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Nicotine renal excretion rate influences
nicotine intake during cigarette smoking.

J Pharmacol Exp Ther. 1985 July;234(1):153-5.

Benowitz NL, Jacob P 3rd.

We examined the hypothesis that rate of elimination of nicotine affects nicotine intake during cigarette smoking. Elimination rate was altered by administering ammonium chloride or sodium bicarbonate throughout the day. Nicotine intake during unrestricted cigarette smoking was measured using metabolic clearance data obtained after i.v. nicotine infusion together with blood and urinary nicotine concentrations measured during 24-hr periods of cigarette smoking. Compared with placebo treatment (urine pH 5.6), urinary acidification (pH 4.5) increased (208%) renal clearance and, to a lesser extent (41%), total clearance and increased (by 7.2 mg) daily urinary excretion of nicotine. Urinary alkalinization (pH 6.7) resulted in a decrease (78%) in renal clearance with a small decrease (3.7 mg) in daily nicotine excretion. Average blood nicotine concentrations were similar in placebo and bicarbonate treatment conditions, but were 15% lower during acid loading. Daily intake of nicotine was 18% greater during acid loading. The compensatory increase in nicotine consumption was only partial, replacing about half the excess urinary nicotine loss. This is the first direct demonstration that rate of elimination can influence self-determined drug consumption in humans.

PMID: 4009497 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=4009497

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Effects of urinary pH on the behavioral
responses of squirrel monkeys to nicotine.

Pharmacol Biochem Behav. 1983 Sep;19(3):553-7.

Grunberg NE, Morse DE, Barrett JE.

The present study evaluated the behavioral effects of nicotine under conditions that manipulated urinary pH. The effects of nicotine were examined on the responding of squirrel monkeys under a multiple fixed-interval, fixed-ratio schedule of stimulus-shock termination when nicotine was administered alone or together with the gastric administration of an acidifier (ammonium chloride) or an alkalinizer (sodium bicarbonate). Responding under the FI schedule was increased markedly across a range of doses of nicotine (0.02-0.20 mg/kg). Responding under the FR was increased to a lesser extent by the lower doses of nicotine (0.02-0.05 mg/kg) and was decreased by doses of nicotine that increased responding under the FI (0.10-0.20 mg/kg). Generally, administration of the acidifier attenuated the effects of nicotine while administration of the alkalinizer potentiated those effects. These findings support the argument that changes in cigarette smoking under conditions that alter urinary pH involve nicotine per se. In addition, a new interpretation of the relationship between urinary pH and cigarette smoking is offered.

PMID: 6314394 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=6314394

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Protons enhance the gating kinetics of the alpha3/beta4 neuronal nicotinic acetylcholine receptor by increasing its apparent affinity to agonists.

Mol Pharmacol. 2002 February;61(2):369-78.

Abdrakhmanova G, Dorfman J, Xiao Y, Morad M.

Department of Pharmacology, Georgetown University School of Medicine, Washington DC 20007, USA.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the nervous system. Although there is a vast literature on the molecular, structural and pharmacological properties of neuronal nAChR, little is known of their pH regulation. Here we report that rapid acidification (pH 6.0) enhances the current through the alpha3/beta4 recombinant nAChRs expressed stably in human embryonic kidney 293 cells and accelerates its activation kinetics without altering selectivity. Acidification also strongly accelerates the decay kinetics ("desensitization") of cytisine- and nicotine-evoked currents (pK(a) approximately 6.1), but the effect is somewhat smaller with acetylcholine and carbachol (undetermined pK(a) values), suggesting that protonation of the agonist contributes to the relaxation of the current. Transient increases of [H(+)](o) from pH 7.4 to 6.0, during the time course of decay of the current, enhances the current and accelerates its decay kinetics in a manner similar to reactivation of current by higher concentrations of agonists. We suggest that protons interact with multiple extracellular sites on alpha3/beta4 nAChRs, decreasing the effective EC(50) values of the agonist and accelerating gating kinetics, in part by promoting agonist-induced block. We speculate that corelease of protons with ACh from the secretory vesicles may induce rapid and reversible conformational changes in the slowly "desensitizing" alpha3/beta4 nAChRs, leading to accelerated signaling.

PMID: 11809862 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11809862

It's Clean-up Time!

We can continue to sell our mind on the rationalization that smoking the alkaloid nicotine helped relieve stress or dig a bit deeper and conclude that we were instead doing was adding the onset of early withdrawal to each and every stressful acid producing event that life threw our way.

Imagine facing daily challenges without being forced to flee into your addiction. It is far far easier being "you" than the neurochemical mess that nicotine has for far too long been allowed to make of your mind.

John (Gold x5)

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