Drug Dependence and Emotional Behavior: Neurophysiological and Neurochemical Approaches

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Inhaled substances are usually first changed into a gaseous form by igniting e.

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The lungs offer a large surface area through which the gaseous form may quickly pass directly into the bloodstream. Injected substances obviously enter the bloodstream directly, although at a somewhat regulated rate. In these last three routes of administration, substances enter the bloodstream in their unmetabolized form.

Neuroanatomy and Physiology of Brain Reward II

Once a substance enters the bloodstream, it is transported throughout the body to various organs and organ systems, including the brain. Substances that enter the liver may be metabolized there. Substances that enter the kidney may be excreted. If a female substance user is pregnant, and the substance is able to cross the placenta, then the substance will enter the fetus' bloodstream. Nursing babies may ingest some substances from breast milk. To enter the brain, a substance's molecules must first get through its chemical protection system, which consists mainly of the blood-brain barrier.

Tight cell-wall junctions and a layer of cells around the blood vessels keep large or electrically charged molecules from entering the brain. However, small neutral molecules like those of cocaine and MA easily pass through the blood-brain barrier and enter the brain. Once inside the brain, substances of abuse begin to exert their psychoactive effects. The human nervous system is an elaborately wired communication system, and the brain is the control center. The brain processes sensory information from throughout the body, guides muscle movement and locomotion, regulates a multitude of bodily functions, forms thoughts and feelings, modulates perception and moods, and essentially controls all behavior.

The brain is organized into lobes, which are responsible for specialized functions like cognitive and sensory processes and motor coordination. These lobes are made up of far more complex units called circuits, which involve direct connections among the billions of specialized cells that the various substances of abuse may affect. The fundamental functional unit of the brain's circuits is a specialized cell called a neuron , which conveys information both electrically and chemically.

The function of the neuron is to transmit information: It receives signals from other neurons, integrates and interprets these signals, and in turn, transmits signals on to other, adjacent neurons Charness, A typical neuron see Figure consists of a main cell body which contains the nucleus and all of the cell's genetic information , a large number of offshoots called dendrites typically 10, or more per neuron , and one long fiber known as the axon.

At the end of the axon are additional offshoots that form the connections with other neurons. Within neurons, the signals are carried in the form of electrical impulses. But when signals are sent from one neuron to another, they must cross the gap at the point of connection between the two communicating neurons.

This gap is called a synapse. At the synapse, the electrical signal within the neuron is converted to a chemical signal and sent across the synapse to the target i. The chemical signal is conveyed via messenger molecules called neurotransmitters that attach to special structures called receptors on the outer surface of the target neuron Charness, The attachment of the neurotransmitters to the receptors consequently triggers an electrical signal within the target neuron.

Approximately 50 to different neurotransmitters have been identified in the human body Snyder, Figure illustrates a typical synaptic connection and depicts the chemical communication mechanism. Neurotransmitters may have different effects depending on what receptor they activate. Some increase a receiving neuron's responsiveness to an incoming signal--an excitatory effect--whereas others may diminish the responsiveness--an inhibitory effect.

The responsiveness of individual neurons affects the functioning of the brain's circuits, as well as how the brain functions as a whole how it integrates, interprets, and responds to information , which in turn affects the function of the body and the behavior of the individual. The brain circuit that is considered essential to the neurological reinforcement system is called the limbic reward system also called the dopamine reward system or the brain reward system.

This neural circuit spans between the ventral tegmental area VTA and the nucleus accumbens see Figure Every substance of abuse--alcohol, cocaine, MA, heroin, marijuana, nicotine--has some effect on the limbic reward system. Substances of abuse also affect the nucleus accumbens by increasing the release of the neurotransmitter dopamine, which helps to regulate the feelings of pleasure euphoria and satisfaction.

Dopamine also plays an important role in the control of movement, cognition, motivation, and reward Wise, ; Robbins et al. High levels of free dopamine in the brain generally enhance mood and increase body movement i. Too little dopamine in certain areas of the brain results in the tremors and paralysis of Parkinson's disease.

Natural activities such as eating, drinking, and sex activate the nucleus accumbens, inducing considerable communication among this structure's neurons. This internal communication leads to the release of dopamine. The released dopamine produces immediate, but ephemeral, feelings of pleasure and elation. As dopamine levels subside, so do the feelings of pleasure. But if the activity is repeated, then dopamine is again released, and more feelings of pleasure and euphoria are produced. The release of dopamine and the resulting pleasurable feelings positively reinforce such activities in both humans and animals and motivate the repetition of these activities.

