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The alkaloid lobeline (Lob) has been studied due to its potential use in treatment of drug abuse. This study evaluates the possible anticonvulsant and neuroprotective activities of Lob to obtain new information on its properties that could confirm it as a candidate in the treatment of alcohol addiction. The anticonvulsant effect of Lob was evaluated using a pilocarpine-induced seizure model. In addition, possible neuroprotective effects were investigated measuring DNA damage using the comet assay, assessing free radical levels by dichlorofluorescein diacetate (DCF) oxidation, and measuring the antioxidant potential using the α, α-diphenyl-β-picrylhydrazyl (DPPH) scavenging assay, besides measuring superoxide dismutase (SOD) and catalase (CAT) enzyme activities in brain tissues. Lobeline increased the latency to the first seizure and decreased the percentage of seizures in a similar way as diazepam, used as control. DNA damage induced by Pil and hydrogen peroxide were decreased in hippocampus and cerebral cortex from mice treated with Lob. The levels of free radicals and CAT activity increased in cortex and hippocampus, respectively, in mice treated with Pil. Lobeline decreased CAT in hippocampus, leading to similar values as in the saline negative control. In conclusion, Lob has anticonvulsant and neuroprotective actions that may be mediated by antioxidant-like mechanisms, indicating its potential as candidate drug in alcoholism therapy. [ABSTRACT FROM AUTHOR]

Lobelia inflata L. is a medicinally important species that contains numerous piperidine alkaloids. The main alkaloid lobeline is used as a respiratory stimulant. Recently, there have been studies that report on its effect on the central nervous system, drug abuse, and multidrug resistance. We have studied the piperidine alkaloid formation of in vitro cultivated L. inflata on solid Murashige and Skoog medium. With the aim of increasing the anti-addictive lobeline production, we have investigated the effect of changing MgSO levels of the medium. The compounds (−)-lobeline, norlobelanine, lobelanidine-(−)-8-ethyl-10-phenyl-norlobelionol, (−)-8-ethyl-10-phenyl-lobelionol, norlobeline, lobelidine, and lobelanine were identified by HPLC-tandem mass spectrometry (MS/MS). We studied the effect of changing the MgSO levels on the content of lobeline and its derivatives for in vitro cultivated L. inflata. The highest lobeline content was measured in roots cultured on 185 mg L MgSO-containing medium; this value was 2.5 times higher (232.4 μg g) than in the control cultures. The greatest (fourfold) increase was observed in lobelidine (71.61 μg g). Addition of MgSO at 740 mg L resulted in the highest lobeline contents in the herba (aerial tissues; 267.8 μg g), whereas maximum lobeline production was achieved by a further increase in the MgSO level (1,480 mg L), due to an intensive increase in biomass production. A slight increase was observed in the amount of lobeline derivatives in the herba grown in 740 mg L MgSO-containing medium. The most significant increase (25%) was recorded in the level of norlobelanine. [ABSTRACT FROM AUTHOR]

Rationale: Evidence suggests that neuronal nicotinic acetylcholine receptor (nAChR) ligand lobeline has antidepressant-like properties. Objectives: The present study investigated the effects of lobeline on nicotine withdrawal-induced depression-like behavior. Methods: Adult C57BL/6J mice were exposed to nicotine (200 μg/ml) in drinking solution for 3 weeks. During withdrawal, depression-like behavior was measured by the forced swim test (FST). We also determined norepinephrine (NE) levels in the prefrontal cortex (PFC) and hippocampus during nicotine withdrawal. Furthermore, we determined the effects of repeated treatment with lobeline or a selective α4β2 nAChR ligand 3-(pyridine-3́-yl)-cytisine on brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding (p-CREB) protein expression in the hippocampus. Results: Withdrawal from chronic nicotine increased immobility time in the FST, a measure for depression-like behavior. Pretreatment with lobeline significantly decreased immobility time during nicotine withdrawal. In addition, pretreatment with lobeline attenuated nicotine withdrawal-induced increased NE levels in the PFC and hippocampus. Further, repeated treatment with lobeline or 3-(pyridine-3́-yl)-cytisine decreased immobility time in the FST and reduced withdrawal-induced increased BDNF and p-CREB expression in the hippocampus. Conclusions: Taken together, our results indicate that lobeline attenuated nicotine withdrawal-induced depression-like behavior likely by targeting brain nAChRs, noradrenergic neurotransmission, and/or hippocampal BDNF. Thus, lobeline may have some potential to prevent smoking relapse by counteracting nicotine withdrawal-induced depression in humans. [ABSTRACT FROM AUTHOR]

