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Drug Abuse and Addiction

Drug Abuse and Addiction

Drug Abuse and Addiction

Description
 Drug addiction is compulsive use of a substance despite negative consequences which can be severe; drug abuse is simply excessive use of a drug or use of a drug for purposes for which it was not medically intended. Drug abuse can lead to drug dependence or addiction. The exact cause of drug abuse and dependence is not known. However, the genetic make-up of the individual, the pharmacology of the particular drug, peer pressure, emotional distress, anxiety, depression, and environmental stress are all factors which seem to be involved. Drug abuse can have serious short- and long-term medical effects, among which are: dangerously increased heart rate and blood pressure; hepatitis or AIDS through shared needles; violent, erratic, or paranoid behavior and hallucinations; clinical depression; sleeplessness and tremors; liver, lung, and kidney impairment; and sudden death (from misuse of inhalants, or from heart attack or stroke).

Who is at Risk?
 Risk factors that predispose people to drug dependence are different from those that predispose to use or abuse. Peer pressure may lead to use or abuse, but at least half of those who go on to addiction have depression, attention-deficit disorder, post-traumatic stress disorder or another psychological problem. Children who grow up in an environment of illicit drug use may first see their parents using drugs. This may put them at a higher risk for developing an addiction later in life for both environmental and genetic reasons.

Sources: A.D.A.M., Inc., Helpguide.org

Treating Cocaine Addiction With Viruses
TSRI scientists have designed a potentially valuable tool for treating cocaine addiction by creating a modified phage-virus that soaks up the drug inside the central nervous system. They coated the virus with an antibody that binds to molecules of cocaine and helps to clear the drug from the brain, which suppresses the positive reinforcing aspects of the drug by eliminating cocaine"s psychoactive properties. The researchers, led by Kim D. Janda, Ph.D., Ely R. Callaway Chair in Chemistry, are taking advantage of the ability of this virus which is a privileged protein that can readily enter the central nervous system.

Americans spend more on cocaine than on all other illegal drugs combined. About 1.7 million people regularly use cocaine in the U.S. - a population larger than that of Philadelphia - and cocaine is the leading cause of heart attacks and strokes for people under 35.

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Serotonin Receptors and Drug Abuse
Nearly 2 million people regularly use cocaine. Loren Parsons, Ph.D., an assistant professor at TSRI, thinks that one of the keys to understanding addiction lies in the fluctuations of serotonin levels in the brain. He is looking at the role of serotonin and serotonin receptors in drug abuse and addiction. Serotonin is a neurotransmitter produced in the central nervous system from amino acids. It plays a big role in a wide range of physiological states, such as sexual behavior, intestinal functions, and affective states like depression. When ethanol, cannabinoids, opioids, or psychostimulants are taken into the body, serotonin levels in the brain are elevated. This elevation in serotonin plays a role in the motivation to continue taking drugs.

Serotonin-1B receptors appear to contribute to the pleasurable effects produced by cocaine and alcohol and the influence of serotonin-1B receptors is altered by long-term drug use. Serotonin-1B receptors have been implicated in the etiology of depression, anxiety and impulsivity during withdrawal, and there"s growing evidence that they could play a role in drug craving. Characterizing mechanisms involved with serotonin will set the groundwork for developing new therapeutics for drug addiction and other diseases. For instance, since serotonin-1B receptors may be involved in the negative aspects of drug withdrawal, it might be beneficial to specifically block these receptors with a medication while a patient is experiencing withdrawal.

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Addiction At A Distance - Brain Reward Decreases And Danger Of Relapse Increases With Heavy Cocaine Use
 A group of researchers from TSRI, led by Athina Markou, Ph.D., have experimentally demonstrated the validity of a new hypothesis of drug addiction that may have important implications for treating chronic cocaine addicts. The hypothesis holds that the body responds to the prolonged and escalated use of cocaine that accompanies cocaine addiction by establishing a new "hedonic set point" - the point at which euphoria is achieved. Over time, this set point is elevated so that it takes more of the drug to achieve the same effect, which in turn elevates the hedonic set point further. After cocaine use is stopped, the set point remains elevated - perhaps for months after the drug has worn off.