Dopamine is believed to play an important role in the reinforcement of and motivation for repetitive actions Di Chiara, ; Wise, , and there is an increasing amount of scientific evidence suggesting that the limbic reward system and levels of free dopamine provide the common link in the abuse and addiction of all substances. Dopamine has even been labeled "the master molecule of addiction" Nash, When the nucleus accumbens is functioning normally, communication among its neurons occurs in a consistent and predictable manner. First, an electrical signal within a stimulated neuron reaches its point of connection i.

The electrical signal in the presynaptic neuron triggers the release of dopamine into the synapse.

The dopamine travels across the synaptic gap until it reaches the target neuron. It then binds to the postsynaptic neuron's dopamine-specific receptors, which in turn has an excitatory effect that generates an internal electrical signal within this neuron. However, not all of the released dopamine binds to the target neuron's receptors. Extra dopamine may be chemically deactivated, or it may be quickly reabsorbed by the releasing neuron through a system called the dopamine reuptake transporter see Figure As soon as the extra dopamine has been deactivated or reabsorbed, the two cells are "reset," with the releasing neuron prepared to send another chemical signal and the target neuron prepared to receive it.

Substances of abuse, and especially stimulants, affect the normal functioning of the dopamine neurotransmitter system Snyder, ; Cooper et al. Psychologists have long recognized the importance of positive and negative reinforcement for learning and sustaining particular behaviors Koob and LeMoal, Beginning in the late s, scientists observed in animals that electrically stimulating certain areas of the brain led to changes in mental alertness and behavior.

Rats and other laboratory animals could be taught to self-stimulate pleasure circuits in the brain until exhaustion. If stimulants such as cocaine or amphetamine were administered, for example, sensitivity to pleasurable responses was so enhanced that the animals would choose electrical stimulation of the pleasure centers in their brains over eating or other normally rewarding activities. The process just described in which a pleasure-inducing action becomes repetitive is called positive reinforcement. Conversely, abrupt discontinuation of the psychoactive substances following chronic use was found to result in discomfort and behaviors consistent with craving.

The motivation to use a substance in order to avoid discomfort is called negative reinforcement. Positive reinforcement is believed to be controlled by various neurotransmitter systems, whereas negative reinforcement is believed to be the result of adaptations produced by chronic use within the same neurotransmitter systems. Experimental evidence from both animal and human studies supports the theory that stimulants and other commonly abused substances imitate, facilitate, or block the neurotransmitters involved in brain reinforcement systems NIAAA, In fact, researchers have posited a common neural basis for the powerful rewarding effects of abused substances for a review, see Restak, Natural reinforcers such as food, drink, and sex also activate reinforcement pathways in the brain, and it has been suggested that stimulants and other drugs act as chemical surrogates of the natural reinforcers.

A key danger in this relationship, however, is that the pleasure produced by substances of abuse can be more powerfully rewarding than that produced by natural reinforcers NIAAA, On a short-term basis, stimulants exert their effects by disrupting or modifying the normal communication that occurs among brain neurons and brain circuits. Cocaine and MA have both been shown to specifically disrupt the dopamine neurotransmitter system. This disruption is accomplished by overstimulating the receptors on the postsynaptic neuron, either by increasing the amount of dopamine in the synapse through excessive presynaptic release or by inhibiting dopamine's pattern of reuptake or chemical breakdown Cooper et al.


The use of cocaine and MA increases the amount of available dopamine in the brain, which leads to mood elevation e. With cocaine, the effects are short-lived; with MA the duration of effect is much longer. As the stimulant level in the brain decreases, the dopamine levels subside to normal, and the pleasurable feelings dwindle away. A growing body of scientific research based on animal research and brain imaging studies in humans suggests that the chronic use of stimulants affect dopaminergic neurons in limbic reward system structures e.

These effects may underlie addiction to stimulants. Although the neurochemical pathways of stimulant addiction are not definitively established, a few researchers have found evidence of changes in the structure and function of brain neurons after chronic stimulant use in humans.

Some researchers propose that the changes may come from dopamine depletion, changes in neurotransmitter receptors or other structures, or changes in other brain messenger pathways that could cause the changes in mood, behavior, and cognitive function associated with chronic stimulant abuse Self and Nestler, Animal studies have demonstrated that high doses of stimulants can have permanent neurotoxic effects by damaging neuron cell-endings e. The question of whether stimulants can produce similar effects in humans remains to be answered.