Exposure to early life stress has been suggested to increase an individual's vulnerability to methamphetamine (MA) dependence. Although there is no cure for drug dependence, the opioid and vesicular monoamine transporter 2 (VMAT2) systems may be useful targets for treatment insofar as they play pivotal roles in the neurochemistry of addiction. Here we investigated the effects of naltrexone (opioid antagonist) and lobeline (VMAT2 inhibitor) on MA-induced place preference in adolescent rodents subjected to early life trauma (maternal separation, MS) and controls, as well as the effects on dopamine and serotonin levels in the striatum. We found: (1) maternal separation attenuated methamphetamine-induced place preference; (2) lobeline and naltrexone treatment had differential effects on serotonin and dopamine concentrations in the striatum, naltrexone increased serotonin levels in the maternally separated animals. The hypothesized effect of early adversity increasing MA-induced place preference may not be apparent in adolescence. However the data are consistent with the hypothesis that early life stress influences neurochemical pathways that predispose an individual to drug dependence. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The goal of the present study was to examine the effects of lobeline, an agonist at nicotinic receptors, on cloned Kv channels, Kv1.5, Kv3.1, Kv4.3, and human ether-a-gogo-related gene (HERG), which are stably expressed in Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. Whole-cell patch-clamp experiments revealed that lobeline accelerated the decay rate of Kv1.5 inactivation, decreasing the current amplitude at the end of the pulse in a concentration-dependent manner with a half-maximal inhibitory concentration (IC) value of 15.1 μM. Using a time constant for the time course of drug-channel interaction, the apparent association ( k), and dissociation rate ( k) constants were 2.4 μΜ s and 40.9 s, respectively. The calculated K was 17.0 μΜ. Lobeline slowed the decay rate of the tail current, resulting in a tail crossover phenomenon. The inhibition of Kv1.5 by lobeline steeply increased at potentials between −10 and +10 mV, which corresponds to the voltage range of channel activation. At more depolarized potentials a weaker voltage dependence was observed ( δ = 0.26). The voltage dependence of the steady-state activation curve was not affected by lobeline, but lobeline shifted the steady-state inactivation curve of Kv1.5 in the hyperpolarizing direction. Lobeline produced use-dependent inhibition of Kv1.5 at frequencies of 1 and 2 Hz, and slowed the recovery from inactivation. Lobeline also inhibited Kv3.1, Kv4.3, and HERG in a concentration-dependent manner, with IC values of 21.7, 28.2, and 0.34 μM, respectively. These results indicate that lobeline produces a concentration-, time-, voltage-, and use-dependent inhibition of Kv1.5, which can be interpreted as an open-channel block mechanism. [ABSTRACT FROM AUTHOR]

In the central nervous, system, vesicular monoamine transporter 2 (VMAT2) is the only transporter that moves cytoplasmic dopamine (DA) into synaptic vesicles for storage and subsequent exocytotic release. Pharmacologically enhancing DA sequenstration by VMAT2, and thus preventing the oxidation of DA in the cytoplasm, may be a strategy for treating diseases such as Parkinson's disease. VMAT2 may also be a novel target for the development of treatments for psychostimulant abuse. This review summarizes the possible role of VMAT2 as a therapeutic target, VMAT2 ligands reported in the literature, and the structure-activity relationship of these ligands, including tetrabenazine analogs, ketanserin analogs, lobeline analogs, and 3-amine-2-phenylpropene analogs. The molecular structure of VMAT2 and its relevance to ligand binding are briefly discussed. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effects of lobeline, an alkaloid constituent of Indian tobacco, on methamphetamine (METH)-induced stereotypy in male ICR mice (41–50 days old), an animal model for amphetamine psychosis. After a single administration of METH (10 mg/kg, i.p.), mice showed an initial short-lasting hyperlocomotion and subsequent stereotyped behaviors with a plateau level 25 min after drug challenge. Pretreatment with lobeline (3.0–30 mg/kg, i.p.) 15 min prior to the drug challenge significantly decreased the intensity of stereotypy and increased its latency to onset in a dose-dependent manner, especially 20 min after the drug challenge. In saline challenge groups, the doses of lobeline examined did not affect spontaneous locomotion nor induced any stereotyped behaviors. High-performance liquid chromatography analysis revealed that the range of lobeline doses examined except 30 mg/kg did not affect apparent monoamine turnover in the cerebral cortex, the region of the striatum and nucleus accumbens, and the region of the thalamus and hypothalamus of the mice 20 and 60 min after the drug challenge. These results suggested that the inhibitory effect of lobeline (3.0–10 mg/kg) on METH-induced stereotypy was not attributed to the change in the apparent monoamine turnover. [ABSTRACT FROM AUTHOR]

