Dopaminutiae.

Part One in a series of short pieces describing my perspective of ongoing research into my favorite neurochemical and its role in the physiology and pathology of addiction. Will there be a Part Two? I have no fucking idea.

Alcoholics, junkies, crackheads, pill poppers, tweakers. Stick 'em in a detox unit together and they'll soon realize they have something in common. They all smoke. But, apart from that, they share a common goal. It can be summed up in two words. Gimme more.

Nerves transmit information which is processed by particular areas of the brain to elicit a response. The information is transmitted as an action potential, a transient change in the resting voltage that exists across a nerve's cell membrane. When this wave of depolarization reaches the nerve ending, pockets of a chemical neurotransmitter are released into the space between that neuron and the next, the synapse.



The neurotransmitter interacts with receptor proteins on the outside of the post-synaptic neuron and the action potential is regenerated. Since persistent neural transmission is generally undesirable, the signal is rapidly terminated by re-uptake of the neurotransmitter by protein channels on the surface of the pre-synaptic nerve ending. Each neuron typically uses one particular neurotransmitter to relay information.
When we consider that this form of neurotransmission can be "filtered" by the impact of other neurons using different neurochemicals, known as neuromodulators, and the fact that each part of the brain uses different sets of neurotransmitters and neuromodulators, we start to see the immense complexity of the brain.

Less than 1% of the brain's neurons use the neurotransmitter dopamine to communicate with other neurons. Yet this fairly simple chemical (its chemical structure is next to Foxy's head, above) plays a central role in behavior such as motivation, pleasure seeking, survival and learning. Disruption of dopamine levels underlies psychosis, schizophrenia, Parkinsons disease and addiction.
Part of the brain is responsible for sensing and processing information that is important for survival and preservation. Sensory information related to fundamental cues that are key to survival, such as food, sex and danger is relayed to the ventral tegmental area (VTA) of the brain, from where it is sent to the nucleus accumbens (NAc) for processing. The response to this processing is either one of attraction (the smell of fresh baked bread, the sight of Jessica Alba/Brad Pitt in a swimsuit - take your pick) or repulsion (the sight and smell of Dick Cheney in a swimsuit). Since it was once thought that pleasant stimuli were the overriding motivators, the NAc used to be referred to as the brain's reward center. Now that its realized that fear signals equally impact the NAc, its function is more often referred to as a salience processor. In chemically dependent individuals, however, the VTA-NAc axis might best be referred to as the Gimme more center of the brain.

All drugs of addiction produce an increase in dopamine levels in the NAc. Some drugs have a direct effect on dopamine levels. Amphetamines increase release of dopamine from pre-synaptic nerve endings. Gimme more tweak. Cocaine decreases reuptake of dopamine by these nerve endings, causing an elevation in synaptic dopamine. Gimme more coke. Other drugs exert their primary action on other neurotransmitter systems, but ultimately impact dopamine levels. Gimme more booze, smokes, smack, vicodin, xanax, ex, weed. Just gimme more.
Normal environmental stimuli, like food and sex, elicit a satiety signal once enough has been experienced, mediated in part by another neurotransmitter, serotonin. However, although some drugs, like nicotine and heroin, may create a temporary feeling of satiety, most drugs, including alcohol, override this signal completely. Enough is never enough.
In response to the ever increasing supply of drug-induced dopamine in chronic addicts, the NAc starts to compensate by decreasing the number of post-synaptic dopamine receptors. This desensitization causes the need for even more drug to achieve the same effect as before and tolerance sets in. The addict becomes faced with two alternatives; continue the upward spiral of tolerance and craving or quit. Titrating off the drug is no longer an option. The former option almost inevitably results in death. Choosing the latter option slowly resets the balance between dopamine and serotonin in the brain and craving becomes less intense and less frequent.

But, why do most addicts relapse, often many years after gaining sobriety? Though there are many reasons, one of the strongest provocations for relapse is drug associated memory. A recovering drunk or crackhead puts him or herself at risk simply by walking into a bar or a crackhouse. Proximity of the previously used drug, even years after use, can trigger powerfully persuasive memories. Often the drug associated memories are more subtle; the clink of ice cubes in a glass tumbler for the recovering alcoholic or the early morning coffee for the ex-smoker.
Two recent scientific studies have shed some light on the nature of this phenomenon and point to possible avenues of clinical intervention.

