Parasympathetic activation reduces hepatic glucose release and increases pancreatic insulin secretion in hyperglycemic conditions. Thus, vagal nerve stimulation (VNS) may potentially be effective in treating type II diabetes. To investigate this possibility, we hypothesized that VNS reduces blood glucose concentration [Glu] via insulin secretion. [Glu] together with insulin and glucagon serum concentrations were determined in anesthetized rats during baseline conditions and 120 min of cervical VNS with the nerve left intact for combined afferent and efferent VNS (n = 9) or the nerve sectioned proximal or distal from the stimulation electrode for selective efferent (n = 8) or afferent (n = 7) VNS, respectively. Afferent VNS caused a strong and sustained increase in [Glu] (+108.9 ± 20.9% or +77.6 ± 15.4%, after 120 min of combined afferent and efferent VNS or selective afferent VNS) that was not accompanied by an increase in serum insulin concentration. However, serum insulin levels increased significantly with selective efferent VNS (+71.2 ± 27.0% after 120 min of VNS) that increased [Glu] only temporarily (+28.8 ± 11.7% at 30 min of VNS). Efferent VNS initially increased serum glucagon concentration which remained elevated for 120 min when efferent VNS was combined with afferent VNS, but returned to baseline with selective efferent VNS. These findings demonstrate that afferent VNS causes a marked and sustained increase in [Glu] that is partly mediated by suppression of pancreatic insulin secretion. In contrast, efferent VNS stimulates pancreatic glucagon secretion that appears to be antagonized by insulin secretion in the case of selective efferent VNS. Selective efferent VNS may potentially be effective in treating type II diabetes.

Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. Here we show that rewarding doses of nicotine activated VTA DAergic neurons in a region-selective manner, preferentially activating neurons in the posterior VTA (pVTA) but not the anterior VTA (aVTA) or tail VTA (tVTA). Nicotine (1µM) directly activated pVTA DAergic neurons in adult mouse midbrain slices but had little effect on DAergic neurons within the aVTA. Quantification of nAChR subunit gene expression revealed that pVTA DAergic neurons expressed higher levels of α4, α6, and β3 transcripts, compared to aVTA DAergic neurons. Activation of nAChRs containing the α4 subunit (α4* nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: Nicotine failed to activate pVTA DAergic neurons in α4 knock-out animals; in contrast pVTA α4* nAChRs were selectively activated by nicotine, in mutant mice expressing agonist hypersensitive α4* nAChRs (Leu9’Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by α4* nAChRs and were significantly larger in pVTA neurons compared to aVTA neurons. Infusion of an α6* nAChR antagonist into the VTA blocked activation of pVTA DAergic neurons in WT mice and Leu9’Ala mice at nicotine doses that only activate the mutant receptor indicating that α4 and α6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA via α4α6* nAChRs. These receptors represent novel targets for smoking cessation therapies.

<b><i>Background:</i></b> Image-guided percutaneous thermal ablation is an established treatment option for early-stage lung cancer in medically inoperable patients but carries a high risk of pleura-related complications, particularly pneumothorax. <b><i>Objective:</i></b> This study aimed to determine if image-guided transbronchial microwave ablation (tMWA) is a feasible approach to treat peripheral stage 1 lung cancer. <b><i>Method:</i></b> A prospective, single-arm, multicenter study sought to enroll 40 adults who were medically inoperable or declined surgery for peripheral stage 1 lung tumors (≤20 mm). Ablation was performed using navigational bronchoscopy and a flexible MWA probe, guided by cone-beam CT with augmented fluoroscopy. Follow-up at 1, 6, and 12 months included CT imaging of the ablation zone and possible tumor recurrence, adverse events (AEs), pulmonary function, and quality of life. <b><i>Results:</i></b> Across 2 sites, 11 tumors (10 NSCLC, 1 carcinoid) were treated in 10 enrolled patients. Median tumor diameter was 13 × 14 mm (7–19 mm) and median minimum ablative margin was 11 mm (5–19 mm). Technical success and technique efficacy were achieved in all patients. No tumor recurrence was seen during 12-month follow-up. No pneumothorax, pleural effusion, or bronchopleural fistula were noted. Minor AEs included scant hemoptysis, pain, cough, and dyspnea. Two serious AEs occurred ≤30 days of ablation and included a COPD exacerbation (day 9) and a death of unknown cause (day 15). The death led the sponsor to halt enrollment. Pulmonary function and quality-of-life indices remained stable. <b><i>Conclusions:</i></b> Image-guided tMWA is a technically feasible approach for peripheral early-stage lung cancer but warrants further evaluation of safety and efficacy in larger cohorts.

The role of neuronal nicotinic acetylcholine receptors (nAChR) containing the β4 subunit in tolerance development and nicotinic binding site levels following chronic nicotine treatment was investigated. Mice differing in expression of the β4 nAChR subunit [wild-type (β4++), heterozygote (β4+−) and null mutant (β4−−)] were chronically treated for 10 days with nicotine (0, 0.5, 1.0, 2.0 or 4.0 mg/kg/hr) by constant intravenous infusion. Chronic nicotine treatment elicited dose-dependent tolerance development. β4−− mice developed significantly more tolerance than either β4++ or β4+− mice which was most evident following treatment with 4.0 mg/kg/hr nicotine. Subsets of [125I]-epibatidine binding were measured in several brain regions. Deletion of the β4 subunit had little effect on initial levels of cytisine-sensitive [125I]-epibatidine binding (primarily α4β2-nAChR sites) or their response (generally increased binding) to chronic nicotine treatment. In contrast, β4 gene-dose-dependent decreases in expression 5IA-85380 resistant [125I]-epibatidine binding sites (primarily β4*-nAChR) were observed. While these β4*nAChR sites were generally resistant to regulation by chronic nicotine treatment, significant increases in binding were noted for habenula and hindbrain. Comparison of previously published tolerance development in β2−− mice (less tolerance) to that of β4−− mice (more tolerance) supports a differential role for these receptor subtypes in regulating tolerance following chronic nicotine treatment.