J receptor activity in idiopathic pulmonary hypertension and its expected change in the presence of pulmonary bed vasodilators.

Juxtapulmonary receptors (J) lying in the lung parenchyma are stimulated naturally by any condition that produces interstitial oedema, transient increases in interstitial volume and pressure or raised pulmonary capillary pressure. There is no information available about the level of their stimulation in patients with idiopathic pulmonary hypertension (IPH) who have high levels of pulmonary artery systolic pressures. The aim of the present study therefore was to find the level of these receptors activity in these patients at their prevailing pulmonary artery systolic pressures. This was done by the established method of determining the dose of i.v. lobeline that gives rise to threshold levels of sensations in the upper chest areas and accelerates respiration. In IPH patients it was found to be as high as 31.6 ± 5.6 µg/kg i.e., twice as much as that known for healthy individuals which is 15 µg/kg. This shows an enhanced stimulation of J receptors in IPH patients. Expectedly when pulmonary artery systolic pressure falls with pulmonary bed vasodilator medication given to IPH patients, a reduction in the natural stimulus of J receptors would also occur leading to a fall in their activity and hence that of the quantum of their reflexes of respiratory acceleration and inhibition of exercise. This finding provides the first insight of a neural mechanism that could be influenced to produce its effects when pulmonary artery systolic pressure falls by pulmonary vasodilator medication.

Lobeline Effects on Cognitive Performance in Adult ADHD.

OBJECTIVE: In preclinical studies, lobeline inhibited hyperactivity induced by nicotine and amphetamine, and improved performance and learning in studies utilizing radial-arm maze and spatial-discrimination water maze. This laboratory proof-of-concept study investigated lobeline as a treatment for ADHD symptoms in adults (31.11 ± 7.08 years). METHOD: Using cognitive tasks and self-report measures, the effects of lobeline (0, 7.5, 15, or 30 mg, s.l.) and methylphenidate (0, 15, or 30 mg, p.o.) were assessed in nine volunteers with ADHD. RESULTS: Evidence suggested that lobeline could modestly improve working memory in adults with ADHD, but no significant improvement in attention was observed. Lobeline administration was associated with mild adverse side effects (nausea). CONCLUSION: Further investigation of lobeline on working memory may be warranted.

The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse.

Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic.

Effect of sublingual nitrate on respiratory reflexes arising from stimulation of juxta-pulmonary capillary (J) receptors by i.v. lobeline and short duration exercise.

Juxta-pulmonary capillary (J or pulmonary C fiber) receptors are stimulated by an increase in pulmonary blood flow and give rise to respiratory acceleration and related sensations and inhibit exercise. However, the reverse, i.e., the effect of reducing pulmonary blood flow on their reflexes, is as yet not known. This was investigated by carrying out a placebo-controlled study on the acute effects of a single dose (0.4 mg) of sublingual glyceryl nitrate (GTN), known to shift blood from the central to the peripheral circulation, on the respiratory parameters of exercising healthy subjects and on their responses to i.v. lobeline. In 10 subjects, GTN use delayed the first appearance of respiratory sensations from 9.08 ± 0.9 min to 11 min (P=0.002), reduced the increase in minute ventilation by the end of 10 min of exercise (P=0.003) and increased its duration by 1-4s and doubled it in the remaining one subject. In a majority of 8 of them, the effect of GTN on i.v. lobeline-induced respiratory reflexes and sensations was a significant increase in the dose required (P=0.006) for producing threshold effects and in the latency of their appearance (P=0.003). The latter feature points to a reduction in blood flow in the lung parenchyma where these receptors are located and to which they are sensitive. As this would have led to a reduced stimulation of these receptors, it would account for the delayed appearance of respiratory symptoms, a reduction in ventilatory increase and prolongation of exercise duration. We demonstrated a mechanism of reducing the stimulus level of J receptors by reducing pulmonary blood flow by means of pharmacological sequestration with GTN use, which then led to a reduction in the magnitude of respiratory and viscerosomatic reflexes, while noting at the same time that changes in blood flow in the pulmonary bed do not directly influence limb muscles, tendons and joints which also determine exercise output.

The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats.