Larvae of the cabbage looper, Trichoplusia ni (Lepidoptera: Noctuidae), often transect leaves with a narrow trench before eating the distal section. The trench reduces larval exposure to exudates, such as latex, during feeding. Plant species that do not emit exudate, such as Plantago lanceolata, are not trenched. However, if exudete is applied to a looper's mouth during feeding on R lanceolata, the larva will often stop and cut a trench. Dissolved chemicals can be similarly applied and tested for effectiveness at triggering trenching. With this assay, I have documented that lactucin from lettuce latex (Lactuca sativa), myristicin from parsley oil (Petroselinurn crispurn), and lobeline from cardinmi flower (Lobelia cardinalis) elicit trenching. These compounds are the first trenching stimulants reported. Several other constituents of lettuce and parsley, including some phenylpropanoids, monoterpenes, and furanocoumarins had little or no activity. Cucurbitacin E glycoside found in cucurbits, another plant family trenched by cabbage loopers, also was inactive. Lactucin, myristicin, and lobeline all affect the nervous system of mammals, with lobeline acting specifically as an antagonist of nicotinic acetylcholine receptors. To determine if cabbage loopers respond selectively to compounds active at acetylcholine synapses, I tested several neurotransmitters, insecticides, and drugs with known neurological activity, many of which triggered trenching. Active compounds included dopamine, serotoniu, the insecticide imidacloprid, and various drugs such as ipratropium, apomorphine, buspirone, and metoclopramide. These results document that noxious plant chemicals trigger trenching, that loopers respond to different trenching stimulants in different plants, that diverse neuroactive chemicals elicit the behavior, and that feeding deterrents are not all trenching stimulants. The trenching assay offers a novel approach for identifying defensive plant compounds with potential uses in agriculture or medicine. Cabbage loopers in the lab and field routinely trench and feed on plants in the Asteracene and Apiaceae. However, first and third instar larvae enclosed on Lobelia cardinalis (Campanulaceae) failed to develop, even though the third instar larvae attempted to trench. Trenching ability does not guarantee effective feeding on plants with canal-borne exudates. Cabbage loopers must not only recognize and respond to trenching stimulants, they must also tolerate exudates during the trenching procedure to disable canalicular defenses. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the mechanisms involved in the effect of nicotinic agonists on the [3H]norepinephrine ([3H]NE) release from rat hippocampal slices. The stimulatory effect of nicotine, cytisine, epibatidine and anatoxin-A was completely blocked by the nicotinic antagonist mecamylamine (10 μM). In contrast, the effect of dimethylphenylpiperazinium (DMPP) was only partially inhibited by mecamylamine but was completely blocked by the NE uptake inhibitor desipramine (DMI, 10 μM). Finally, the effect of lobeline was not affected by mecamylamine and was only partially blocked by DMI. Our data indicate that the majority of nicotinic agonists increase the release of [3H]NE exclusively via stimulation of nicotinic acetylcholine receptors (nAChRs). DMPP, in addition to the stimulation of nAChRs, also evokes a carrier-mediated release. Lobeline has no stimulatory effect on nAChRs, induces a carrier-mediated release and has a further action of unidentified mechanism. Our results suggest that special caution is required for the interpretation of data, when DMPP or lobeline are used as nicotinic agonists. [ABSTRACT FROM AUTHOR]