The TSRI group demonstrated that this "allostasis" of the hedonic set point correlates with increased relapse into cocaine use during withdrawal. Allostasis is a concept in physiology where an organism maintains the stability of a physiological parameter outside of the homeostatic (normal) range. Markou has developed the ability to monitor cocaine use and the activity of the brain reward system in laboratory models. The study shows that addicts may not be seeking pleasure as much as they are seeking to quell their bodies" inability to deal with a cocaine-altered brain reward system. The investigators are attempting to identify possible treatments based on these findings that might prevent addicts from relapsing into drug use.

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Researching Novel Treatment Approaches For Nicotine Addiction
Tobacco smoking, attributed at least partially to the addictive properties of nicotine, continues to be a worldwide problem. On the average, 23.1% of the U.S. population smokes tobacco. In the U.S. alone, tobacco smoking leads to serious illness in an estimated 8.6 million people and approximately 440,000 deaths annually. Basic research investigating the mechanisms of nicotine dependence may provide insights into the development of novel behavioral and pharmacological approaches to treat nicotine dependence and tobacco smoking. Similarly to dependence on other drugs of abuse, it is hypothesized that both positive and negative reinforcement processes play critical roles in the development and maintenance of dependence on nicotine.

The work of TSRI researcher Athina Markou, Ph.D. and her colleagues focuses on exploring these two aspects of nicotine dependence. They focus on the role of the glutamate and GABA transmission in brain structures that control emotion, reward and motivation. Glutamate is the main excitatory neurotransmitter in the brain, while GABA is the main inhibitory neurotransmitter in the brain. Their recent work has indicated that modulation of GABA and glutamate transmitter function may be novel approaches that may assist people in quitting smoking.

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Scripps Research Microarray-based Addiction Research Team At Work
 Addiction, particularly to drugs of abuse, is a serious and growing problem for society. New technologies are providing tools for investigating the genetic basis of conditions such as drug addiction, and offer hope that successful interventions can be developed to help alleviate the effects of drug addiction. A project led by TSRI Professor Steven Henriksen, Ph.D., is designed to identify genes or gene products whose expression patterns are regulated by repeated administration of a non-toxic dose regimen of methamphetamine, similar to that experienced by a human addict.

The project is designed to characterize patterns of gene expression upon initiation and expression of behavioral sensitization to methamphetamine in the striatum and pre-frontal cortex (PFC) using DNA "chip" technology, and to identify novel genes in the striatum and PFC with expression patterns associated with behavioral sensitization to METH.

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Studying The Mechanisms That Underlie Dependency To Addictive Drugs
 TSRI Professor George Koob, Ph.D., working with a large array of international collaborators, leads efforts on the mechanisms that underlie dependency to addictive drugs. A major element is the refinement of animal models of substance abuse based on self-administration, through long-term indwelling venous catheters, of nicotine, opiates, and psychostimulants; and respiratory or oral administration of ethanol. Recent studies indicate that rats made dependent on alcohol with intermittent exposure and repeated withdrawal increased ethanol consumption significantly more rapidly than did animals allowed to stay continuously dependent. Rats allowed continuous access to cocaine had increases in brain reward threshold that paralleled their increased intake of the drug, a process known as escalation. This process can be partially overcome by microinjections of the anti-alcohol drug acamprosate, thought to be a glutamate coagonist, into the extended amygdale. Those results suggest that cocaine dose escalation is associated with a dysregulation of the reward system of the brain that marks the transition from use to actual dependence and represents a marker for the underlying biological processes.

Koob and his colleagues showed that regardless of whether animals have been allowed to become dependent on alcohol, cocaine, or cannabinoids, withdrawal leads to enhanced stress responses that can be treated with antagonists of corticotrophin-releasing factor. Such enhanced stress responding may persist for weeks after withdrawal from dependence and may account in part for the vulnerability to relapse into dependence with renewed drug use. Koob and his colleagues found that the phosphatidylinositol-3"-kinase pathway is a critical signal transduction pathway in the mechanisms underlying sensitization to cocaine with repeated doses and that withdrawal from ethanol dependence is marked by long-lasting activation of the extracellular signal regulated protein kinase and hence, by implication, in the transduction of the drug effect into dysregulation of gene expression.