RATIONALE: Previous research suggests that the vesicular monoamine transporter-2 (VMAT2) is a novel target for the treatment of methamphetamine (METH) abuse. OBJECTIVE: The effects GZ-793A, a novel, selective, and potent lobelane analog, on the rewarding effects of METH, cocaine, and palatable food in rats were determined. METHOD: GZ-793A (3-30 mg/kg, s.c.) was administered 20 min prior to each session in which the groups of rats pressed a lever for infusions of METH (0.03 mg/kg/infusion), cocaine (0.3 mg/kg/infusion), or food pellets. Tolerance to repeated GZ-793A (15 mg/kg, s.c. for 7 days) on METH self-administration and food-maintained responding was determined. The ability of increasing doses of METH (0.001-0.56 mg/kg, i.v.) to surmount inhibition produced by GZ-793A (15 mg/kg, s.c.) was determined. Self-administration of GZ-793A (0.01-0.3 mg/kg/infusion, i.v.) was tested as a substitute for METH infusion. GZ-793A (15 mg/kg, s.c.) was administered 20 min prior to METH or saline conditioning in a place preference test. RESULTS: GZ-793A specifically decreased METH self-administration, without the development of tolerance. Increasing the unit dose of METH did not surmount the inhibition produced by GZ-793A on METH self-administration. GZ-793A did not serve as a substitute for self-administered METH. GZ-793A blocked METH-induced conditioned place preference (CPP) and did not induce CPP alone. CONCLUSIONS: These results indicate that VMAT2 is a viable target for pharmacological inhibition of METH reward and that GZ-793A represents a new lead in the discovery of a treatment for METH abuse.

Antiepileptic activity of lobeline isolated from the leaf of Lobelia nicotianaefolia and its effect on brain GABA level in mice.

OBJECTIVE: To investigate the anticonvulsant activity of the lobeline isolated from the Lobelia nicotianaefolia in chemoconvulsant-induced seizures and its biochemical mechanism by investigating relationship between seizure activities and altered gamma amino butyric acid (GABA) in brain of mice in Pentylenetetrazol (PTZ) seizure models. METHODS: The anticonvulsant activity of the isolated lobeline (5, 10, 20 and 30 mg/kg, i.p.) was investigated in PTZ and strychnine induced seizures in mice and the effect of isolated lobeline on brain GABA level in seizures induced by PTZ. Diazepam was used as reference anticonvulsant drugs for comparison. RESULTS: Isolated lobeline (10, 20 and 30 mg/kg, i.p.) significantly delayed and antagonized (P < 0.050-0.001) the onset of PTZ-induced seizures. It also antagonized strychnine induced seizures. The mortality was also prevented in the test group of animals. In biochemical evaluation, isolated lobeline (5, 10 and 20 mg/kg, i.p.) significantly increased the brain GABA level. And at dose of 30 mg/kg GABA level showed slight decrease in PTZ model. CONCLUSIONS: In our findings, isolated lobeline (20mg/kg) exhibited potent anticonvulsant activity against PTZ induced seizures. Also a biochemical evaluation suggested significant increase in barain GABA level at 20 mg/kg i.p. of isolated lobeline. Hence, we may propose that lobeline reduces epileptic seizures by enhancing the GABA release supporting the GABAergic mechanism.

Dose-dependent attenuation of heroin self-administration with lobeline.

Behavioural studies have yielded results that show lobeline has the ability to attenuate d-methamphetamine self-administration. Further in vivo and in vitro studies have demonstrated a blockade of mu-opioid receptors with lobeline. The present investigation examined the ability of lobeline to attenuate heroin intravenous (i.v.) self-administration when administered prior to testing. Male Sprague-Dawley rats were surgically implanted with jugular catheters and trained to lever press for i.v. heroin infusions (18 microg/kg) under a fixed ratio-2 schedule wherein two active lever presses resulted in heroin delivery. Rats then were tested for heroin self-administration after pretreatment with subcutaneous lobeline injections (0.3, 1.0, or 3.0 mg/kg, 15 min prior to testing sessions). At doses of 1.0 and 3.0 mg/kg, lobeline attenuated self-administration of heroin. The results suggest a potential for lobeline to be used in pharmacotherapy for opioid abuse.

A multicenter phase 3 trial of lobeline sulfate for smoking cessation.

OBJECTIVE: To evaluate the safety and efficacy of sublingual lobeline sulfate for smoking cessation. METHODS: A multicenter (3 sites), double-blind, parallel, placebo-controlled, phase 3 smoking cessation trial of sublingual formulation of lobeline sulfate. A total of 750 smokers (250 per site) were randomized to either treatment (lobeline sulfate) or placebo with individual smoking cessation counseling lasting up to approximately 10 minutes. RESULTS: Efficacy revealed no statistical significance (P = 0.62) for lobeline sulfate as a smoking cessation aid. CONCLUSION: Sublingual formulation of lobeline sulfate does not appear to be an effective smoking cessation aid.

Lobeline attenuates progressive ratio breakpoint scores for intracranial self-stimulation in rats.

