From: Reece <@.au> Newsgroups: alt.drugs.hard Subject: Re: Drug Memories: My first opiate experience.. Date: Tue, 04 Sep 2001 10:12:40 +0800 [...] This article was extracted from an article in Harvard Medical School Health Publications Vol. 1, No. 13, 1999. Reprinted WITHOUT permission. Addiction and the Brain ----------------------------------- Drug addiction has always created concerns that go beyond the need to understand its causes and develop treatments. As individuals and as a society, we have been unable to decide whether it is a disease, a vice, or a behavior problem -- something that people do to themselves or something that happens to them. Now, with the help of scientific innovations that include images of the living brain and detailed molecular analysis of neurons, researchers are beginning to learn about addiction as a biological process. Their discoveries may not only aid in the search for treatments but throw indirect light on these moral, social, and philosophical issues, and even on the nature of desire and habit in general. The reward system Unlike most psychiatric disorders, drug addiction can be reliably produced and easily recognized in animals. Healthy laboratory rats will voluntarily take only a few non-nutritious chemicals, the same substances to which human beings become addicted. Even their patterns of intake resemble human addictive patterns, drug by drug. The target of these chemicals is a circuit that runs between the midbrain and the prefrontal region of the cerebral cortex. The central link in the circuit, which joins two regions known as the ventral tegmental area (VTA) and nucleus accumbens (NAC), is known as the medial forebrain bundle. The NAC is part of the basal forebrain, which also contains the seat of planning and judgment in the prefrontal cortex, as well as the amygdala, sometimes described as a factory of the emotions. This circuit serves as a reward system that sets automatic priorities for the organism by guaranteeing the persistence of actions that are useful for survival and reproduction. It tells us what to avoid and what to approach. Stimulation of the NAC gives pleasure and serves as a strong positive reinforcer. Human beings and other animals tend to repeat any action that provides the stimulation, even if it means working hard and long. Addictive drugs capture this system and subvert its normal functions. Rats will press a lever repeatedly for intravenous injections of cocaine or heroin, just as they do for direct stimulation of the NAC by an implanted electrode. If an experimenter supplies an unlimited amount for a while and then takes the drug away, a rat will press frantically in the hope of receiving more and then give up. After that, for a while, it may not work even for direct stimulation of the brain. It has become temporarily insensitive to normal signals of reward, and no action seems pleasurable. The role of dopamine The drugs achieve this effect by suddenly intensifying the activity of the neurotransmitter dopamine (DA) in the medial forebrain bundle. We know that this transmitter is the key to an understanding of addiction because injury or drugs that lower its activity make the reward circuit less sensitive. Addictive drugs take many different routes to their final target. Cocaine blocks the mechanism by which dopamine is reabsorbed into the cells that release it. Amphetamines provoke the release of dopamine. Nicotine acts on a receptor for the neurotransmitter acetylcholine in the reward system and may prevent the enzyme monoamine oxidase from breaking up the dopamine molecule. Other addictive drugs act more indirectly on neurons that feed impulses into the DA system. Opiates work at receptors for the brain's own morphine-like substances, the endorphins and enkephalins (which may also constitute an alternative reward system). The sedative-hypnotic drugs, including alcohol, barbiturates, and benzodiazepines, act in various parts of the brain on neurons that release the inhibitory transmitter gamma-aminobutyric acid (GABA), which directs neurons to stop firing. In other brain regions, alcohol influences the excitatory transmitter glutamate and certain opioid receptors. Dopamine and motivation The reward system affected by addictive drugs serves the purpose of regulating motivation. Through the prefrontal cortex, we learn about the world and develop expectations based on experience. Through its link to the NAC, these expectations are compared with stimuli the brain is receiving at any given moment. If the reward is greater than expected, dopamine is released in the basal forebrain as a signal for action to continue receiving the stimulus. In this way, we lay down memories of experiences that prove useful for survival, coordinate desires with expectations, and create new motives for action. By enhancing DA transmission, addictive drugs disturb natural feedback and control in this system and may cause long-lasting changes in its functioning. As the brain adapts to the excess of dopamine, natural production declines and DA receptors become less numerous and sensitive. Tolerance rises, and eventually pleasure is almost absent. But addicts still want the drug and still use it, because most other experiences have become even less rewarding. They need the drug just to feel normal. They have seemingly lost the power to regulate their desire, which they may experience as somehow no longer their own but imposed on them by an external force. This disturbed state is not the same as the condition that is sometimes called physical dependence and wrongly identified with addiction itself. Addicts withdrawing from heroin may suffer for a week from