Researchers hope that recently developed brain imaging techniques will help provide the answer. At this time, there is only speculation that such permanent damage may underlie the long-term cognitive impairments seen in some chronic stimulant users. The continuing development and application of new technologies will help expand our knowledge of the neurological effects of stimulants in humans.

The medical aspects of stimulant use disorders are discussed in Chapter 5. Addiction is a complex phenomenon with important psychological and social causes and consequences. However, at its core, it involves a biological process: the effects of repeated exposure to a biological agent a substance on a biological substrate the brain over time Nestler and Aghajanian, Ultimately, adaptations that substance exposure elicits in individual neurons alter the functioning of those neurons, which in turn alters the functioning of the neural circuits in which those neurons operate. This eventually leads to the complex behaviors e.

A general definition of substance abuse is the habitual use of a substance not needed for therapeutic purposes, such as solely to alter one's mood, affect, or state of consciousness. The continued abuse of the substance may lead to adverse physiological, behavioral, and social consequences. A substance-dependent individual will continue his use despite these adverse consequences. Moderate chronic use or severe short-term use of substances may lead to abuse, which may eventually lead to addiction components Ellinwood, ; Hall et al.

Chronic substance abuse results in a complex set of physiological and neurological adaptations. These adaptations are simply the body's attempt to adjust to or compensate for substance-induced impairments. Substance addiction or substance dependence is manifested by 1 psychological craving see the following section ; 2 tolerance the need for increasing amounts of the substance to reproduce the initial level of response, or sometimes to simply stave off the unpleasant effects of withdrawal ; 3 sensitization discussed in the section on the medical effects of stimulants ; and 4 symptoms of withdrawal upon cessation of use, indicating physiological dependence.

Social and behavioral manifestations of dependence include the reduced ability to function at work or home and may include displays of erratic, moody, or anxious behavior. Similar to other substances of abuse, moderate chronic use or severe short-term use of stimulants in any form may lead to abuse or dependence Ellinwood, ; Hall et al. Clinical observations of abuse patterns for both cocaine and MA have noted that, in general, there is an estimated 2- to 5-year latency period between first use and full-blown addiction.

However, clinical experience and anecdotal evidence suggest that the latency period may be shortened to less than 1 year by rapid routes of administration e. With increasing use, the user may develop tolerance to the effects of stimulants and may need to keep increasing the amount taken to produce the desired psychological effects. As chronic abuse progresses, users prefer the stimulant over enjoyable activities and eventually may prefer it over food and sex Hall et al. At that point, the individual will usually continue her use even when faced with continuing adverse consequences--the hallmark of substance dependence.

Abrupt discontinuation of the psychoactive substance following chronic use generally results in discomfort, dysphoria, and behaviors consistent with craving. The user is now motivated to use a substance in order to avoid discomfort and dysphoria. This shift from substance use as positive reinforcement to negative reinforcement is, perhaps, one of the foremost characteristics of late-stage addiction. The degree to which learning and memory sustain the addictive process has only recently been addressed.

Researchers believe that each time a neurotransmitter like dopamine floods across a synapse, circuits that trigger thoughts and memories and that motivate action become hardwired in the brain. The neurochemistry supporting addiction is so powerful that people, objects, and places associated with substance use are also imprinted on the brain. Craving, a central aspect of addiction, is a very strong learned response with powerful motivational properties often associated with specific memories i.

Cues--any stimuli substance-using friends, locations, paraphernalia, moods repeatedly paired with substance use over the course of a client's addiction--can become so strongly associated with the substance's effects that the associated conditioned stimuli can later trigger arousal and an intense desire for the substance and lead to relapse. High relapse rates are common in cocaine addiction even after physical withdrawal and abstinence have been achieved. Brain-imaging studies have shown that cue-induced drug craving may be linked to distinct brain systems involved in memory e.

Brain structures involved in memory and learning, including the dorsolateral prefrontal cortex, amygdala, and cerebellum, have been linked to cue-induced craving Grant et al. A network of these brain regions integrates emotional and cognitive aspects of memory and triggers craving when it reacts to cues and memories.

These cues and memories also play an important role in reinforcing substance use Grant et al. Most substance treatment programs recognize the power of these factors in triggering relapse and warn clients to avoid everything previously associated with their substance use--a tall order for a client in an urban environment saturated with the substance and its associated reminders. Treatment approaches that address these learning and memory issues of addiction may prove effective.