The alkaloid lobeline inhibits the function of vesicular monoamine and dopamine transporters and diminishes the behavioral and neurochemical effects of nicotine and amphetamines. In the present study, we examined the interaction of systemic administration of lobeline on breakpoint scores on a progressive ratio (PR) schedule of intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB). Rats were run in two 30 min sessions, separated by a 10 min timeout period. At the end of the first session, each rat was injected with either 0, 0.5, 1.0 or 2.0 mg/kg (i.p.) lobeline. Positive controls known to suppress and to augment ICSS responding included the adrenergic antagonist prazosin (0, 0.5 and 2.0 mg/kg, i.p.) and the psychostimulant cocaine (0, 1.25, and 5.0 mg/kg, i.p.). Analyses of changes in average PR breakpoint scores between the 2 sessions revealed that lobeline significantly suppressed PR scores at doses of 0.5, 1.0 and 2.0 mg/kg, as did 0.5 mg/kg and 2.0 mg/kg prazosin. These changes are unlikely to reflect motoric effects of these drugs inasmuch as neither lobeline nor prazosin alter locomotion at these doses. In contrast, PR breakpoint scores were significantly increased at 5.0 mg/kg cocaine, a dose that is sufficient to elevate locomotion in the rat. These results are consistent with the view that lobeline modulates brain reinforcement processes.

Lobeline augments and inhibits cocaine-induced hyperactivity in rats.

Lobeline has high affinity for nicotinic receptors and alters presynaptic dopamine storage and release in brain. Moreover, lobeline decreases the reinforcing and locomotor-activating properties of methamphetamine, suggesting that lobeline may be a pharmacotherapy for psychostimulant abuse. This study determined if lobeline alters cocaine-induced hyperactivity and if lobeline alters the induction and/or expression of sensitization to cocaine. On Days 1-12, male rats were administered lobeline (0.3 or 1.0 mg/kg) or saline, placed in an automated activity monitor for 20 min, administered cocaine (10, 20 or 30 mg/kg) or saline and returned to the monitor for 60 min. On Day 13, the effect of lobeline on the induction and expression of sensitization to cocaine was determined. Lobeline did not alter the effect of cocaine after acute injection. However, 1.0 mg/kg lobeline attenuated cocaine (10 and 20 mg/kg)-induced hyperactivity after repeated administration and prevented the development of sensitization to these cocaine doses. Interestingly, 0.3 mg/kg lobeline augmented cocaine (10 mg/kg)-induced hyperactivity after repeated administration. Lobeline did not alter the effect of 30 mg/kg cocaine. The present results indicate a complex interaction of lobeline with cocaine and support other research indicating a role for nicotinic receptors in the development of sensitization to psychostimulants.

Changes in respiratory sensations induced by lobeline after human bilateral lung transplantation.

1. The sensations evoked by the injection of lobeline into the right antecubital vein were studied in 8 subjects after bilateral lung transplantation and 10 control subjects. In control subjects, two distinct sensations were experienced. There was an early noxious sensation (onset approximately 10 s) followed by a late sensation of breathlessness (onset approximately 26 s) associated with involuntary hyperventilation. The early sensation was accompanied by respiratory and cardiovascular changes. 2. In contrast to control subjects, the early respiratory events and the noxious sensations evoked by injections of lobeline (18-60 microg kg(-1)) did not occur in subjects with recent bilateral lung transplantation. This suggests that the early respiratory sensations are mediated by the discharge of receptors in the lungs. 3. The late hyperventilation and the accompanying sensation of breathlessness occurred in both transplant and control subjects and are therefore likely to be mediated by receptors elsewhere in the body, presumably systemic arterial chemoreceptors stimulated by lobeline. 4. In control subjects, but not transplant subjects, there was a consistent decrease in mean arterial pressure associated with the lobeline injection. This suggests that pulmonary afferents mediate the hypotension. 5. For transplant subjects studied more than a year after transplantation, there was some evidence that the noxious respiratory sensations evoked by lobeline had returned. This suggests that some functional reinnervation of pulmonary afferents may occur.

The variability and repeatability of indices derived from the single-breath diagram for CO2 in horses with chronic obstructive pulmonary disease and the effect of lobelin hydrochloride on these indices.

Several indices of ventilatory heterogeneity can be identified from the volumetric capnogram and its graphic presentation, the single-breath diagram for CO2 (SBD-CO2). Physiologically based indices of pulmonary function (VTE, VCO2, FACO2, VDBohr% VDBohr%, VD/VTE, A1/A2) were calculated for healthy horses (group I, n = 5) and for horses with subclinical (group II, n = 7) or clinically manifest chronic obstructive pulmonary disease (COPD) (group III, n = 8) during tidal breathing and after medication with lobelin hydrochloride (Lobelin). We investigated the variability and repeatability of the lung function indices in healthy horses and in those with COPD both during tidal breathing and after administration of Lobelin, a centrally acting respiratory stimulant. In particular, we were interested in whether the discriminating ability of SBD-CO2-derived lung function indices would be increased between different patient groups after administration of Lobelin compared to those for the resting values. Of the indices studied, VTE, FACO, VDBohr% and A1/A2 appeared to be those with good to excellent repeatability in discriminating healthy horses from those with COPD. Stimulating respiration with Lobelin gave no advantage in the repeatability of the lung function indices or in differentiating between horses with different degrees of COPD.

