Toxic Ants, Chinese Snakes, and Indian Tobacco (15)
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The final two agonists of nAChR’s that are of note both preferentially target α7 receptors, which are a class that particularly interest researchers of schizophrenia. Ribbon worms (Nemertines, formally) and Aphaenogaster ants produce an alkaloid toxin named anabaseine. Though it causes paralysis in crustaceans and insects, vertebrates (thankfully) don’t succumb to the poison. Structurally similar to nicotine, it binds to most nAChRs, causing a release of dopamine and norepinephrine. The University of Florida at Gainesville and Taiho Pharmaeuticals developed an analogue from it called GTS-21 which has a greater affinity for α7 receptors than α4β2 receptors. It is being studied for its neuroprotective effects with hopes of applications for AD and ADHD-stricken individuals.
A CHINESE SNAKE
The Chinese many-banded krait snake’s bungarotoxin venom also targets α7 receptors and has inspired an analogue called SEN12333. It has great affinity for the α7 receptors, has shown neuroprotective effects, and is being studied for the treatment of AD and schizophrenia. Though this review has focused on agonists of the nAChRs, it is worthwhile to note the effects of the selective agonist and antagonist lobeline, a pyridine alkaloid found in a variety of plants, including the Lobelia inflata, better known as Indian tobacco.
A mild agonist of the α3β2 and an allosteric modulator of the α4β2 receptor, lobeline also stimulates the release of dopamine and norepinephrine and potently inhibits dopamine’s reuptake, though, peculiarly, it does not show habituation in animal studies. Despite its lack of habituation, it is tolerance forming. Lobeline has been shown to reduce depressive symptoms and voluntary ethanol consumption in mice, reduce ADHD activity derived from nicotine and amphetamine use, improve working memory in humans with ADHD, and have neuroprotective effects from the damage occurred from seizures.
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 Kem, W. R. (2000). The brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21). Behavioural brain research, 113(1-2), 169-181.  Pohanka, M. (2012). Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology. International journal of molecular sciences, 13(2), 2219-2238.  Roncarati, R., Scali, C., Comery, T. A., Grauer, S. M., Aschmi, S., Bothmann, H., ... & Zanelli, U. (2009). Procognitive and neuroprotective activity of a novel α7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders. Journal of Pharmacology and Experimental Therapeutics, 329(2), 459-468.  Dwoskin, L. P., & Crooks, P. A. (2002). A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. Biochemical pharmacology, 63(2), 89-98.  Damaj, M. I., Patrick, G. S., Creasy, K. R., & Martin, B. R. (1997). Pharmacology of lobeline, a nicotinic receptor ligand. Journal of Pharmacology and Experimental Therapeutics, 282(1), 410-419.  Roni, M. A., & Rahman, S. (2017). Lobeline attenuates ethanol abstinence-induced depression-like behavior in mice. Alcohol, 61, 63-70.  Sajja, R. K., & Rahman, S. (2011). Lobeline and cytisine reduce voluntary ethanol drinking behavior in male C57BL/6J mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35(1), 257-264.  Martin, C. A., Nuzzo, P. A., Ranseen, J. D., Kleven, M. S., Guenthner, G., Williams, Y., ... & Dwoskin, L. P. (2018). Lobeline effects on cognitive performance in adult ADHD. Journal of attention disorders, 22(14), 1361-1366.  e Silva, L. D. D. C., Pereira, P., Regner, G. G., Boaretto, F. B. M., Hoffmann, C., Pflüger, P., ... & Picada, J. N. (2018). DNA damage and oxidative stress induced by seizures are decreased by anticonvulsant and neuroprotective effects of lobeline, a candidate to treat alcoholism. Metabolic brain disease, 33(1), 53-61.