nausea, tremors, aching muscles, diarrhea, and fever. Alcohol or barbiturate withdrawal can be even more unpleasant, causing seizures, delirium, and in rare cases, death. But stimulant drugs, which are equally addictive, do not cause equally severe physical withdrawal reactions. When mice lacking one type of nerve receptor for dopamine are repeatedly given morphine, they eventually suffer a typical physical withdrawal reaction but have no tendency to go on taking the drug. The vast majority of patients who take high doses of opiates for severe pain respond in the same way. As a well-known study by Lee Robins and her colleagues revealed, so did most soldiers who used heroin in Vietnam. Physical dependence in this sense is not linked to the reward or motivation system, and it is probably evoked in different brain regions by different drugs. In one experiment, rats were given a choice between plain water and water containing morphine, in a solution either sweetened with sugar or made bitter with quinine. The rats generally drank large amounts of the drug solution in the first few days and then settled at a moderate level that was lower if it contained quinine and higher if it contained sugar. This level tended to rise after a few months. Then the experimenters took the drug out, left it out for several months, and put it back. Now some of the rats took much more than before (in human addicts, this is known as the abstinence violation effect), and their intake was neither reduced by quinine nor increased by sugar. The drug had come to matter more and other objects of desire and aversion less. This transformation occurred only when the rats were originally offered the alternative of pure water. If they were forced to drink the morphine solution, they responded like medical morphine users, with a physical withdrawal reaction but no subsequent urge to take the drug. They were not addicted because they had never chosen to use it and their motivation system was intact. Relapse The conscious form taken by the addictive disturbance of motivation is a varying but powerful mixture of feelings and impulses that is sometimes called craving or a protracted withdrawal reaction. The symptoms include irritable restlessness, indeterminate physical discomfort, and mild depression, all creating a tendency to relapse even after long abstinence. Sometimes a single dose of the drug itself is enough to start a binge and reestablish the addiction, as Alcoholics Anonymous recognizes in its motto, "It's the first drink that gets you drunk." Another cause of relapse is classical conditioning. Members of AA are told to avoid "people, places, and things" associated with alcohol, because any mood or circumstance associated with use of the drug may become a conditioned stimulus. The sight of a crack pipe, bottle, or needle or the onset of anger, sadness, or anxiety can reawaken desire for the drug. A type of classical conditioning often used in animal experiments is place preference. An animal will take the drug more readily when it is returned to the environment where it first developed the addiction -- like an alcoholic who passes a familiar bar or a heroin addict who sees the street corner where he used to wait for a connection. At such moments of temptation, brain scans indicate increased activity in the amygdala. It is as though the brain preserves an implicit emotional memory of its predilection that is always available for retrieval by the right cue. Inside the neuron Biologists and neurologists are now exploring the interior of neurons to uncover the ultimate sources of addiction. When a neurotransmitter like dopamine locks into receptors on the surface of a cell, it opens channels to the interior and pervasively influences activity within. Molecules known as G-proteins are directed to turn on other molecules, the second messengers, which eventually cause phosphate groups to attach themselves to regulatory proteins. Through this process of phosphorylation, genes in the nucleus are switched on, issuing directions to manufacture substances that neurons need for learning and other normal functions. Neural connections are strengthened and long-term memories are formed. Feedback from the process regulates the sensitivity of receptors and the opening and closing of neuronal access channels. If a drug repeatedly displaces neurotransmitters or modifies their actions, the structure and activity of brain cells themselves can change in pervasive and persistent ways. Outside influences The capacity of drugs to disturb the balance of the brain does not depend on their chemical properties alone. Most drug users never become addicts, and many other conditions and circumstances determine whether a particular person uses a particular drug in a compulsive way. Substances are more addictive when taken in pure and concentrated form, and more addictive when smoked or injected directly into the bloodstream than when eaten or drunk. There are also striking individual differences in susceptibility that arise from heredity, culture, social circumstances, and good or ill fortune. Robins showed that most men who used heroin in Vietnam, even if they took it as much and as often as stateside addicts, had no tendency to relapse into addiction after returning to this country. The men who did relapse usually had drug or alcohol problems and antisocial tendencies before joining the Armed Forces. Even rats have individual personalities that affect their vulnerability to addictions. The leaders of a rat colony, the ones who appear to be admired and imitated, tend to take less than others when they are offered addictive drugs. Genetics of addiction Individual