Activation of a4b2*/a6b2* Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors
نویسندگان
چکیده
Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT ); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for a4b2, ABT-089 [2-methyl-3-[2(S)pyrrolidinylmethoxy]pyridine], and a7, ABT-107 [5-(6-[(3R)-1azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole] (AbbVie, North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and b2-containing nAChRs were measured using [H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotinedependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.
منابع مشابه
JPET #211706 1 Activation of α4β2*/α6β2* Nicotinic Receptors Alleviates Anxiety During Nicotine Withdrawal Without Upregulating Nicotinic Receptors
متن کامل
Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors.
Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT); however, treatment with this drug fails to alleviate anxiety in ind...
متن کاملConstruction of SH-EP1-a4b2-hAPP695 Cell Line and Effects of Nicotinic Agonists on b-amyloid in the Cells
1) Nicotinic acetylcholine receptors in central nervous system are thought to be new targets for Alzheimer’s disease. However, the most involved nicotinic receptor subtype in Alzheimer’s disease is unclear. a4b2 receptor is the most widely spread subtype in brain, involving in several important aspects of cognitive and other functions. We constructed cell line by transfecting human amyloid prec...
متن کاملThe Activation and Inhibition of Human Nicotinic Acetylcholine Receptor by RJR-2403 Indicate a Selectivity for the α4β2 Receptor Subtype
Human nicotinic acetylcholine (ACh) receptor subtypes expressed in Xenopus oocytes were characterized in terms of their activation by the experimental agonist RJR-2403. Responses to RJR-2403 were compared with those evoked by ACh and nicotine. These agonists were also characterized in terms of whether application of the drugs had the effect of producing a residual inhibition that was manifest a...
متن کاملChronic Exposure to Nicotine Upregulates the Human a4b2 Nicotinic Acetylcholine Receptor Function
Widely expressed in the brain, the a4b2 nicotinic acetylcholine receptor (nAChR) is proposed to play a major role in the mechanisms that lead to and maintain nicotine addiction. Using the patch-clamp technique and pharmacological protocols, we examined the consequences of long-term exposure to 0.1–10 mM nicotine in K-177 cells expressing the major human brain a4b2 receptor. The acetylcholine do...
متن کامل