Cognitive mechanisms underlying relapse to nicotine.

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.

Short- and long-lasting consequences of in vivo nicotine treatment on hippocampal excitability.

The potential for relapse following cessation of drug use can last for years, implying the induction of stable changes in neural circuitry. In hippocampal slices from rats treated with nicotine for 1 week, withdrawal from nicotine in vivo produces an increase in CA1 pyramidal cell excitability that persists up to 9 months. Immediately upon drug cessation, the enhanced excitability depends on input from regions upstream of CA1, while the long-term excitability change (> 4 weeks) is expressed as an increase in the intrinsic excitability of CA1 neurons.

Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization.

Tumor-associated macrophages are known to influence cancer progression by modulation of immune function, angiogenesis, and cell metastasis, however, little is known about the chemokine signaling networks that regulate this process. Utilizing CT26 colon cancer cells and RAW 264.7 macrophages as a model cellular system, we demonstrate that treatment of CT26 cells with RAW 264.

Cellular events in nicotine addiction.

In the 25 years since the observation that chronic exposure to nicotine could regulate the number and function of high affinity nicotine binding sites in the brain there has been a major effort to link alterations in nicotinic acetylcholine receptors (nAChRs) to nicotine-induced behaviors that drive the addiction to tobacco products. Here we review the proposed roles of various nAChR subtypes in the addiction process, with emphasis on how they are regulated by nicotine and the implications for understanding the cellular neurobiology of addiction to this drug.

Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling.

Hypoxia induces expression of the urokinase receptor (uPAR) and activates uPAR-dependent cell signaling in cancer cells. This process promotes epithelial-mesenchymal transition (EMT). uPAR overexpression in cancer cells also promotes EMT.

Demonstration of functional alpha4-containing nicotinic receptors in the medial habenula.

The medial habenula (MHb) exhibits exceptionally high levels of nicotinic acetylcholine receptors (nAChRs), but it remains unclear whether all expressed nAChR subunit mRNAs are translated to form functional receptors. In particular alpha4 subunits have not been reported to have any functional role, despite strong alpha4 mRNA expression in the ventrolateral MHb. We studied a strain of knock-in mice expressing fluorescent alpha4* nAChRs (alpha4YFP), as well as a knock-in strain expressing hypersensitive alpha4* nAChRs (alpha4L9'A).

High-resolution imaging of the dynamic tumor cell vascular interface in transparent zebrafish.

Cell metastasis is a highly dynamic process that occurs in multiple steps. Understanding this process has been limited by the inability to visualize tumor cell behavior in real time by using animal models. Here, we employ translucent zebrafish and high-resolution confocal microscopy to study how human cancer cells invade in tissues, induce angiogenesis, and interact with newly formed vessels.

The low-density lipoprotein receptor-related protein regulates cancer cell survival and metastasis development.

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. In this study, we show that LRP-1 is abundantly expressed in severe combined immunodeficient (SCID) mouse xenografts by various human cancer cell lines that express very low or undetectable levels of LRP-1 when cultured in 21% O2 in vitro (standard cell culture conditions). To test whether LRP-1 expression in vivo may be explained by hypoxia in the xenografts, CL16 cells, which are derived from the MDA-MB-435 cell line, were cultured in 1.

uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells.

Hypoxia activates genetic programs that facilitate cell survival; however, in cancer, it may promote invasion and metastasis. In this study, we show that breast cancer cells cultured in 1.0% O(2) demonstrate changes consistent with epithelial-mesenchymal transition (EMT).

Simvastatin enhances learning and memory independent of amyloid load in mice.

Objective: 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.

Ca2+ flux and signaling implications by nicotinic acetylcholine receptors in rat medial habenula.

The fraction of inward current carried by Ca(2+) (FCa(2+)) 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 [Ca(2+)], measured with patch-clamp and indo-1 fluorescence, respectively. In physiological concentrations of extracellular Ca(2+) (2 mM) at -50 mV, the percentage of current carried by Ca(2+) 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 Ca(2+) influx through voltage-gated Ca(2+) channels, the concentration of intracellular Ca(2+) buffer, and Ca(2+) sequestration and release from intracellular stores, only Ca(2+) uptake by mitochondria was shown to confound the analysis.

Regulation of nicotinic acetylcholine receptor desensitization by Ca2+.

The relationship between the concentration of intracellular Ca2+ ([Ca2+](i)) and recovery from desensitization of nicotinic acetylcholine receptors (nAChRs) in rat medial habenula (MHb) neurons was investigated using the whole cell patch-clamp techniques in combination with microfluorescent [Ca2+](i) measurements. Recovery from desensitization was assessed with a paired-pulse agonist application protocol. Application of 100 microM nicotine (5 s) caused pronounced desensitization of nAChRs, after which recovery proceeded with two components.

Erythropoietin promotes MCF-7 breast cancer cell migration by an ERK/mitogen-activated protein kinase-dependent pathway and is primarily responsible for the increase in migration observed in hypoxia.

Recent studies indicate that cancer cells express erythropoietin receptor (EpoR). In this study, we have shown that erythropoietin (Epo) activates the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and promotes migration in MCF-7 breast cancer cells. Epo-stimulated MCF-7 cell migration was blocked by the MEK inhibitor PD098059 and by dominant negative MEK-1, indicating an essential role for ERK.

Rapid upregulation of alpha7 nicotinic acetylcholine receptors by tyrosine dephosphorylation.

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.

Activation and desensitization of heteromeric neuronal nicotinic receptors: implications for non-synaptic transmission.

Consideration of the activation and desensitization properties of neuronal nicotinic acetylcholine receptors (nAChRs) predicts that there should be a range of concentrations over which low ambient levels of agonist can continuously open nAChR channels. These findings support the idea that postsynaptic nAChRs may participate in unconventional cellular signaling mediated by the release of acetylcholine from diffusely distributed non-synaptic cholinergic varicosities.

Interactions of atropine with heterologously expressed and native alpha 3 subunit-containing nicotinic acetylcholine receptors.

(1) Atropine, a classical muscarinic antagonist, has been reported previously to inhibit neuronal nicotinic acetylcholine receptors (nAChRs). In the present study, the action of atropine has been examined on alpha3beta4 receptors expressed heterologously in Xenopus oocytes and native nAChRs in medial habenula neurons. (2) At concentrations of atropine often used to inhibit muscarinic receptors (1 micro M), responses induced by near-maximal nicotine concentrations (100 micro M) at negative holding potentials (-65 mV) are inhibited (14-30%) in a reversible manner in both alpha4 and alpha3 subunit-containing heteromeric nAChRs.

Desensitization of neuronal nicotinic receptors.

The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a well-defined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels.

Prolonged stimulation of presynaptic nicotinic acetylcholine receptors in the rat interpeduncular nucleus has differential effects on transmitter release.

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.