differences in sensitivity to the addictive powers of drugs are almost certainly influenced strongly by genetics. Different strains of rats and mice prefer and avoid different drugs. Some animals have a congenital liking or dislike for alcohol, and some will not readily take even heroin or cocaine. At a given dose of alcohol, the sons of alcoholic parents feel less intoxicated than average, and their posture and gait are altered less. This apparent resistance, also found in susceptible rats, is an early sign of vulnerability to alcoholism. To put it another way, men (and rats) who can drink others under the table are the most likely future alcoholics. According to one theory, a high capacity for drink reflects a powerful counteracting response of the body and brain that is a sign of sensitivity rather than insensitivity to the effects of alcohol. Addiction may follow if the reward and motivation system is equally sensitive but less adaptable. Researchers have also speculated that some people genetically at risk for addiction have a congenitally high level of stress hormones or a deficit in dopamine function that is temporarily corrected by their drug of choice. There are probably many genetic routes to addiction. For example, alcohol addicts are often divided into two classes. Type I alcoholics are usually male, vulnerable to drug addictions of all kinds, and inclined to crime and other antisocial behavior. Type II alcoholics, whose symptoms are usually less severe and develop at a later age, are more often female and rarely have antisocial tendencies. Studies of adopted children suggest that these types are genetically distinct. Depression, chronic anxiety, attention deficit disorder, and other mental disorders that are under genetic influence may also raise the risk of addiction by reducing the capacity for rewarding experiences. Researchers have looked for specific gene variants associated with addictions by examining DNA patterns (markers) that are transmitted in families along with an addictive propensity. Results so far have been disappointing, but variations in genes that direct the manufacture of dopamine receptors may turn out to be significant. Social aspects of addiction Social circumstances influence vulnerability and resistance to addiction in many ways. First, to state the obvious, a drug must be available in sufficient amounts to sustain an addiction. But it may be just as important that other sources of satisfaction are not available. Experimental animals are often confined under uniform, highly restrictive conditions -- sometimes isolated in cages with catheters implanted in their veins. These arrangements promote addiction by cutting off other opportunities for rewarding experience. It is not surprising that isolated rats take more of an addictive drug than animals living in normal rat colonies (although both isolation and rat personality make less difference once an addiction is fully established). If human beings differ more than rats in individual susceptibility, it is not only because their brains are more complex but also because they live in more varied environments. People risk addiction most when they lack other capacities, interests, and choices, other ways to solve problems, other sources of attachment to something outside themselves. The brain's motivation system is more easily disturbed when varied sources of reward and expectation are not preserving its balance. In this way, the potential for addiction is affected by economic conditions, cultural traditions, formal and informal social controls, and the companionship and approval of other drug users. Since the chemical stuff of addiction is already present in the brain, it does not even require an external substance. Injecting a drug is the quickest and often the most unhealthful and socially destructive way to disturb the motivation system. Certainly it is the easiest way to study the system in animals. But pathological gambling and other consuming habits that are sometimes called addictions might work on the brain indirectly with similar results. Money is the original stimulus for gamblers, but eventually they go on playing even when reason tells them they will lose. They are driven by emotional memories of past gains, and the thrill associated with the mere possibility of winning has become stronger than other pleasures. Problems of treatment Partly because addiction causes long-lasting changes in the brain, it is a chronic condition that sometimes requires long-term care and treatment. Repeated relapses should be expected (although, for reasons that are not clear but probably include loss of tolerance for the physical side effects, drug addictions often lose their strength with age). Sometimes the brain changes can be partially reversed, and often ways can be found to compensate for them. Addiction will probably prove difficult to counteract by chemical means alone. Fairly effective drug treatments are available for some of its secondary symptoms, especially the acute withdrawal reactions produced by opiates and sedatives. Anticonvulsants prevent seizures, beta-blockers reduce anxiety and agitation, and clonidine alters the sensitivity of the locus ceruleus, the brain region where opiate withdrawal effects are concentrated. There are also drugs that neutralize the pleasurable effects of opiates and alcohol. Acamprosate discourages drinking, probably by altering the transmission of glutamate; disulfiram (Antabuse) prevents the digestive system from assimilating alcohol, making drinkers nauseated and sometimes seriously ill. Naltrexone and naloxone block receptors for the action of opiates and alcohol. Another common technique