Cigarette Smoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors

Higher β2*-nAChR availability is thought to functionally reflect higher numbers of desensitized receptors.

“Higher β2*-nAChR availability is thought to functionally reflect higher numbers of desensitized receptors13, 14.”

Smokers experience craving within 2 h of their last cigarette despite continued occupancy of the receptor by nicotine.

“Smokers experience craving within 2 h of their last cigarette despite continued occupancy of the receptor by nicotine13.”

In a PET imaging study, β2* occupancy was ∼88% after just 1 cigarette, with corresponding plasma levels that have been shown to lead to 50% desensitization of α4β2 nAChRs.

“In a recent positron emission tomography (PET) imaging study, β2* occupancy was ∼ 88% percent after just 1 cigarette, with corresponding plasma levels that have been shown to lead to 50% desensitization of α4β2 nAChRs (Brody et al., 2006).”

Smoking one cigarette led to greater than 88% receptor occupancy, suggesting that smokers maintain saturation of β2*-nAChRs over the day.

“Additionally, smoking one cigarette led to greater than 88% receptor occupancy13 suggesting that smokers maintain saturation of β2*-nAChRs over the day.”

Maintained nAChR desensitization may be important for relieving nicotine withdrawal in human smokers.

“For instance, it has been suggested that maintained nAChR desensitization may be important for relieving nicotine withdrawal in human smokers (Brody et al., 2006) as is discussed below.”

Regular smokers approach complete saturation of CNS α4β2* nAChRs throughout the day.

“it was found that regular smokers approach complete saturation of CNS α4β2* nAChRs throughout the day (Brody et al. 2006).”

After 2 days of smoking abstinence, cravings in tobacco-dependent individuals were reduced only once nAChRs were again nearly saturated.

“After 2 days of abstaining from smoking, participants’ cravings were reduced only once nAChRs were again nearly saturated.”

α4β2 nAChRs desensitize at nicotine concentrations lower than those required for activation and are mostly desensitized in brains of smokers.

“These receptors desensitize at nicotine concentrations lower than those required for activation (Fenster et al. 1999) and, as a result, are mostly desensitized in brains of smokers (Brody et al. 2006).”

[3H]2-FA-85380 binds selectively to β2-containing nAChRs.

“In contrast, [3H]2-FA-85380 binds selectively to b2-containing nAChRs (Brody et al, 2006; Deuther-Conrad et al, 2006; Vaupel et al, 2005).”

Reports that surprisingly low concentrations of nicotine saturate α4β2 receptors for surprisingly long periods may partially measure the effects of much higher nicotine concentrations at receptors in acidic organelles.

“Reports that surprisingly low concentrations of nicotine saturate α4β2 receptors, and for surprisingly long periods, may partially measure the effects of much higher nicotine concentrations at receptors in such organelles (80,81).”

Assuming the effective concentration to occupy 50% of 2FA-labeled receptors in humans is 0.87 ng/mL, residual nicotine occupancy should be less than 1%.

“Assuming that the effective concentration to occupy 50% of the receptors labeled by 2FA in humans is 0.87 ng/mL (31), the percentage occupancy of receptors by residual nicotine should be less than 1%.”

Brody et al. reported that nicotine from smoking to satiety occupies 95% of nAChRs and that smoking a single cigarette reduces available receptors by 88%.

“Brody et al. (31) reported that nicotine from smoking to satiety occupies 95% of nAChRs in a study using 2FA as the radioligand. Smoking a single cigarette reduces available receptors by 88% (31).”