In last week's issue of the journal Nature, the world's leading science publication (yours truly has a couple of papers published in it, LOL!), Liu et al studied the effect of repeated doses of cocaine on the VTA in mouse brains. Mice and rats are most often used in addiction physiology experiments because their brains are sufficiently similar to those of humans to allow extrapolation of the results to people, besides alcoholics and addicts are not the most reliable of subjects. Cocaine is most often used as the drug of addiction because it directly impacts dopamine-using neurons and rats and mice evidently like it.
The researchers found that repeated doses of cocaine induced a phenomenon called long term potentiation (LTP) in the VTA of mouse brains. LTP is a basic form of memory in which subtle long lasting changes in synaptic function can store information. They determined that the effect of cocaine was to block the impact of another neurotransmitter, GABA, on dopamine synapses. GABA is a so-called inhibitory neurotransmitter which tunes out many neuronal pathways. Its receptors are a major target of both alcohol and benzodiazepines like valium and librium, indeed the researchers found that valium inhibited cocaine-induced LTP. The results suggest that stimulation of GABA receptors in the VTA might be an effective way to reduce craving and drug associated memory in individuals addicted to cocaine and quite possibly many other drugs. Notably the anti-epileptic drug vigabatrin, which mimics GABA, is currently in clinical trials for coke addiction.

In a recent issue of the journal Neuron, the effect of cocaine on the retrieval of memories elicited by environmental cues in rodents was examined. The establishment and maintenance of drug associated memories by conditional stimuli is known as consolidation. The retrieval of these memories involves a reinforcement process termed reconsolidation which requires the activation of a pattern of genes within neurons. Miller and Marshall identified a signaling pathway inside the NAc which appears to mediate reconsolidation in response to an environmental cue. Such signaling pathways are chains of molecular events which transduce a message, in this case from dopamine, from outside a cell to the cell's nucleus where gene programs are activated to produce proteins. The particular pathway activated by dopamine is one very familiar to scientists working in the field of cancer research, since it is hyperactivated in many types of cancer. For this reason it has been the subject of intensive research and drugs have been developed to block the passage of information along the pathway. Using one such drug, the researchers showed that inhibiting the pathway markedly reduced stimulus-elicited reconsolidation. Although the drug used is probably too toxic for use in chemically dependent people, the results identify multiple potential targets for clinical intervention.

Taken together, the studies reaffirm that expanding our understanding of how drug associated memories are retrieved may lead to the development of specific drugs to reduce drug craving and the danger of relapse in recovering addicts.
Until then,
Gimme more espresso, gimme more smokes, gimme more diet red bull. Just fucking gimme more!

Then and now.

In one of my few memories from childhood I remember the parties my parents used to throw. We would be allowed to stay up to greet their guests, most of whom we knew well. There would be much laughter and a sense of anticipation of the party ahead. Dad was renowned for throwing the best parties. After the guests had arrived we'd go to bed and as I lay in bed the soothing sound of conversation and laughter percolating up from downstairs would soon send me to sleep, happy in the knowledge that I, too, would one day be able to join in the partying.
The next morning I would get up early and creep quietly down the stairs, the same ones i'd run up as fast as possible at night to avoid being jumped on by whatever it was that lurked in the shadows of the landing. I'd go straight to our large living room - we lived in a huge boarding house at the school where Dad was a teacher, and all the rooms were large, or so they seemed to me - and stand in the doorway. It would be quite dark, the curtains still drawn shut, and there would be many, many glasses of all description on the tables and floor, some empty, many half empty. Ashtrays filled to overflowing with extinguished cigarettes and cigars nestled between the glasses. The air would be musty and stale, at once both acrid and aromatic, with lingering traces of perfume. I'd walk carefully around the room, stopping to pick up glasses, sometimes taking a sip of their half empty contents. They all tasted quite disgusting but i knew that one day I'd discover the reason that adults so clearly enjoyed drinking these drinks.
Soon enough Mum would come down to clear up and, after drawing the curtains open, I'd help carry the glasses out to the kitchen for washing and i'd empty the ashtrays. I'd draw the curtains, rearrange the furniture while Mum vacuumed and the living room would be back to its usual self, clean and bright.

