Molecular Site of Action for Alcohol: Ethanol-Receptive Elements
Alcohol does not bind to any given receptor in a classic steric or allosteric manner, in contrast to other drugs of abuse. It has, however, been shown to interact at the molecular level with specific neuronal elements, termed ethanol-receptive elements, to produce changes in specific synaptic targets at the cellular and system levels, resulting in its pharmacological effects (for further reading, see Harris et al., 2008). Low to moderate doses of alcohol (10–50 mM, which reflect blood alcohol levels of 0.04 to 0.2 g% from in vivo administration) have wide-ranging effects on the nervous system, acting directly on the GABA receptor complex, serotonin 5-HT3 receptors, and glycine receptors and inhibiting glutamate receptors, potassium channels, G-proteins, and protein kinases (Figure 6.8). Alcohol is a small molecule with low binding energy compared with other drugs of abuse. This is reflected in the requirement for much higher doses of alcohol to produce intoxication (millimolar levels compared with nanomolar levels for other drugs, such as opioids and psychostimulants). These pharmacological characteristics of alcohol suggest that multiple alcohol-receptive sites in the brain are required to influence the structure and function of proteins, possibly via water-filled membrane pockets.
The way that alcohol affects specific protein-receptive pockets was first modeled using the LUSH protein in the Drosophila fruit fly. LUSH is an odorant binding protein that is used by the fly to sense alcohols and was purposefully named for its role in alcohol’s effects. Short carbon-chain alcohols, such as ethanol, bind at only a single site in the LUSH protein, and this binding dramatically stabilizes the protein. In a separate study, pharmacologically relevant concentrations of ethanol stabilized the opening of a ligand-gated ion channel of a bacterial variant homolog of GABA and glycine receptors. Crystal structures of the alcohol-sensitized variant showed that alcohol binds to a transmembrane hydrophilic cavity between channel subunits and may stabilize the open form of the channel (Figure 6.9). This type of cavity may be preserved in human alcohol-sensitive glycine and GABAA receptors, suggesting a structural basis for what have previously been termed ethanol-receptive elements.
Figure 6.8 Probable synaptic sites of alcohol action in central neurons. Alcohol facilitates γ-aminobutyric acid (GABA) release in the nucleus accumbens, ventral tegmental area, and central nucleus of the amygdala, and these actions may be mediated in some cases by presynaptic GABAB receptors. In chronic alcohol-treated animals, GABA release increases at some of these sites. Alcohol acutely inhibits the release of glutamate in both the nucleus accumbens and central nucleus of the amygdala, possibly through metabotropic glutamate (Glut) receptors (mGluR), μ opioid receptors (μOR), or calcium (Ca2+) channels. In chronic alcohol-treated animals, an increase in release is observed. Enk, enkephalin; PKA, protein kinase A; PKC, protein kinase C.
Figure 6.9 X-ray structures of wildtype and alcohol-sensitized GLIC, in which GLIC F140A mutant co-crystallized with alcohol (Protein Data Bank ID 4HFE). The GLIC receptor is a bacterial (Gloeobacter violaceus) Ligand-gated Ion Channel, homologous to brain ligand-gated ion channels, such as γ-aminobutyric acid-A (GABAA) receptors and nicotinic acetylcholine receptors. GLIC is a protein-gated, cation-selective channel. Like nicotinic acetylcholine receptors, it is a functional pentameric oligomer. The blow-up of the small box shows the binding cavity in the protein that contains ethanol (orange and red spheres). The complete GLIC pentameric protein complex is shown above the box. GLIC was mutated by changing one amino acid, F (phenylalanine), to A (alanine), at the 14’ position in the protein. The other letters and numbers represent the amino acids at specific positions. M indicates a membrane-spanning section of the protein. [Taken with permission from Sauguet L, Howard RJ, Malherbe L, Lee US, Corringer PJ, Harris RA, Delarue M. Structural basis for potentiation by alcohols and anesthetics in a ligand-gated ion channel. Nature Communications, 2013, (4), 1697.]
I drank Fumé Blanc at the Ritz-Carlton Hotel, and I drank double shots of Johnnie Walker Black on the rocks at a dingy Chinese restaurant across the street from my office, and I drank at home. For a long time I drank expensive red wine, and I learned to appreciate the subtle differences between a silky Merlot and a tart Cabernet Sauvignon and a soft, earthy Beaucastel from the south of France, but I never really cared about those nuances because, honestly, they were beside the point. Toward the end I kept two bottles of Cognac in my house: the bottle for show, which I kept on the counter, and the real bottle, which I kept in the back of a cupboard beside an old toaster. The level of liquid in the show bottle was fairly consistent, decreasing by an inch or so, perhaps less, each week. The liquid in the real bottle disappeared quickly, sometimes within days. I was living alone at the time when I did this, but I did it anyway and it didn’t occur to me not to: it was always important to maintain appearances.