For example, Childress developed treatment strategies to help clients reduce craving and arousal during encounters with substance-related stimuli Childress, In the laboratory, clients are given repeated, passive exposure to substance-reminding cues in a substance-free protected environment.

The research finds that initial arousal and strong craving produced by the cues eventually decrease Childress, Better understanding of the relationship of learning and memory to the addiction process may lead to new treatment approaches. The recent development of noninvasive brain imaging has created a powerful new tool for demonstrating not only the short-term effects of substance use, but also the longer term consequences of chronic substance abuse and addiction.

These tools have allowed researchers to boldly go where they previously could not--literally into the depths of a living human brain. Such noninvasive techniques can depict normal and abnormal functioning of different brain areas by measuring metabolic activity i. They can identify substance-induced structural changes and physiological adaptations. But how can researchers measure changes in neural circuitry? However, it is a daunting task to determine if synapses have been added or lost in a particular region, given that the human brain has something like billion neurons and each neuron makes on average several thousand synapses.

It is clearly impractical to scan the brain looking for altered synapses, so a small subset must be identified and examined in detail. But which synapses should be studied? Given that neuroscientists have a pretty good idea of what regions of the brain are involved in particular behaviors, they can narrow their search to the likely areas, but are still left with an extraordinarily complex system to examine.

There is, however, a procedure that makes the job easier. The dendrites of a cell function as the scaffolding for synapses, much as tree branches provide a location for leaves to grow and be exposed to sunlight. The usefulness of Golgi's technique can be understood by pursuing this arboreal metaphor.

There are a number of ways one could estimate how many leaves are on a tree without counting every leaf. Then, by simply multiplying branch length by leaf density, one could estimate total leafage. A similar procedure is used to estimate synapse number. Furthermore, there is a roughly linear relationship between the space available for synapses dendritic surface and the number of synapses, so researchers can presume that increases or decreases in dendritic surface reflect changes in synaptic organization.

By using Golgi-staining procedures, various investigators have shown that housing animals in complex versus simple environments produces widespread differences in the number of synapses in specific brain regions. In general, such experiments show that particular experiences embellish circuitry, whereas the absence of those experiences fails to do so e.

Until recently, the impact of these neuropsychological experiments was surprisingly limited, in part because the environmental treatments were perceived as extreme and thus not characteristic of events experienced by the normal brain. It has become clear, however, not only that synaptic organization is changed by experience, but also that the scope of factors that can do this is much more extensive than anyone had anticipated.

Factors that are now known to affect neuronal structure and behavior include the following:. We discuss two examples to illustrate. The reason for this difference is not understood, however. It was our expectation that there would be quantitative differences in the effects of experience on synaptic organization, but to our surprise, we also found qualitative differences.

Thus, like many investigators before us, we found that the length of dendrites and the density of synapses were increased in neurons in the motor and sensory cortical regions in adult and aged animals housed in a complex environment relative to a standard lab cage. In contrast, animals placed in the same environment as juveniles showed an increase in dendritic length but a decrease in spine density. In other words, the same environmental manipulation had qualitatively different effects on the organization of neuronal circuitry in juveniles than in adults.


Brain Plasticity and Behavior

To pursue this finding, we later gave infant animals 45 min of daily tactile stimulation with a little paintbrush 15 min three times per day for the first 3 weeks of life. Our behavioral studies showed that this seemingly benign early experience enhanced motor and cognitive skills in adulthood. The anatomical studies showed, in addition, that in these animals there was a decrease in spine density but no change in dendritic length in cortical neurons; yet another pattern of experience-dependent neuronal change.

Parallel studies have shown other changes, too, including neurochemical changes, but these are beyond the current discussion. Armed with these findings, we then asked whether prenatal experience might also change the structure of the brain months later in adulthood. Indeed, it does. For example, the offspring of a rat housed in a complex environment during the term of her pregnancy have increased synaptic space on neurons in the cerebral cortex in adulthood.

Although we do not know how prenatal experiences alter the brain, it seems likely that some chemical response by the mother, be it hormonal or otherwise, can cross the placental barrier and alter the genetic signals in the developing brain. Our studies showing that experience can uniquely affect the developing brain led us to wonder if the injured infant brain might be repaired by environmental treatments.

What was surprising, however, was that prenatal experience, such as housing the pregnant mother in a complex environment, could affect how the brain responded to an injury that it would not receive until after birth. This type of study has profound implications for preemptive treatments of children at risk for a variety of neurological disorders.

