Neurotoxicological Profile Assessment of Lobeline after Acute Treatment in Mice

Abstract

Lobeline is a natural alkaloid with high affinity for nicotinic acetylcholine receptors, and it is a promising candidate for addiction treatment in human beings. This work evaluated the toxicological profile of lobeline with different behavioural models and investigated its effect on DNA damage (comet assay and micronucleus test) in mice. Acute administration of lobeline (5 or 10 mg/kg; i.p.) did not impair the parameters measured in the habituation and inhibitory avoidance test, suggesting that it has no effect on memory acquisition in these tasks. Lobeline did not affect the number or the latency to the first head-dip in the hole board test, indicating that it was not anxiolytic/anxiogenic in this model. No genotoxic effects were observed in blood, liver and brain tissues collected 24 hr after the single injection of lobeline (both doses). There was no increase in micronucleus frequency in mice treated with lobeline, indicating the absence of toxicity in bone marrow of the animals. Therefore, the acute treatment with high doses of lobeline did not impair the behavioural parameters measured in this work. Additionally, the drug was not able to produce DNA damage.Lobeline ( Fig. 1) is a natural alkaloid found in Lobelia inflata and has a long history of therapeutic use, as emetic and respiratory stimulant and tobacco smoking cessation agent, among other applications [1,2]. Lobeline is a nAChR ligand that has high affinity for both heteromeric and homomeric nicotinic acetylcholine receptors (nAChR), which are responsible for its antagonist as well as agonist actions [3].Some works have evaluated the effects of lobeline on behaviour. It showed anxiolytic properties and was able to inhibit the behavioural and neurochemical effects of psychostimulants in animal models [4]. Lobeline reduced voluntary ethanol drinking behaviour [5] and ethanol-induced increase in midbrain dopamine function in rodents [6]. Recently, it was reported that lobeline presents antidepressant-like effect that could be mediated in part by interaction with neuroendocrine and brain noradrenergic systems [4].Lobeline also binds and inhibits the function of vesicular monoamine transporter (VMAT) and dopamine transporter (DAT) [3,4]. Results suggest that it functions as a l-opioid antagonist. It diminishes the reinforcing properties of methamphetamine in rodents and is proposed as a treatment for nicotine and methamphetamine addiction [3].In the elevated plus-maze and marble-burying test, used as animal models to measured anxiety-like behaviour, lobeline demonstrated anxiolytic effect likely by targeting nAChRs [7].Considering the pharmacological profile of lobeline and its potential as a new therapeutic drug, the goal of this study was to investigate the toxicological profile of high lobeline doses on locomotor activity, anxiety and memory in mice. Additionally, we evaluated the DNA damage in several tissues with the comet assay and the mutagenicity in bone marrow with micronucleus test, because there are few studies on lobeline genotoxic...