I drank when I was happy and I drank when I was anxious and I drank when I was bored and I drank when I was depressed, which was often. I started to raid my parents’ liquor cabinet the year my father was dying. He’d be in the back of their house in Cambridge, lying in the hospital bed in their bedroom, and I’d steal into the front hall bathroom and pull out a bottle of Old Grand-dad that I’d hidden behind the toilet. It tasted vile – the bottle must have been fifteen years old – but my father was dying, dying very slowly and gradually from a brain tumor, so I drank it anyway and it helped. A love story. Yes: this is a love story.
It’s about passion, sensual pleasure, deep pulls, lust, fears, yearning hungers. It’s about needs so strong they’re crippling. It’s about saying good-bye to something you can’t fathom living without.
I loved the way drink made me feel, and I loved its special power of deflection, its ability to shift my focus away from my own awareness of self and onto something else, something less painful than my own feelings. I loved the sounds of drink: the slide of a cork as it eased out of a wine bottle, the distinct glug-glug of booze pouring into a glass, the clatter of ice cubes in a tumbler. I loved the rituals, the camaraderie of drinking with others, the warming, melting feelings of ease and courage it gave me.
Our introduction was not dramatic; it wasn’t love at first sight, I don’t even remember my first taste of alcohol. The relationship developed gradually, over many years, time punctuated by separations and reunions. Anyone who’s ever shifted from general affection and enthusiasm for a lover to outright obsession knows what I mean: the relationship is just there, occupying a small corner of your heart, and then you wake up one morning and some indefinable tide has turned forever and you can’t go back – You need it; it’s a central part of who you are.
Still, I look in the mirror sometimes and think, “What happened?” I have the CV of a model citizen or a gifted child, not a common drunk. Hometown: Cambridge, Massachusetts, backyard of Harvard University. Education: Brown University, class of ‘81, magna cum laude. Parents: esteemed psychoanalyst (dad) and artist (mom), both devoted and insightful and keenly intelligent.
In other words, nice person, from a good, upper-middle-class family. I look and I think, “What happened?” Of course, there is no simple answer. Trying to describe the process of becoming an alcoholic is like trying to describe air. It’s too big and mysterious and pervasive to be defined. Alcohol is everywhere in your life, omnipresent, and you’re both aware and unaware of it almost all the time; all you know is you’d die without it, and there is no simple reason why this happens, no single moment, no physiological event that pushes a heavy drinker across a concrete line into alcoholism. It’s a slow, gradual, insidious, elusive becoming.
When you love somebody, or something, it’s amazing how willing you are to overlook the flaws. Around that same time, in my thirties, I started to notice that tiny blood vessels had burst all along my nose and cheeks. I started to dry-heave in the mornings, driving to work in my car. A tremor in my hands developed, then grew worse, then persisted for longer periods, all day sometimes.
I did my best to ignore all this. I struggled to ignore it, the way a woman hears coldness in a lover’s voice and struggles, mightily and knowingly, to misread it. The phrase is high-functioning alcoholic. Smooth and ordered on the outside; roiling and chaotic and desperately secretive underneath, but not noticeably so, never noticeably so. I remember sitting down in my cubicle that morning, my leg propped up on a chair, and thinking: I wonder if she knows. I wonder if anyone can tell by looking at me that something is wrong. I used to wonder that a lot, that last year or two of drinking –Something is different about me, I’d think, sitting in an editorial meeting and looking around at everyone else, at their clear eyes and well-rested expressions. Can anybody see it? The wondering itself made me anxious, chip- ping away at the edges of denial.
Perception versus reality. Outside versus inside. I never missed a day of work because of drinking, never called in sick, never called it quits and went home early because of a hangover. But inside I was falling apart. The discrepancy was huge.
Beneath my own witty, professional façade were oceans of fear, whole rivers of self-doubt. I once heard alcoholism described in an AA meeting, with eminent simplicity, as “fear of life.” and that seemed to sum up the condition quite nicely. I, for example, had spent half my professional life as a reporter who lived in secret terror of the most basic aspects of the job, of picking up the phone and calling up strangers to ask questions. Inside, I harbored a long list of qualities that made my own skin crawl: a basic fragility; a feeling of hypersensitivity to other peoples’ reactions, as though some piece of my soul might crumble if you looked at me the wrong way; a sense of being essentially inferior and unprotected and scared. Feelings of fraudulence are familiar to scores of people in and out of the working world – the highly effective, well-defended exterior cloaking the small, insecure person inside – but they’re epidemic among alcoholics. You hide behind the professional persona all day; then you leave the office and hide behind the drink.
Sometimes, in small flashes, I’d be aware of this. One night after work, on my way to a bar to meet a friend for drinks, a sentence popped into my head. I thought: This is the real me, this person driving in the car. I was anxious. My teeth were clenched, partly from spending a long day hunched over the computer and partly from the physical sensation of wanting a drink badly, and I was aware of an undercurrent of fear deep in my gut, a barely definable sensation that the ground beneath my feet wasn’t solid or real. I think I understood in that instant that I’d created two versions of myself: the working version, who sat at the desk and pounded away at the keyboard, and the restaurant version, who sat at a table and pounded away at white wine. In between, for five or ten minutes at a stretch, the real version would emerge: the fearful version, tense and dishonest and uncertain. I rarely allowed her to emerge for long. Work – all that productive, effective, focused work – kept her distracted and submerged during the day. And drink – anesthetizing and constant – kept her too numb to feel at night.
