Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry.

Antagonism of nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb) or interpeduncular nucleus (IPN) triggers withdrawal-like behaviors in mice chronically exposed to nicotine, implying that nicotine dependence involves the sensitization of nicotinic signaling. Identification of receptor and/or neurophysiological mechanisms underlying this sensitization is important, as it could promote novel therapeutic strategies to reduce tobacco use. Using an approach involving photoactivatable nicotine, we previously demonstrated that chronic nicotine (cNIC) potently enhances nAChR function in dendrites of MHb neurons. However, whether cNIC modulates downstream components of the habenulo-interpeduncular (Hb-IP) circuit is unknown. In this study, cNIC-mediated changes to Hb-IP nAChR function were examined in mouse (male and female) brain slices using molecular, electrophysiological, and optical techniques. cNIC enhanced action potential firing and modified spike waveform characteristics in MHb neurons. Nicotine uncaging revealed nAChR functional enhancement by cNIC on proximal axonal membranes. Similarly, nAChR-driven glutamate release from MHb axons was enhanced by cNIC. In IPN, the target structure of MHb axons, neuronal morphology, and nAChR expression is complex, with stronger nAChR function in the rostral subnucleus [rostral IPN (IPR)]. As in MHb, cNIC induced strong upregulation of nAChR function in IPN neurons. This, coupled with cNIC-enhanced nicotine-stimulated glutamate release, was associated with stronger depolarization responses to brief (1 ms) nicotine uncaging adjacent to IPR neurons. Together, these results indicate that chronic exposure to nicotine dramatically alters nicotinic cholinergic signaling and cell excitability in Hb-IP circuits, a key pathway involved in nicotine dependence.SIGNIFICANCE STATEMENT This study uncovers several neuropharmacological alterations following chronic exposure to nicotine in a key brain circuit involved in nicotine dependence. These results suggest that smokers or regular users of electronic nicotine delivery systems (i.e., "e-cigarettes") likely undergo sensitization of cholinergic circuitry in the Hb-IP system. Reducing the activity of Hb-IP nAChRs, either volitionally during smoking cessation or inadvertently via receptor desensitization during nicotine intake, may be a key trigger of withdrawal in nicotine dependence. Escalation of nicotine intake in smokers, or tolerance, may involve stimulation of these sensitized cholinergic pathways. Smoking cessation therapeutics are only marginally effective, and by identifying cellular/receptor mechanisms of nicotine dependence, our results take a step toward improved therapeutic approaches for this disorder.

Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids.

Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.

Differential Nicotinic Modulation of Glutamatergic and GABAergic VTA Microcircuits.

Ventral tegmental area (VTA) neurons receive glutamatergic and/or GABAergic input from other local neurons within the VTA. Nicotinic acetylcholine receptor (nAChR) activity is capable of modulating such intra-VTA transmission, but the mechanisms are unclear. Here, we isolated monosynaptic glutamate or GABA transmission from mouse medial VTA (mVTA) to lateral VTA (latVTA) using pharmacology and optogenetics, and we studied the ability of nicotine to modulate these modes of transmission. The action of nicotine on mVTA to latVTA glutamate transmission was bidirectional; nicotine enhanced glutamate release in half of the recorded latVTA cells and inhibited release in the other half. Nicotine-mediated reduction in glutamate release was reversed by blockade of GABAA receptors. This, coupled with expression data demonstrating coexpression of vesicular glutamate transporter 2 (VGluT2) and glutamate decarboxylase 2 (Gad2) in mVTA neurons, suggests that nicotine is able to stimulate GABA corelease from mVTA VGluT2+ neurons. Nicotine had an altogether different effect on mVTA to latVTA GABA release from Gad2+ cells; nicotine suppressed GABA release from mVTA Gad2+ terminals in nearly all cells tested. Together, these data uncover a complex system of local circuitry in the VTA that is modulated by nAChR activity. These actions of nicotine, which occurred at concentrations of nicotine found in the artificial CSF of cigarette smokers, may play a role in the adaptive response of the reward system to repeated nicotine exposure.

Area Deprivation and Postpartum Readmission Facility Location and Timing.

This cohort study evaluates the role that community-level socioeconomic status plays in hypertension-related hospital readmission within 12 weeks after delivery.