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T.H.C. and The Brain
 TSRI Assistant Professor Paul Schweitzer, Ph.D., is funded by a National Institute of Health grant entitled, Cannabinoids and Central Neuronal Activity, the purpose of which is to ask what role the brain"s endogenous cannabinoid system plays in memory formation and how this system may be disrupted by the consumption of marijuana. Marijuana contains as a principle active ingredient the cannabinoid tetrahydocannabinol (THC), which binds to the same receptors as the body"s natural endogenous cannabinoids. This fact has made marijuana the subject of heated debate in the last decade because THC is able to mimic the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to cannabinoid receptors called "CB1" on cells of the spinal cord and pain-modulating centers of the brain to decrease sensitivity to pain.

Patients with multiple sclerosis, cancer, AIDS, and a number of other conditions have sought marijuana for years to treat their various symptoms. Binding to nerve cells of the hippocampus and other cells elsewhere in the body, THC creates a range of side effects as it activates CB1-mediated signaling, including distorted perception, difficulty in problem-solving, loss of coordination, increased heart rate and blood pressure, anxiety, and panic attacks. Schweitzer"s goal is to determine the cellular outcome of exposure to cannabinoids. One of his main goals is the potential applications that would follow if the endogenous cannabinoid system could be manipulated to achieve a desired effect. The challenge for scientists is to use the cannabinoid system to produce effective, long-lasting relief from pain or viable appetite modulation without the deleterious side effects of marijuana use.

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Studying Human Cognition To Determine Risk Of Drug Use
 TSRI Associate Professor John Polich, Ph.D., has centered his research around an event-related potential known as P300. P300 results when the cognitive system discriminates different stimuli, attention is given to the input, and memory processes are engaged. The P300 is produced whenever the mental representation of the stimulus environment is changed. In other words, P300 is what happens in everyone"s brain when they"re confronted with something out of the ordinary, something that doesn"t fit into their knowledge base. It"s a universal response that can be readily measured and used to study human cognition.

Polich has taken his understanding of P300 and applied it to young adults to see if, indeed, these universal brain wave readings could help predict which subjects were at high risk for future onset of alcoholism or other drug use. Polich studied a group of 18- to 24-year-old undergraduates who were pre-screened for a family history of alcoholism. The subjects were given both auditory and visual tasks and responded with a button press to target stimuli. The students determined to be high-risk produced smaller P300 amplitudes than low-risk students; however the auditory tasks did not show such strong differences.

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Scientists Describe Smoker"s Enzyme
 A team of scientists at The Scripps Research Institute has solved the structure of a human molecule called CYP2A6, which is the principal enzyme in the body that degrades nicotine. CYP2A6 is a protein that can be found in the endoplasmic reticulum of cells in the liver, where it is but one of a gauntlet of enzymes responsible for removing toxic chemicals from the body. In the case of nicotine, though, CYP2A6 almost single-handedly breaks down the chemical in the bloodstream as it circulates through the liver. The recently solved structure reveals in fine detail the exact active site shape of the enzyme. Having the structural details makes it more feasible for researchers to design an inhibitor - somewhat the way that a clothing designer could fashion a great outfit for an individual given the person"s exact measurements.

Because of its singular importance for metabolizing nicotine, blocking this enzyme would decrease the craving felt by a smoker, as less nicotine goes further. This could help smokers trying to quit through patches, gums, or any other standard nicotine replacement therapy by reducing replacement nicotine needs to very low doses. According to TSRI Professor Eric F. Johnson, Ph.D., the enzyme CYP2A6 activates some of the carcinogens in tobacco smoke, and by inhibiting it, production of the carcinogenic metabolites can be prevented. Johnson conducted the study with TSRI colleagues, including Professor C. David Stout, Ph.D. and former Research Associate Jason K. Yano, Ph.D.

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Finding Suggests An Operational
Model For Drug Craving
TSRI Professor Friedbert Weiss, Ph.D. uses microdialysis of neurotransmitters to measure the release of these substances in animals self-administering abused drugs after discrete environmental challenges. He found that when subjects were re-exposed to the environmental sensory cues that were present when the subjects first began to self-administer stimulants continuously, the subjects had an increased willingness to work for the drug. This finding suggests an operational model of drug craving and provides a means to investigate this critical factor in risk for relapse.

