Posted by undopaminergic on June 1, 2008, at 6:12:20
Prompted by another thread, I did a small review of nicotinic acetylcholine receptors (nAchRs). These receptors occur in various locations of the body, some of the most notable ones being the central nervous system (CNS, ie. brain), muscles, and adrenal medulla.
Muscular nAchRs are involved in the contraction of skeletal muscles, and these receptors can be blocked by curare compounds, including the natural alkaloid tubocurarine and many synthetic analogues such as vecuronium, pancuronium, and so on. Known as nondepolarising neuromuscular blocking agents, these drugs are used in combination with anaesthetics and mechanical ventilation during surgery and other medical procedures.
Activation of nAchRs of the adrenal medulla results in the release of adrenaline (of which epinephrine is a popular synonym). Physiologically, they are activated by acetylcholine released from sympathetic nerve endings, but they can also be manipulated pharmacologically by nicotine and other substances.
Nicotinic receptors of the CNS play a number of roles, some of which are briefly discussed below.
A few nicotinic compounds of interest are:
1. Nicotine itself. Classically, nicotine is administered through inhalation of tobacco smoke, or by transmucosal absorption from oral tobacco products. More recently, nicotine chewing gum has become popular, and so have patches that facilitate transdermal absorption of nicotine. Nicotine is also used as a pesticide, and it is probably for this purpose that the alkaloid is produced by Nicotiana tabacum and a number of other plants.
Nicotine is extremely addictive, and although the withdrawal syndrome is relatively mild in comparison with that associated with many other substances, long-term abstinence is very difficult to achieve for many addicts.
According to Wikipedia, chronic use of nicotine enhances the sensitivity of the reward pathways of the brain, which is in contrast to heroin, cocaine, and probably other drugs of abuse. This leads to the interesting question of whether nicotine might be medicinally useful for other purposes than smoking cessation and maintenance therapy for the avoidance nicotine withdrawal symtoms.
2. bupropion (Wellbutrin), is a noncompetitive antagonist of the alpha3beta4 nAchRs, and one of its metabolites may show significant antagonism of alpha4beta2 nAchRs as well. In addition to its use as an antidepressant, bupropion is approved for smoking cessation in many countries. According to Wikipedia, antagonism of the alpha3beta4 nAchRs also reduces the self-administration of morphine and methamphetamine in rats, so bupropion may possibly have a role in the treatment of other addictions than that to nicotine. An interesting question is whether bupripion's nicotinic mechanisms of action play a role in its efficacy as an antidepressant.
3. memantine has significant potency as an antagonist of alpha7 nicotinic receptors. Among other things, this accounts for the prevention of MDMA-toxicity by memantine.
4. varenicline (Champix or Chantix) is a relatively new drug marketed for smoking cessation. It is a potent partial agonist (approx. 13% efficacy relative to acetylcholine) at alpha4beta2 nAchRs, a less potent but more effective partial agonist (75% efficacy) at alpha3beta4 nAchRs, a weak partial agonist (less than 10% efficacy) at alpha6 nAchRs, and finally, a potent full agonist (about 93% efficacy) at alpha7 nAchRs.
Varenicline has been linked to traffic accidents, and to various neuropsychiatric adverse events. One might wonder whether this is related to its agonism of alpha7 nicotinic receptors.
5. cytisine is an alkaloid produced by a number of plants. It's a nicotinic receptor agonist, but I currently have no details on its profile at different receptors. It's apparently quite toxic, although perhaps less so than nicotine, and it has been used recreationally.
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Comments and additions are requested, especially regarding additional roles of nicotinic receptors, details on their involvement in reward processing and interactions with dopamine. Furthermore, additions to the list of nicotinic drugs are of interest, and so are further details on the ones already mentioned.
poster:undopaminergic
thread:832325
URL: http://www.dr-bob.org/babble/neuro/20080418/msgs/832325.html