The long-term behavioral consequences of abusing such psychoactive drugs are now well documented, but much less is known about how repeated exposure to these drugs alters the nervous system. One experimental demonstration of a very persistent form of drug experience-dependent plasticity is known as behavioral sensitization. For example, if a rat is given a small dose of amphetamine, it initially will show a small increase in motor activity e. When the rat is given the same dose on subsequent occasions, however, the increase in motor activity increases, or sensitizes, and the animal may remain sensitized for weeks, months, or even years, even if drug treatment is discontinued.

Amphetamines both decrease the re-uptake of dopamine and directly increase the neuronal release of dopamine 1,2,3,4. Many experiments have shown the importance of dopamine in the rewarding effects of amphetamines. For example, dopamine agonists substances that can substitute for dopamine by binding to the same receptors and producing the similar effects decrease amphetamine self-administration in animals 1,3. On the other hand, dopaminergic blockade antagonists decreases amphetamine self-administration in rats by preventing amphetamine binding, thereby preventing its dopaminergic effects 3.

Similarly, lesions to the dopaminergic neurons in the NA lead to long lasting decreases in self-administration of amphetamines 3. These examples emphasize how drugs increase dopamine levels and stimulate the reward pathway. Nicotine is thought to affect the brain reward system by increasing dopamine concentrations through interacting with nicotinic acetylcholine receptors.

Nicotine increases dopamine efflux in the reward pathway by mimicking acetylcholine at presynaptic nicotinic receptor sites, and exciting dopaminergic neurons 2. Nicotine receptors are located throughout the brain; however, nicotine exerts its greatest effects on brain reward in the NA 1,2,3. Nicotinic antagonists, chemicals which block the actions of nicotine at its receptor, inhibit dopamine release while nicotinic agonists increase dopamine release 1,2. Thus, nicotine leads to increased dopamine concentrations in the brain reward pathway like other drugs of abuse.

Caffeine is the psychoactive drug that is most commonly used throughout the world Caffeine blocks the actions of adenosine, an inhibitory neurotransmitter, by binding to its receptor and preventing post binding changes from taking place 2. Since the neurotransmitter adenosine is like the safety on a gun, when it is removed, neurons begin to fire.

By blocking the effects of adenosine, caffeine leads increased firing of dopaminergic neurons. This is especially evident in the NA 4,5. A balance between the negative effects of the drug and positive feelings associated with stimulation of the brain reward system determine if an individual will enjoy and continue using the substance or not 1,2. The closer positive and negative effects are to the actual time of drug use, the more likely we are to associate these effects with the drug. Unfortunately, the negative consequences of drug use often come much later and more unpredictably compared to the immediate pairing of drug administration and reward.

For example, the later potential negative consequences of chronic drinking such as liver disease may not be as important as the immediate rewarding positive effects of drinking. Some approaches to treatment attempt to consistently pair the negative consequences of drug administration with drug administration.

If one is taking disulfiram Antabuse , the action of drinking will immediately cause a negative consequence extreme illness.

Trauma and Addiction: Crash Course Psychology #31

The immediate negative consequence of drinking now competes with the normally immediate positive reward of drinking to combat illness. By changing the time course of positive and negative drug effects through behavioral interventions or pharmaceutical interventions, we may be able to better treat addictions in the future. Pharmacotherapy of Drug Addiction:. Pharmacotherapeutic interventions have been developed to decrease drug use by influencing the brain reward system.

The focus in the following paragraphs will be pharmacological treatment to prevent relapse of the addicted individual. General strategies for pharmacological treatment of drug addiction include creating aversion to the addicted drug, bringing consequences or punishment closer to the reinforcement of drug use, modification of neurotransmitters to decrease drug intake, and long-term substitution with a less addictive and cross-tolerant medication 1. Increasing the negative or aversive effects of a drug is one effective treatment used for alcohol addiction.

Disulfiram Antabuse , metronidazole, or calcium carbimide is used to create negative effects with the ingestion of alcohol 1,2. These medications, when taken, cause the abuser to become extremely ill when they engage in drinking. Instead of experiencing the negative effects of alcohol the next day hangover or years later liver disease , they experience unpleasant effects such as nausea, vomiting, and flushing in closer proximity to ingestion which opposes the normally immediate positive reward of the drug see above.

What Is Dopamine?