In studies to identify potential long-lasting abuse liability associated with limited allowances of cocaine, as with "recreational" use in humans, Dr. Weiss and colleagues recently found that a single 2-hour cocaine self-administration experience resulted in a persistent craving behavior (attempting to press the lever that previously signaled drug injection) for at least 9 months, indicating that recall of the effects of a single drug experience can convey drug motivational signals despite months of abstinence. In studies of increased responsiveness to repeated doses of amphetamine (sensitization), Dr. Weiss discovered that selective antagonism of one form of glutamate receptor can retard or diminish the longer term drug-craving effects, particularly those that can be triggered by repeat exposure to the conditional sensory stimuli of the prior drug experiences. Also, he found that blockade of the phosphatidylinositol-3´-kinase step blocked the expression of behavioral sensitization to cocaine but did not block the acute locomotor stimulatory effects of cocaine.

Neuronal Actions Of Drugs Of Abuse
 TSRI Associate Professor Donna Gruol, Ph.D., attempts to understand and describe complex brain-related phenomena - such as the causes of addiction and craving. She studies the electrical activity of neurons - how ion channels on the neurons work to let charged particles in and out of a cell and how neurons propogate such a signal to its axon where it communicates over the synapse with another neuron. She looks at individual neurons and works out how they communicate with each other in different parts of the brain, and how those parts of the brain interact with other parts of the brain. In her 20-plus-year career at TSRI, Gruol has studied a wide range of topics, including how alcohol and drugs of abuse interact with cells of the central nervous system, and has overseen a project that modeled binge drinking in teenagers.

She focuses on the cellular actions of drugs of abuse on CNS neurons during development, when many neuronal subtypes have enhanced vulnerability to the effects of drugs of abuse. Early exposure of the CNS to drugs of abuse alters neuronal development, interferes with the formation of synaptic connections between neurons, and produces long-term effects on behavior and memory. However, little information exists on the cellular actions that underlie these effects of drugs of abuse. Gruol hypothesizes that acute and chronic exposure to drugs of abuse during CNS development interferes with cellular mechanisms that regulate neuronal excitability. To address these questions, she uses a multidisciplinary approach involving electrophysiological techniques to measure neuronal excitability, fluorescence-based imaging to measure intracellular concentrations of calcium, and immunohistochemical methods to measure the cellular expression and localization of proteins of interest.

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Researchers Link Effects Of Withdrawal To Compulsive Drug Use And Craving
A team of scientists at The Scripps Research Institute; the National Institutes of Health Animal Center; and the University of Tokushima Graduate School (Japan) has provided some of the first evidence that compulsive drug use stems not from obtaining a drug's pleasurable effects, but from an aversion to drug withdrawal. The finding could be used to help develop human therapies to block aspects of drug craving. The study was led by Paul Kenny, Ph.D., an assistant professor at Scripps Research's campus in Jupiter, Florida, and Scott Chen, of the National Institutes of Health Animal Center. The research fills many gaps in our understanding of how the brain changes during drug addiction. While scientists had previously shown that drugs such as heroin stimulate the brain's pleasure centers and thereby motivate drug consumption, the role of withdrawal-associated inhibitory effects on brain pleasure centers in motivating drug intake had been more difficult to quantify. This is a missing piece of the puzzle that scientists have been interested in for many years. Withdrawal was important anecdotally, but there had been no solid empirical data demonstrating an instrumental role of withdrawal in addiction-like behaviors.

Kenny and colleagues now provide strong evidence that withdrawal contributes to the development of compulsive drug consumption in addicts. During the study, rodents were permitted to self-administer various levels of heroin. Those receiving the highest levels showed withdrawal-like decreases in the activity of the brain's reward systems. Crucially, as this withdrawal effect got worse, their drug intake became greater. As levels of drug consumption increase, the withdrawal state becomes more profound. Taking more of the drug alleviates withdrawal, but also makes the underlying condition worse. A vicious cycle is set up where a person is taking more of the drug to relieve a progressively worsening withdrawal. Importantly, the researchers also identified a previously unknown source of drug craving, provoked by stimuli linked to withdrawal through Pavlovian conditioning. In the study, cues in the environment - a buzzer and light - repeatedly paired with drug withdrawal by themselves came to precipitate a withdrawal-like state and to prompt drug seeking. Through classical conditioning, these cues alone could precipitate drug-seeking behaviors. Thus, in addition to memories of the pleasurable effects of drugs, memories of aversive drug withdrawal may also drive drug craving and relapse. This line of research has the potential to aid in the development of new therapies for addiction. If the underlying biology is understood, it may be able to be blocked to eliminate craving and prevent relapse among drug addicts.

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