I woke up and tried to focus through the gray blur. I could see the hard, gray floor I was lying on and, by moving my eyes, the lighter gray wall opposite. I moved my head slightly up and down and saw, on one side, a toilet bowl in front of another gray wall and, on the other, black metal bars. It was hot, very hot, and the stench of urine filled the still air. I tried to sit up and winced as pain swept through most of my upper torso. Slowly I pulled myself into a sitting position and the pain started to ease until it was a dull soreness around my ribs and stomach. I pulled up my shirt and lokked for bruises. None. I figured I should stop feeling sorry for myself, it couldn't be that bad if there were no bruises.
I drifted in and out of half-sleep until I heard the lock being turned. I looked up and a cop was standing at the door pointing to his right. He didn't say anything, he just pointed. I slowly got to my feet and the pain returned. I stumbled towards the barred door and followed the direction of his finger. I didn't expect him to help, didn't want him to, and he didn't. At the main desk the duty sergeant pointed to the door. I walked out. The sun was bright, blinding. When i was able to see again I inched down to the steps and started the long walk home.
As I walked up Broadway I tried to piece together the strands of memory of the previous day and night. I had been at an afternoon lab party, that much i remembered. Playing with the kids, talking, laughing and drinking, and drinking. After I got home I must have hit the gin pretty hard. i remembered standing outside B.'s door yelling at him to come out drinking with me. He'd tried to calm me down, that much i remembered, but must have given up after a while. The cops arrived and bundled me into the cop car. One of our neighbors must have called them. I would find out who it was and go and thank them. The cell was full when they threw me in. Any cash and cigarettes I'd had were soon gone. My cellmates scared the hell out of me, drunk as i was, and i needed out. I vaguely remembered banging on the bars, shouting for them to let me out. Their warnings to shut the fuck up went unheeded - what did they expect?
I bummed a cigarette off a homeless guy and for the first time noticed the dried blood on my hands. As i walked past the medical center i started to question whether it was indeed the Nashville Police Department that were responsible for the pain still emanating from my upper body. I decided to let it go. Better them than my cellmates.
Eventually I got home. I walked into my apartment, the carpet was strewn with broken glass - so that's where the blood came from. I headed for the fridge and opened it. Beer. Thank God. I grabbed a six pack, headed for the couch and switched on the TV. I was going to have to go out for gin and cigarettes but it could wait. For a while.

"This is a life-changing event for you!" insisted M. from behind her reception desk. I was skeptical and more focussed on what lay behind the closed doors of the detox unit to my right. S. and I said our farewells and I walked in. Less than three hours later, sitting in my room, it started to rain. It doesn't rain in San Diego in September. I found it hard not to wonder whether this was an omen of some sort. Washing away a dusty film of false protection or just a sign of the approaching storm? Sure enough, that night the thunderstorm arrived. We don't get thunderstorms in September. Another portent? Or just confirmation that we've fucked up our atmosphere beyond saving. Probably.
Though my old friend was, of course, not allowed to be there with me, my new, transient, chemical friend helped me through the next four days. I was introduced to "groups", sharing and, of course, The Big Book. We've yet to become friends, and maybe never will, but at least I no longer demonize it. My fellow in-patients and i killed the time exchanging our stories, our secrets, deceits and hiding places. For the first time, whether it was booze, crack, H or vicodin, i realized the undeniable, unbreakable bond we shared, whether we liked it or not.
One morning we were sitting outside in the designated smoking area, smoking, when three elderly folk walked by. They were clearly lost, pointing this way and that, no doubt trying to find a particular building or unit within the huge hospital complex. One of them started to walk towards us, apparently to ask for directions. Before reaching us one of the ladies shouted after him, "Don't asked them, they probably don't even know where they are!" We cracked up. She was right.

And now? Well, now is really just exactly what its all about. When i was drinking the past offered little consolation and less to learn from. Yet i insisted to myself that my blurred, hazy memories of what had gone would serve to guide me through the future, to change its inevitable course. For more than twenty years i labored under this delusion. Characteristic of the alcoholic #27; we do the same thing over and over and over again, expecting different results. So now the past is past, like a mountain stream its still there but its not the same, and though i can guess where its going, i can neither predict its course nor change it. So its down to "now". AA and Leah have written about this recently - it ain't easy but i'm gettin there. And though I won't dwell on it, i'll occasionally look back, not in anger, just look back at the times spent with my estranged friend. Just now and then.