is the substitution of less harmful addictive substances, oral methadone and levo-alpha-acetyl-methadol (LAAM), for more harmful ones, intravenous heroin and morphine. A nicotine patch can be used to reduce craving for cigarettes while the smoker tries to quit. Limits of treatment But this kind of treatment has limited value. For example, there is no drug that will reliably prevent people from using cocaine or make them stop taking it. Drugs that lower the activity of dopamine have not proved effective, although more selective ones that act on particular kinds of DA receptors may turn out to be useful. Researchers have inoculated experimental rats with a vaccine that works by provoking the body to produce antibodies against cocaine. Methylphenidate (Ritalin), an amphetamine-like stimulant, in some ways bears the same relation to cocaine that methadone bears to heroin. It is taken by mouth, enters and leaves the brain more slowly than cocaine, and evokes a less intense response both when it enters and when it leaves. Unfortunately, methylphenidate reduces the craving for cocaine only temporarily. But the main obstacle to chemical treatment of addiction is the difficulty of persuading addicts to participate. Heroin addicts usually refuse to take naltrexone, and alcoholics often discard their Antabuse. Even if they do accept these treatments for a while, they are in danger of eventual relapse, because addiction is a disorder of motivation. They can easily arrange to prevent themselves from feeling pleasure when they use the drug. What they cannot do is prevent themselves from wanting it. As the philosopher and psychologist William James pointed out, we can often renounce the immediate satisfaction of a desire for the sake of long-term health and happiness if we can group the desire with others in a general category and make a rule that applies to them all. Addiction often persists because the addict is unwilling or unable (the distinction becomes doubtful) to acknowledge the kind of problem it is, the category to which it belongs. The word often used today to describe this condition is "denial." For each of the many situations and moods in which they are impelled to take the drink or drug, addicts can supply a different justification, excuse, or rationalization. Often they are able to change only when they come to understand that all their many allegedly different reasons for drinking or taking drugs belong under the heading of addiction. That is why Alcoholics Anonymous insists that its members repeatedly tell themselves and others, "I am an alcoholic." But generalizing in order to act on principle depends on coordination between the seat of planning and judgment in the prefrontal cortex and the centers of desire and reward in the medial forebrain bundle. In some people, especially antisocial personalities, this coordination may be poor from an early age. Instead of following rules to guide their actions, they tend to do what they want when they can. Since they are reluctant to choose among motives or delay the satisfaction of desires, they are highly likely to abuse alcohol and other drugs and eventually develop addictions that are especially difficult to treat. More often, addiction itself impairs the coordination of judgment and desire by decreasing the value of all other experiences so much that the drug effect is preferred even as it becomes less and less rewarding. When an addict calls on reserves (presumably from pathways in the brain that remain intact), acknowledges the problem, and seeks treatment, it may be not just a means to recovery but a sign that recovery has already begun, because judgment is reassuming control over motivation. In fact, research has shown that most addicts do eventually find a way to quit on their own, although sometimes not before irreparable damage has been done to their health or their lives. Is addiction a brain disorder? Critics who are impressed by the role of rules and voluntary action in the onset and progress of drug addiction question whether it should be regarded as a brain disorder. The risk, they say, is that underlying problems will be ignored, moral irresponsibility encouraged, or the choice of solutions unnecessarily limited. For the same reason that addicts are often ambivalent about their habits, the rest of us are unsure about how to cope with them. Should we be finding ways to treat an illness, or should we be using whatever means are necessary, including coercion, to persuade unhappy and troublesome people to abandon their bad behavior and reform their lives by acting on different motives? We make different choices in different contexts. We pay taxes to rehabilitate addicts, but they are also imprisoned for the possession and use of drugs, although it would be unthinkable to treat victims of any other disorder that way. These contradictory attitudes and social policies are responses to different aspects of a complicated situation. Because motivation and desire can be disturbed in many ways, addiction does not have a single simple meaning. Different kinds of addiction have different causes and consequences. No single best method of prevention, management, or treatment exists for all hereditary proclivities, social conditions, states of mind, or personal characteristics that promote the development of overpowering and self-destructive habits. There are many roads to what the poet, philosopher, and opium addict Samuel Taylor Coleridge called "insanity of the will", and a variety of potential escape routes, from counteracting chemicals to self-help groups, psychotherapy, religious experience, and social change. Reece I'm a Bitter Man (Since 1923)