The effects of nicotinic receptor ligands on performance in a task measuring sustained attention, or vigilance, were tested. This task required the animals to discriminate between signal and non-signal events. The sequence of signal (central panel light illumination for 500, 50 or 25 ms) and non-signal presentations was randomized over three blocks of 54 trials each (27 signal trials, 9 per length, and 27 non-signal trials). A left lever press following a signal was counted as a hit, and a right lever press following a non-signal event was counted as a correct rejection. Hits and correct rejections were rewarded, whereas misses and false alarms (defined as incorrect right and left lever presses, respectively) were not. Baseline performance was characterized by a signal length dependent ability of the animals to discriminate between signal and non-signal events. Administration of nicotine (0.19, 0.62, 1.9 µmol) or of two novel nicotinic receptor agonists, ABT-418 and A-82695, did not produce main effects on vigilance performance. Lobeline (1.9, 6.2, 19 µmol), a nicotinic receptor ligand with mixed agonist/antagonist activities, impaired the animals' ability to discriminate between signal and non-signal events. The antagonist mecamylamine (5, 15, 50 µmol) potently impaired performance while increasing the number of errors of omission. The lack of effect of nicotine largely corresponds with the findings from previous studies on the acute effects of nicotine in intact subjects and nonsmoking humans. While the detrimental effects of lobeline may have been related to the antagonist effects of this compound, the reasons for the differences between the effects of nicotine and lobeline still remain unsettled. These data support the hypothesis that nicotine receptor mechanisms are maximally activated in intact animals performing this task, and suggest that effects of acute nicotinic agonist treatment would not produce further cognitive benefit for these animals. [ABSTRACT FROM AUTHOR]

The effects of nicotine and related compounds on locomotor activity were compared in experimentally naive rats and in animals chronically exposed to nicotine and the photocell test chambers. In experimentally naive rats, all nicotinic compounds decreased locomotion in a dose-related manner and the rank order of potency was (−)-nicotine>(+)-nornicotine>(+)-nicotine > cytisine > lobeline > anabasine. Mecamylamine attenuated the locomotor depressant effects of most of the agonists, except lobeline. In rats previously exposed to nicotine and the test apparatus for several weeks, (−)-nicotine increased locomotor activity in a dose-related manner, with a maximal increase to 400% of baseline at a dose of 0.4 mg/kg. One or more doses of (+)-nicotine, (+)-nornicotine and anabasine also increased locomotor activity in these animals, although the maximal effects seen were in all cases less than the maximal effect of (−)-nicotine. Cytisine and lobeline failed to increase locomotor activity at any dose tested. These conclusions were not altered by consideration of the time-courses for the effects of the different drugs. Thus, the results confirm that the locomotor stimulant and depressant effects of nicotine can be dissociated from each other, a finding that may be explained by differences in their actions at nicotinic receptors. [ABSTRACT FROM AUTHOR]

The effects of nicotine, lobeline, anabasine, cytisine, coniine, sparteine, piperidine, acetylcholine, tetramethylammonium (TMA) and dexamphet-amine, given as i.a. bolus injections, were studied in the cat superior cervical ganglion (SCG) in situ and compared with those of (DMPP) 1,1-dimethyl-4-phenylpiperazinium described in a preceding paper. Two main events are thought to determine the ganglionic response to these agents. A non-selective conductance increase of the ganglion cells by stimulation of nicotinic receptors is responsible for depolarization, firing, facilitation of ganglionic transmission and depolarization block. The accumulation of Na resulting from the altered conductance activates an electrogenic Na- pump which tends to increase the membrane potential and causes a delayed unspecific depression of ganglionic excitability. After agents with a brief agonistic action (acetylcholine, DMPP, TMA), the two mechanisms lead to a distinct biphasic effect on ganglionic polarity (initial depolarization, later hyperpolarization) and transmission (early and later block); with the nicotinic agonists of long duration of action the effect of the electrogenic Na-pump was obscured by the long-lasting activation of nicotinic receptors and was usually revealed only by special pharmacological procedures. An additional preganglionic depression of transmitter release is very likely. A desensitization of nicotinic receptors occurred after high single or repeated doses of nicotine, resulting in a selective unsurmountable block. A competitive block of nicotinic receptors occurred after coniine. Local anaesthetic properties of lobeline and dexamphetamine interfered with the two main events when high doses were given. The only effect of sparteine was to produce a short-lasting hexamethonium-like block of transmission. [ABSTRACT FROM AUTHOR]

Hairy roots were obtained following inoculation of the stems of Lobelia inflata L. with Agrobacterium rhizogenes strain ATCC 15834. These hairy roots contained agropine and mannopine. In addition, lobeline was detected by HPLC and confirmed by mass spectrometry. Various media were tested for the growth of hairy roots as well as for the content of lobeline in hairy roots. The growth rate of hairy roots cultured in Nitsch and Nitsch's medium was approximately one third of those cultured in other media. The lobeline content of hairy roots (18-54 μg/g dry weight) cultured in these media was the same order of magnitude compared with that of roots of L. inflata (24 μg/g dry weight) cultivated in pots. The hairy roots cultured in Nitsch and Nitsch's medium were morphologically different from those cultured in other media. [ABSTRACT FROM AUTHOR]

