These compounds enable effective treatment of neurological disorders involving cognitive deficits (including Alzheimer’s and Parkinson’s diseases), depression and drug dependences such as tobacco (nicotine) and betel nut addictions. Neurological diseases including drug addictions are a major health cost to human societies. By 2030, more than 8 million individuals will die annually from illnesses caused by tobacco use, while 600 million individuals remain addicted to some form of betel nut or quid, a psychoactive substance that is carcinogenic. Drugs available to help individuals quit an addictive habit often have undesirable side effects or are ineffective. Researchers at the University of Florida have developed a variety of nicotinic receptor agonists (activators) based on a marine natural product named anabaseine that selectively stimulate only one of a large number of nicotinic receptors found in the mammalian brain; the alpha7 receptor is a major mediator of brain activity associated with learning and memory. Stimulation of this receptor also has anti-inflammatory actions that are thought to be involved in neuroprotective action in neurodegenerative disease animal models. On the other hand, antagonists based on a plant compound, cytisine, are important in treating tobacco and other chemical addictions. Empirical results suggest that when combined, the two types of compounds offer a more effective reduction in nicotine addiction than currently available drugs.
Safe and efficient treatment of neurological disorders and addictions
These compounds target selective expression of alpha-7 and alpha-4-beta-2; nicotinic acetylcholine receptor (nAChR) subtypes that impact cognition, mood, and neuroprotection. Research shows that alpha-4-beta-2 is always associated with addiction. But fewer alpha-7 receptors are expressed if the host suffering from addiction is stressed or suffering from depression. To treat depression, anabaseines can selectively promote alpha-7 receptors while acting as antagonists for alpha-4-beta-2 receptors, which would otherwise interfere with the positive effects of the drug. When individuals suffering from nicotine addiction use nicotine, alpha-4-beta-2 rewards them, creating a dependence effect. To combat nicotine addiction, preliminary research suggests that partial agonists modestly stimulate the same reward circuit of alpha-4-beta-2 receptors that nicotine does, ultimately reducing cravings and blunting the peaks of receptor activation that cigarette smoking or betel quid chewing would create. Unfortunately, available drugs that suppress the rewarding effects of nicotine by inhibiting alpha-4-beta-2 receptors may cause worsened depression or even suicide. By using partial agonists for alpha-7 receptors, drug developers can stimulate alpha-7 receptors unopposed by a concurrent alpha-4-beta-2 inhibitory effect and decrease the function of alpha-4-beta-2 nAChR to treat dependence while counteracting depression.