Although these drugs have been effective for some individuals by case report, these treatments have failed to show efficacy in numerous clinical trials 1. However recent work by Carroll et al demonstrates that Antabuse can be effective in preventing cocaine dependent individuals from relapsing into cocaine By manipulating neurotransmitters in the reward pathway, we can potentially modify cravings for drugs of abuse. This can be accomplished in two ways. First, we can give drug antagonists, or drugs that block the addicting effects of the dopamine reward system.

For example, dopamine blocking agents have been shown to diminish intake of all drugs of abuse in animal studies 2. However, application in humans has been less promising. In humans, the euphoria induced by amphetamine administration is attenuated by dopamine blocking agents. Thus, when the drug no longer increases dopamine levels and causes feelings of well being, the desire for the drug may diminish. Bupropion, a dopamine agonist, has been shown in nicotine addiction but has not been shown to be effective in cocaine addiction. Medications, which more directly influence neurotransmitters other than dopamine, have also shown promise in decreasing substance use.

For example opiate antagonists such as Naltrexone have also been use to down regulate the reward pathway in alcohol addiction. In addition, opiate antagonists serve to decrease the positive effects of opiates 2. Fluoxetine, a serotonergic agent, has been shown to decrease alcohol consumption in nondepressed alcohol dependant adults as well Thus, by manipulating neurotransmitter levels, we may reduce consumption of substances. One example is the use of methadone to treat heroin addiction.

Methadone does not have the euphoric effects that heroin does; however, it does adequately stimulate the brain reward system and provides a safer alternative to heroin use.

Anxiolytic Effects of Drugs: Approaches, Methods and Problems

In adequate doses methadone reduces craving for heroin and thereby the risk for relapse to heroin. Methadone, an orally administered opiate, is associated with less risk of acquiring HIV, hepatitis C, and criminal activity - all of which are highly associated with heroin dependence 2. Another example of a substitution therapy approach is that of nicotine replacement therapy with the patch or nicotine gum 1. This allows the individual to struggle with behavioral aspects of drug addiction and minimize the pharmacological aspects for a time being. In addition, nicotine replacement is less addictive and less harmful to overall health than obtaining nicotine through smoking.

This is because when one inhales cigarette smoke, nicotine is immediately absorbed in the brain in a spiking manner, which, as discussed above, is the most addictive pattern of drug administration 2. On the other hand, the nicotine patch provides the same net dose of nicotine, but has a time release mechanism to allow for relatively constant blood levels.

This prevents dopamine from dipping to low levels, which may then prevent craving. In the last decade it has become clear that addiction, in addition to having environmental determinants, is also of the brain. Scientists have found that a common reward pathway exists in the brain. When stimulated by drugs of abuse, addiction often occurs especially in those who are genetically or otherwise neurochemically vulnerable.

This pathway, located in the primitive limbic system, has evolved over time to promote behaviors that increase the survivability of organisms, such as feeding and reproductive behaviors. Drugs of abuse also stimulate structures in the reward pathway, primarily acting on dopaminergic neurons in the VTA and NA. These drugs not only stimulate areas of the brain that have evolved to encourage adaptive behaviors; they stimulate these areas more effectively than the survival behaviors themselves! Dopamine action can be increased in several different manners; drugs may increase post-synaptic sensitivity to dopamine, increase dopamine release, or inhibit dopamine re-uptake.

Drugs of abuse may accomplish this by acting directly on dopaminergic neurons or indirectly through other neurons and neurotransmitters. Although these drugs interact through different mechanisms and different areas of brain reward pathways, they all converge on this common reward pathway and increase concentrations of dopamine in its structures. As the mechanism of the reward pathway and its interactions with other areas in the brain become clearer, new pharmacotherapies and behavioral treatments may be developed to effectively treat substance use disorders and decrease its devastating human cost.

Substance Abuse: A comprehensive Textbook 3 rd Edition. Drugs of Abuse and Addiction: Neurobehavioral Toxicology. CRC Press Ritz, Mary. Reward Systems and Addictive Behavior. Chapter 5, Pg Molecular mechanisms of addictive substances. Chapter 6. Koob, G. The Neurobiology of Drug Addiction. The Journal of Neuropsychiatry and Clinical Neurosciences ; Bardo, Michael. Dager, S; Layton, Matt; et al.

Am J Psychiatry , Feb. Childress, A; Mozley, D; et al. Am J Psychiatry , Jan Little, K; Zhang, L; et al. Am J Psychiatry ; Alcohol Health and Research World. Graham, A; Schultz; T. Principles of Addiction Medicine.