Brain monoamine oxidase A inhibition in cigarette smokers

Abstract

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [ 11 C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg͞day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [ 11 C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term k 3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean k 3 values for the whole brain were 0.18 ؎ 0.04 and 0.13 ؎ 0.03 cc brain (ml plasma )؊1 min ؊1 for nonsmokers and smokers, respectively; P < 0.0003). Tranylcypromine treatment reduced k 3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.There are approximately 1 billion cigarette smokers in the world today and about 3 million die each year from smokingassociated illnesses (1). This places a sense of urgency on understanding the neuropharmacological properties of tobacco smoke and their relationship to smoking behavior and epidemiology. For example, it is not understood why smoking is more prevalent in depression and why smoking cessation is less successful in depressed patients (2, 3). Though it is unlikely that any one factor accounts for the strong association between smoking and depression, it is possible that tobacco smoke may have antidepressant properties. One of the molecular targets proposed to link smoking and depression is monoamine oxidase (MAO) (4, 5), an enzyme which was first associated with mood over 40 years ago when it was discovered that MAO inhibitors had antidepressant properties (6, 7).MAO exists in two subtypes (MAO A and B) that are different gene products (8, 9). In the brain, MAO A oxidizes serotonin and norepinephrine and is found primarily in catecholaminergic neurons, whereas MAO B oxidizes benzylamine and phenethylamine and is localized in serotonergic neurons and in glial cells (10). Both forms oxidize dopamine (11). The antidepressant effects of the nonselective MAO inhibitors are generally attributed to the inhibition of MAO A (12).We recently reported that smokers have reduced brain MAO B relative to nonsmokers and former smokers (13).Others have fo...

Functional brain imaging of tobacco use and dependence

“…When compared to former smokers and non-smokers, average reductions for current smokers are 30% and 40% for MAO A and B (Fowler et al, 2003a). These reductions are the result of chronic smoking behavior rather than a single administration of intravenous nicotine (Fowler et al, 1998a) or smoking a single cigarette (Fowler et al, 1999, and are less than those seen with antidepressant MAO inhibitors (Fowler et al, 1994;Fowler et al, 1996b). Additionally, a human post-mortem study of chronic smokers demonstrated a modest reduction in MAO A binding that did not reach statistical significance (Klimek et al, 2001).…”

“…Fowler and colleagues have performed a series of elegant studies demonstrating decreases in monoamine oxidase (MAO) A and B activity in cigarette smokers using the PET tracers [ 11 C] clorgyline (Fowler et al, 1996b) and ([ 11 C]L-deprenyl-D2) (Fowler et al, 1996a(Fowler et al, , 1998b, respectively. When compared to former smokers and non-smokers, average reductions for current smokers are 30% and 40% for MAO A and B (Fowler et al, 2003a).…”

Evidence That Brain MAO A Activity Does Not Correspond to MAO A Genotype in Healthy Male Subjects

“…Stress-induced monoamine surges could be particularly damaging during fetal and childhood development. Thus, the determination of brain MAO A levels corresponding to high and low MAO A genotype at different developmental stages as well as their interaction with environmental factors such as smoking that can further inhibit brain MAO (Fowler et al 1996a(Fowler et al , 1996b pregnancy merits further investigation. Similarly, future studies to MAO evaluate the relationship between MAO A genotype and brain MAO A levels in diverse neuropsychiatric populations will allow determination of whether MAO A in the adult brain is differentially regulated in some neuropsychiatric diseases.…”

“…The relationship between MAO A genotype and brain MAO A activity has never been examined in vivo in healthy human subjects, however. The purpose of this study was to determine whether high and low MAO A genotypes correspond to high and low brain MAO A activity in normal healthy male subjects using the MAO A radiotracer, [ 11 C]-clorgyline and positron emission tomography (PET; Fowler et al 1996aFowler et al , 2001). …”

Greater Monoamine Oxidase A Binding in Alcohol Dependence

“…Previous investigations of MAO-A activity in postmortem brain of AD were primarily negative, with no change reported in prefrontal cortex, and a decrease reported in the hypothalamus and caudate (7,8). Unfortunately, these studies were inconclusive because none of them addressed several recently discovered biases that influence MAO-A levels, such as cigarette smoking (9,10), exposure to current or past major depressive episodes (11)(12)(13), and impulsive-aggressive personality traits (14,15). The latter covary with MAO-A levels, likely because of a neurodevelopmental influence of inherited MAO-A levels (16).…”