Inside-out neuropharmacology of nicotinic drugs

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology

An evaluation of the implementation of Georgia's Pre-k program: Report of the findings from the Georgia Early Childhood Study (2002-03)

After ten years, Georgia continues to lead the nation in providing full day, publicly subsidized Pre-K to four-year-olds whose parents choose to enroll them. In this report, we assess the extent to which differences in the way Pre-K is implemented affect children's development. Do teachers with higher levels of education have more positive impacts on children's development? Do teaching styles make a difference in terms of children's outcomes by the end of kindergarten? Do children taught using certain curricula fare better than those taught using others? Answers to questions such as these can assist Pre-K administrators in refining Georgia's program and inform those in other states who are developing or expanding their prekindergarten programs

Discovery of Griffiths phase in itinerant magnetic semiconductor Fe_{1-x}Co_xS_2

Critical points that can be suppressed to zero temperature are interesting because quantum fluctuations have been shown to dramatically alter electron gas properties. Here, the metal formed by Co doping the paramagnetic insulator FeS$_2$, Fe$_{1-x}$Co$_x$S$_2$, is demonstrated to order ferromagnetically at $x>x_c=0.01\pm0.005$ where we observe unusual transport, magnetic, and thermodynamic properties. We show that this magnetic semiconductor undergoes a percolative magnetic transition with distinct similarities to the Griffiths phase, including singular behavior at $x_c$ and zero temperature.Comment: 10 pages, 4 figure

Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease

Chronic exposure to nicotine results in an upregulation of neuronal nicotinic acetylcholine receptors (nAChRs) at the cellular plasma membrane. nAChR upregulation occurs via nicotine-mediated pharmacological receptor chaperoning and is thought to contribute to the addictive properties of tobacco as well as relapse following smoking cessation. At the subcellular level, pharmacological chaperoning by nicotine and nicotinic ligands causes profound changes in the structure and function of the endoplasmic reticulum (ER), ER exit sites, the Golgi apparatus and secretory vesicles of cells. Chaperoning-induced changes in cell physiology exert an overall inhibitory effect on the ER stress/unfolded protein response. Cell autonomous factors such as the repertoire of nAChR subtypes expressed by neurons and the pharmacological properties of nicotinic ligands (full or partial agonist versus competitive antagonist) govern the efficiency of receptor chaperoning and upregulation. Together, these findings are beginning to pave the way for developing pharmacological chaperones to treat Parkinson's disease and nicotine addiction

Magnetic and thermodynamic properties of cobalt doped iron pyrite: Griffiths Phase in a magnetic semiconductor

Doping of the band insulator FeS$_2$ with Co on the Fe site introduces a small density of itinerant carriers and magnetic moments. The lattice constant, AC and DC magnetic susceptibility, magnetization, and specific heat have been measured over the $0\le x\le 0.085$ range of Co concentration. The variation of the AC susceptibility with hydrostatic pressure has also been measured in a small number of our samples. All of these quantities show systematic variation with $x$ including a paramagnetic to disordered ferromagnetic transition at $x=0.007\pm 0.002$. A detailed analysis of the changes with temperature and magnetic field reveal small power law dependencies at low temperatures for samples near the critical concentration for magnetism, and just above the Curie temperature at higher $x$. In addition, the magnetic susceptibility and specific heat are non-analytic around H=0 displaying an extraordinarily sharp field dependence in this same temperature range. We interpret this behavior as due to the formation of Griffiths phases that result from the quenched disorder inherent in a doped semiconductor.Comment: 22 pages including 27 figure

Multifaceted contributions : health workers and smallpox eradication in India

Smallpox eradication in South Asia was a result of the efforts of many grades of health-workers. Working from within the confines of international organisations and government structures, the role of the field officials, who were of various nationalities and also drawn from the cities and rural enclaves of the countries in these regions, was crucial to the development and deployment of policies. However, the role of these personnel is often downplayed in official histories and academic histories, which highlight instead the roles played by a handful of senior officials within the World Health Organization and the federal governments in the sub-continent. This article attempts to provide a more rounded assessment of the complex situation in the field. In this regard, an effort is made to underline the great usefulness of the operational flexibility displayed by field officers, wherein lessons learnt in the field were made an integral part of deploying local campaigns; careful engagement with the communities being targeted, as well as the employment of short term workers from amongst them, was an important feature of this work

Nicotinic Receptor Subtype-Selective Circuit Patterns in the Subthalamic Nucleus

The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either α4β2 or α7 nAChRs. STN neurons containing α4β2 nAChRs (α4β2 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing α7 nAChRs (α7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of α4β2 neurons but exerted strong inhibition in 58% of α7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects α4β2 nAChRs in STN: this treatment increased the number of α4β2 neurons, upregulated α4-containing nAChR number and sensitivity, and enhanced the basal firing rate of α4β2 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving α4β2 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons

Brain Region-Specific nAChR and Associated Protein Abundance Alterations Following Chronic Nicotine and/or Menthol Exposure

The identification of biomarkers that are altered following nicotine/tobacco exposure can facilitate the investigation of tobacco-related diseases. Nicotinic acetylcholine receptors (nAChRs) are pentameric cation channels expressed in the mammalian central and peripheral nervous systems and the neuromuscular junction. Neuronal nAChR subunits (11) have been identified in mammals (α2-7, α9-10, β2-4). We examined changes in β2 nAChR subunit protein levels after chronic nicotine, (±)-menthol, or nicotine co-administered with (±)-menthol in nine murine brain regions. Our investigation of β2 nAChR subunit level changes identified the hypothalamus as a novel region of interest for menthol exposure that demonstrated increased β2 nAChR levels after (±)-menthol plus nicotine exposure compared to nicotine exposure alone. Using mass spectrometry, we further characterized changes in membrane protein abundance profiles in the hypothalamus to identify potential biomarkers of (±)-menthol plus nicotine exposure and proteins that may contribute to the elevated β2 nAChR subunit levels. In the hypothalamus, 272 membrane proteins were identified with altered abundances after chronic nicotine plus menthol exposure with respect to chronic nicotine exposure without menthol. A comprehensive investigation of changes in nAChR and non-nAChR protein expression resulting from (±)-menthol plus nicotine in the brain may establish biomarkers to better understand the effects of these drugs on addiction and addiction-related diseases