My reflection in the mirror looked awful: my skin was pale and my face was drawn and I had large dark circles under my eyes. I had on a scoop-necked sweater and I could see little burst blood vessels all over my chest, red marks that looked like the beginnings of a rash. My twin sister Becca, a doctor, would see those periodically and tell me she thought they were alcohol related, and I always thought. Nonsense: they’re from too much sun, back when I was younger. In any event, I looked like hell, and somewhere inside I understood that if I kept this up, kept drinking and working and flailing around like this, I’d die, slowly, but literally kill myself.
Around the time that Wicky died, I started taking those little quizzes about drug and alcohol abuse that you sometimes find in women’s magazines or pamphlets at the doctor’s office, and I started answering a lot of the questions positively. Do you find yourself having a drink or two before you go to a party where you know alcohol will be served, just to “get yourself in the mood?” Yes. Do you find yourself gulping drinks? Um ... check. Do you drink more when you’re under stress? Sure. But some of the questions seemed a little obvious, even kind of stupid. Do you drink alone? Well, of course I drink alone; I live alone. What kind of a question is that? The knowledge that some people can have enough while you never can is the single most compelling piece of evidence for a drinker to suggest that alcoholism is, in fact, a disease, that it has powerful physiological roots, that the alcoholic’s body simply responds differently to liquor than a nonalcoholic’s. Once I started to drink, I simply did not know how or when to stop: the feeling of need kicked in, so pervasively that stopping didn’t feel like an option. My friend Bill explains it this way to his mother, who has a hard time wrapping her mind around the disease concept of alcoholism and who holds fast to the belief that he could have controlled his drinking if only he’d exerted enough will. He says, “Mom, next time you have diarrhea, try controlling that.” Crude, perhaps, but he gets the point across. The need is more than merely physical: it’s psychic and visceral and multilayered. There’s a dark fear to the feeling of wanting that wine, that vodka, that bourbon: a hungry, abiding fear of being without, being exposed, without your armor. In meetings you often hear people say that, by definition, an addict is someone who seeks physical solutions to emotional or spiritual problems. I suppose that’s an intellectual way of describing that brand of fear, and the instinctive response that accompanies it: there’s a sense of deep need, and the response is a grabbiness, a compulsion to latch on to something outside yourself in order to assuage some deep discomfort.
And there it was again, the connection: Repression + Drink = Openness. At heart, alcoholism feels like the accumulation of dozens of such connections, dozens of tiny fears and hungers and rages, dozens of experiences and memories that collect in the bottom of your soul, coalescing over many many many drinks into a single liquid solution.
You drink long and hard enough and your life gets messy. Your relationships (with nondrinkers, with yourself) become strained. Your work suffers. You run into financial trouble, or legal trouble, or trouble with the police. Rack up enough pain and the old math – Discomfort + Drink = No Discomfort – ceases to suffice; feeling “comfortable” isn’t good enough anymore. You’re after something deeper than a respite from shyness, or a break from private fears and anger. So after a while you alter the equation, make it stronger and more complete. Pain + Drink = Self-Obliteration. From: Knapp C, Drinking: A Love Story, Dial Press, New York, 1996.
One classic action of alcohol is that it potentiates GABA-gated currents by activating GABA-mediated chloride ion uptake by the GABA-benzodiazepine ionophore complex. Some researchers have argued that the actions of alcohol on the GABA-benzodiazepine ionophore complex are GABA receptor subunit-dependent. Alcohol may require the presence of the α4β1δ, α4β3δ, α6β3δ, and δ subunits. Other extra-synaptic GABA receptors that are composed of α4β3δ subunits in some cells have been hypothesized to be the primary targets for alcohol in the GABA receptor systems that facilitate alcohol’s effects on sleep, anxiety, memory, and cognition. However, total knockout of any of these specific GABA receptor subunits does not dramatically change alcohol sensitivity.
Another mechanism by which receptors and ion channels are modulated by alcohol occurs via changes in protein kinase phosphorylation (that is, turning the functions of proteins on and off). Alcohol facilitates protein kinase Cγ (PKCγ)-mediated phosphorylation and inhibits PKCε-mediated phosphorylation. PKCγ knockout mice are less sensitive to alcohol’s effects on GABAA receptors, while PKCε knockout mice are more sensitive to alcohol’s effects on GABAA receptors (for further reading, see Ron and Messing, 2013). Alcohol also inhibits adenosine reuptake by inhibiting equilibrative nucleoside transporter-1, which increases extracellular adenosine levels and activates adenosine A2 receptors. This activation, in turn, activates the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) system via the cAMP-PKA second-messenger system. Thus, alcohol has two notable direct and sensitive molecular effects: to change ion channel function and to modify signal transduction pathways to alter neurotransmitter function, again presumably via water-filled membrane pockets that change protein function. How such molecular actions actually translate to the release of endogenous transmitters that are known to cause intoxication remains an area to be explored in the alcohol research field.