this period. These results imply that a brief pulse of glutamate in the synaptic cleft is sufficient to account for the slow e.p.s.c.
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The fraction of inward current carried by Ca2+ ( FCa2+) through nicotinic acetylcholine receptors (nAChRs) on acutely isolated rat medial habenula (MHb) neurons was calculated from experiments that simultaneously monitored agonist-induced... more
The fraction of inward current carried by Ca2+ ( FCa2+) through nicotinic acetylcholine receptors (nAChRs) on acutely isolated rat medial habenula (MHb) neurons was calculated from experiments that simultaneously monitored agonist-induced membrane currents and intracellular [Ca2+], measured with patch-clamp and indo-1 fluorescence, respectively. In physiological concentrations of extracellular Ca2+ (2 mM) at −50 mV, the percentage of current carried by Ca2+ was determined to be roughly 3–4%, which is in close agreement with measurements from other heteromeric nicotinic receptors expressed in peripheral tissue. Among factors that may have affected this measurement, such as Ca2+ influx through voltage-gated Ca2+ channels, the concentration of intracellular Ca2+ buffer, and Ca2+ sequestration and release from intracellular stores, only Ca2+ uptake by mitochondria was shown to confound the analysis. Furthermore, we find that because of the high density of nAChRs on MHb cells, low concen...
Research Interests: Calcium, Neurophysiology, Patch-clamp and imaging techniques, Animals, Calcium channels, and 10 moreNicotinic Acetylcholine Receptors, Calcium Signaling, Acetylcholine, Synaptic Transmission, Habenula, Neurons, Rats, Psychology and Cognitive Sciences, fluorescent dyes, and Medical and Health Sciences
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Excitatory synaptic transmission in the central nervous system relies predominantly on stimulation of L-glutamate-gated ion channels in postsynaptic membranes. Activation of these channels not only mediates millisecond to millisecond... more
Excitatory synaptic transmission in the central nervous system relies predominantly on stimulation of L-glutamate-gated ion channels in postsynaptic membranes. Activation of these channels not only mediates millisecond to millisecond signalling but can also have long term influences on synaptogenesis and synaptic plasticity. Recent work has resolved some longstanding problems involving the identity of the transmitter, the postsynaptic localization of the receptor subtypes, and the time course of the transmitter in the synaptic cleft.
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Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in... more
Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in Alzheimer's disease. Recent studies have indicated statins, a class of cholesterol-lowering drugs, as a potential therapy for Alzheimer's disease. Our objective was to determine whether administering a statin drug (simvastatin) would protect against the development of behavioral deficits in an established mouse model of Alzheimer's disease. Tg2576 mice and their nontransgenic littermates were treated with simvastatin and assessed by behavioral tests and biochemical analyses. Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. Moreover, levels of amyloid beta protein in the brains of treated mice did not differ from those of untreated mice. Simvastatin treatment was associated with increased expression levels of protein kinase B (Akt) and endothelial nitric oxide synthase in the mouse brain. Our findings demonstrate that the effects of simvastatin on learning and memory are independent of amyloid beta protein levels. The mechanisms by which simvastatin exerts its beneficial effects may be related to modulation of signaling pathways in memory formation.