Respiratory responses of mature horses to intravenous lobeline bolus.

The respiratory stimulant lobeline has been used in equine clinical practice to increase inspiratory and expiratory airflow rates at rest in order to facilitate investigation of both lower and upper airway function. Some of the responses to lobeline in the pony have been reported, but the detailed time course, effect of dose, possible side effects and reproducibility associated with lobeline administration have not been described in the horse. Respiratory airflow rates and oesophageal pressure were measured with a Fleisch No. 5 pneumotachometer and lightweight facemask and a microtip pressure transducer catheter, respectively. The output of the Fleisch pneumotachometer was calibrated for flow rates up to +/- 70 l/s. Seven mature horses with no clinical signs of respiratory disease were studied. Investigations were conducted to determine: (1) the responses to different doses of lobeline (0.15, 0.20, 0.25 and 0.30 mg/kg bwt) as a rapid i.v. bolus (6 horses); (2) arterial blood gases during and after lobeline administration (0.20 mg/kg bwt; 3 horses); and (3) the reproducibility of lobeline-stimulated hyperpnoea (5 horses; 2 doses of 0.20 mg/kg bwt lobeline, 15 min apart). All horses tolerated the lobeline-stimulated hyperpnoea well, although one always coughed or snorted at the onset. Mild tremor was noted following the highest dose in several horses. Apnoea of approximately 40 s was common after the hyperpnoea. Both tidal volume (VT) and frequency (fR) increased with lobeline dose. During peak hyperpnoea at a dose of 0.30 mg/kg bwt, peak inspired flow rate (PIF), peak expired flow rate (PEF) and minute ventilation (VE) were mean +/- s.e. 41+/-5 l/s, 61+/-10 l/s and 920+/-99 l/min, respectively. The hyperpnoea also caused marked changes in arterial PaO2, PaCO2 and pHa at 90 s after lobeline (0.20 mg/kg bwt) administration (mean +/- s.e. 146.0+/-6.9 mmHg, 20.6+/-0.8 mmHg and 7.707+/-0.020, respectively) compared to at rest (mean +/- s.e. 104.0+/-4.0 mmHg, 50.6+/-2.8 mmHg and 7.432+/-0.012). Dynamic lung compliance (Cdyn) was unaltered by lobeline administration. The lobeline-induced hyperpnoea was highly reproducible, with no significant difference in any of the parameters during 2 stimulations 15 min apart. Lobeline induced highly reproducible responses without any apparent adverse effects and may be useful in the investigation of pulmonary function in healthy horses and those with airway disease.

Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test.

The effects of nicotinic receptor agonists on the elevated plus-maze test of anxiety were investigated in CD1 mice after intraperitoneal injections. Nicotine and lobeline, but not cytisine, exhibited a significant increase in the time spent by the mice in the open arms, a measure of anxiolytic activity. Nicotine also increased the total number of arm entries, a measure of general activity, but this effect was secondary to its anxiolytic-like properties. Nicotinic receptor antagonists on their own did not modify the behavior of mice in the maze. The effect of nicotine was mediated by central nicotinic receptors as it was blocked by the centrally-acting nicotinic antagonists mecamylamine and chlorisondamine, but not by hexamethonium (a peripherally acting blocker). Cotinine, the major metabolite of nicotine, was evaluated at different times after systemic injections and had no effect in the plus-maze. The anxiolytic-like profile induced by nicotinic receptor stimulation was not associated with potentiation of alcohol effects, a liability associated with the benzodiazepine therapy. This study demonstrates the anxiolytic-like properties of nicotine and lobeline in mice, and suggests that central nicotinic receptors are involved in the expression of emotional behavior.

Studies on vomitory effect of some acridine compounds.

Vomitory effect of 16 chosen acridine derivatives was observed on pigeons. The expected effect of the preparations as well as their interaction with, causing vomiting lobeline were considered. Two groups were distinguished: 1) preparations which alone caused vomitory reaction (C-283, C-410, C-541, C-609, C-684, C-702, C-829, C-835, C-846, C-1006 and C-1020). 2) Preparations which caused this effect while combined with a subthreshold dose of lobeline (C-429, C-516, C-666, C-857 and C-1005). Dependence of the effects on chemical structure and pharmacological activity of the compounds is discussed.