Tobacco smoking interferes with GABAA receptor neuroadaptations during prolonged alcohol withdrawal.

Understanding the effects of tobacco smoking on neuroadaptations in GABAA receptor levels over alcohol withdrawal will provide critical insights for the treatment of comorbid alcohol and nicotine dependence. We conducted parallel studies in human subjects and nonhuman primates to investigate the differential effects of tobacco smoking and nicotine on changes in GABAA receptor availability during acute and prolonged alcohol withdrawal. We report that alcohol withdrawal with or without concurrent tobacco smoking/nicotine consumption resulted in significant and robust elevations in GABAA receptor levels over the first week of withdrawal. Over prolonged withdrawal, GABAA receptors returned to control levels in alcohol-dependent nonsmokers, but alcohol-dependent smokers had significant and sustained elevations in GABAA receptors that were associated with craving for alcohol and cigarettes. In nonhuman primates, GABAA receptor levels normalized by 1 mo of abstinence in both groups--that is, those that consumed alcohol alone or the combination of alcohol and nicotine. These data suggest that constituents in tobacco smoke other than nicotine block the recovery of GABAA receptor systems during sustained alcohol abstinence, contributing to alcohol relapse and the perpetuation of smoking.

Changes in the cholinergic system between bipolar depression and euthymia as measured with [123I]5IA single photon emission computed tomography.

BACKGROUND: The cholinergic system is substantially altered in individuals with major depression and is partially restored when depression remits. We quantified the availability of ß2-subunit-containing nicotinic acetylcholine receptors (ß2*-nAChR) in subjects with bipolar disorder. METHODS: Twenty-five subjects with bipolar disorder (15 depressed, 10 euthymic) and 25 sex- and age-matched control subjects had a [(123)I]5IA-85380 single photon emission computed tomography scan to quantify ß2*-nAChR VT/fP (total volume of distribution, corrected for individual differences in metabolism and protein binding of the radiotracer). Average VT/fP was compared between groups and correlated with clinical characteristics. Postmortem analysis of ß2*-nAChRs was conducted using equilibrium binding with [(125)I]5IA in subjects with bipolar disorder and matched control subjects. RESULTS: We showed significantly lower ß2*-nAChR availability (20%-38%) in subjects with bipolar depression compared with euthymic and control subjects across all brain regions assessed (frontal, parietal, temporal, and anterior cingulate cortex, hippocampus, amygdala, thalamus, striatum). The postmortem binding study in which endogenous acetylcholine was washed out did not show a statistically significant difference in ß2*-nAChR number in temporal cortex of the bipolar depressed and control groups (15% difference; p = .2). CONCLUSIONS: We show that the alteration in the cholinergic system observed during a depressive episode appears to resolve during euthymia. We suggest that lower VT/fP observed in vivo may be due to a combination of higher endogenous acetylcholine levels during depression, which could compete with radiotracer binding to the receptor in vivo, and lower receptor number in bipolar depression. Identification of differences in cholinergic signaling in subjects with bipolar depression may improve our understanding of its etiology and reveal new treatment targets.

Effect of a nicotine vaccine on nicotine binding to ß2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

OBJECTIVE: Nicotine promotes smoking partly by binding to ß2-containing nicotinic acetylcholine receptors (ß2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of ß2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty. Developing nicotine vaccines could improve treatments. The authors used [123I]5-I-A-85380 single photon emission computed tomography (SPECT) to evaluate the effect of 3'-AmNic-rEPA on the amount of nicotine that binds to ß2*-nAChRs in smokers' brain cortical and subcortical regions. METHOD: Eleven smokers who smoked an average of 19 cigarettes per day, had smoked for 10 years on average, and met criteria for nicotine dependence were given SPECT scans on two days: before and after immunization with 4-400 µg of 3'-AmNic-rEPA. On scan days, three 30-minute baseline emission scans were followed by intravenous administration of nicotine (1.5 mg/70 kg body weight) and up to nine 30-minute emission scans. RESULTS: ß2*-nAChR availability was quantified as VT/fP (total distribution volume divided by free plasma concentration), and nicotine binding was derived by the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding. Nicotine bound to ß2*-nAChRs correlated positively with nicotine injected before but not after vaccination. The daily number of cigarettes and desire for a cigarette decreased after vaccination. CONCLUSIONS: This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to ß2*-nAChRs and disrupt the relationship between administered nicotine and nicotine available to occupy ß2*-nAChRs.

Quantification of smoking-induced occupancy of beta2-nicotinic acetylcholine receptors: estimation of nondisplaceable binding.

UNLABELLED: 5-(123)I-iodo-85380 ((123)I-5-IA) is used to quantitate high-affinity nicotinic acetylcholine receptors (beta(2)-nAChRs) on human SPECT scans. The primary outcome measure is V(T)/f(P), the ratio at equilibrium between total tissue concentration (free, nonspecifically bound, and specifically bound) and the free plasma concentration. Nondisplaceable uptake (free plus nonspecific) of (123)I-5-IA has not been measured in human subjects. Nicotine has high affinity for beta(2)*-nAChRs (nAChRs containing the beta(2)* subunit, for which * represents other subunits that may also be part of the receptor) and displaces specifically bound (123)I-5-IA. In this study, we measured nicotine occupancy and nondisplaceable binding in healthy smokers after they had smoked to satiety. METHODS: Eleven nicotine-dependent smokers (mean age +/- SD, 35.6 +/- 14.4 y) completed the study. One subject was excluded from subsequent analyses because of abnormal blood nicotine levels. Subjects abstained from tobacco smoke for 5.3 +/- 0.9 d and participated in a 15- to 17-h SPECT scanning day. (123)I-5-IA was administered by bolus plus constant infusion, with a total injected dose of 361 +/- 20 MBq. At approximately 6 h after the start of the infusion, three 30-min SPECT scans and a 15-min transmission-emission scan were acquired to obtain baseline beta(2)*-nAChR availability. Subjects then smoked to satiety (2.4 +/- 0.7 cigarettes), and arterial (first 40 min) and venous (until study completion) plasma nicotine and cotinine levels were collected. About 1 h after subjects had smoked to satiety, up to six 30-min SPECT scans were acquired. V(T)/f(P) data, computed from the tissue and plasma radioactivity measurements from the presmoking baseline and postsmoking scans, were analyzed using the Lassen plot method. RESULTS: Receptor occupancy after subjects had smoked to satiety was 67% +/- 9% (range, 55%-80%). Nondisplaceable uptake was estimated as 19.4 +/- 5.8 mL x cm(-3) (range, 15-28 mL x cm(-3)). Thus, in the thalamus, where mean V(T)/f(P) is 93 mL x cm(-3), nondisplaceable binding represents approximately 20% of the total binding. CONCLUSION: These results are in agreement with previous findings and suggest that when satiating doses of nicotine are administered to smokers, imaging of receptor availability can yield valuable data, such as quantifiable measures of nondisplaceable binding.