Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline.

Previous work has suggested that cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.

Inhibition of brain choline uptake by isoarecolone and lobeline derivatives: implications for potential vector-mediated brain drug delivery.

Delivery of certain compounds to brain is restricted by the nature of the blood-brain barrier (BBB). Many valuable pharmaceuticals are excluded from the CNS due to hydrophilicity or charge. These limitations have been overcome by numerous methods. One method we use is to take advantage of saturable nutrient transporters located at the barrier. These systems transport hydrophilic and charged nutrients into brain such as choline, a quaternized neurotransmitter precursor. Using knowledge of their substrate specificity, it is possible to deliver agents into brain using these nutrient carriers. In this report, derivatives of lobeline and isoarecolone were evaluated to determine if they may gain access to brain by the blood-brain barrier basic amine transporter using the in situ brain perfusion technique. These compounds do bind the blood-brain barrier basic amine transporter and may enter brain by this transport system.

Neuronal nicotinic receptor antagonist reduces anxiety-like behavior in mice.

Brain cholinergic neurotransmission has been implicated in the modulation of anxiety in humans and evidence suggests that drugs targeting neuronal nicotinic acetylcholine receptor (nAChR) could have potential for the treatment of anxiety. The objective of present study was to examine anxiolytic effects of lobeline (0.04 or 0.1 mg/kg), a nAChR antagonist, in C57BL/6J mice using elevated plus-maze (EPM) and marble-burying test. Lobeline (0.04 mg/kg) significantly increased open arm time on EPM and reduced number of marbles buried. Similarly, mecamylamine (0.3 mg/kg) produced anxiolytic effects, while peripherally acting hexamethonium (0.3 mg/kg) failed to produce any response. These results provide evidence that lobeline has anxiolytic potential and nAChR antagonists may represent a new class of anxiolytics in humans.