In frog sartorius muscles, lobeline had no effect on resting membrane potentials but prevented depolarization of the fibers by nicotine. The blockade caused by lobeline was not antagonized by elevated concentrations of nicotine. Procedures that prevented depolarization of the fibers by nicotine had no effect on the anti-nicotinic effects of nicotine. It was concluded that receptor desensitization in skeletal muscle does not require depolarization of the fibers. [ABSTRACT FROM AUTHOR]

Evidence is presented to show that nicotine and lobeline cause desensitization of frog sartorius muscle cells. Nicotine (3.3 to 166 μM) caused a dose-dependent depolarization. The membrane potential returned to control in 30-40 min in the presence of nicotine. The duration of the nicotine-induced depolarization was not related to the nicotine concentration. In contrast, the duration of the depolarization induced by carbachol (109-546 μM) decreased as the concentration of carbachol was increased. The desensitization caused by lobeline (3-300 μM) differed from that caused by nicotine and other cholinomimetic agents in that it was not preceded by a depolarization-repolarization sequence of change in the muscle cell membrane. At the time of repolarization after nicotine or during exposure to lobeline the application of a second dose of nicotine had no effect or caused a depolarization that was low in amplitude and brief in duration (<3 min). In contrast to nicotine and lobeline d-tubocurarine ( d-TC: 1.4-14 μM) reduced the amplitude of the nicotine depolarization but did not affect the duration 930 to 40 min). Tetraethylammonium (1-5 mM) reduced the amplitude and duration (5-15 min) of the nicotine-induced depolarization. Nicotine caused an increase in K efflux which paralleled the time course of the nicotine-induced depolarization. Lobeline and d-TC did not stimulate K efflux. After the muscles had been soaked for 30 to 60 min in nicotine, lobeline or d-TC, the stumulation of K efflux caused by a second dose of nicotine was decreased. The nicotine-induced stimulation of K efflux in desensitized muscles paralleled the nicotine-induced changes in the muscle membrane potential seen during desensitization. On the basis of the duration of the nicotine-induced depolarization it was concluded that lobeline's antinicotinic effect was due to desensitization. These data further suggest that nicotine acts as a metaphilic agonist and that lobeline acts as a metaphilic antagonist. [ABSTRACT FROM AUTHOR]

The actions of d-tubocurarine, lobeline and nicotine were studied at the end-plate region of frog sartorius muscle fibers bathed in Frog-Ringer solution containing 12 mM MgCl. End-plate potentials (EPPs) evoked by stimulation of the sciatic nerve were monitored with KCl-filled microelectrodes using standard techniques. Quantal content ( m) was calculated from the coefficient of variation of 110 repetitively evoked EPPs at 1 Hz. Both d-tubocurarine (10 M) and lobeline (10 M and 2×10 M) decrease the amplitude of the evoked EPP without causing significant change in the resting potential of the end-plate membrane. Nicotine (10 M and 3×10 M) causes initial depolarization and subsequent repolarization of the end-plate membrane. During both these phases, the EPP amplitude progressively declines. The decrease in EPP amplitude caused by d-tubocurarine and lobeline is due primarily to an interference with the postjunctional action of the transmittor as evidenced by a decrease in quantal size ( q) without significant alteration in m. In contrast, the decrease in EPP amplitude caused by nicotine during its phase of maximum depolarization is accounted for by a decrease in both q and m. The depression of the EPP amplitude when the end-plate membrane has repolarized under the influence of nicotine is due to receptor desensitization. These results indicate that at the frog neuromuscular junction the actions of lobeline more closely resemble those of d-tubocurarine rather than nicotine. The depression of m during nicotine-induced depolarization of the end-plate membrane may be related to a similar depolarization of the motor nerve ending. [ABSTRACT FROM AUTHOR]

Rats were trained to enter one arm of a T-maze after the subcutaneous administration of 0.4 mg/kg and to enter the opposite arm following the injection of an equal volume of saline. Administration of 0.4 mg/kg nicotine isomethonium iodide hydroiodide, 0.4-10.0 mg/kg lobeline sulfate, 2.0 and 4.0 mg/kg d-amphetamine sulfate and 0.25-2.0 mg/kg arecoline hydrobromide produced responses which resembled the established saline effect. Pretreatment with 10.0 mg/kg lobeline had no significant effect on the nicotine-cued response. The inability of these structurally and/or functionally similar drugs to produce a nicotine-like discriminative effect is discussed. [ABSTRACT FROM AUTHOR]