Neuroanatomy and Physiology of the “Brain Reward System”
in Substance Abuse
How does experimental use of substances of abuse lead to drug addiction in some individuals? How do these drugs cause intoxication? Part of the answer lies in a common reinforcement pathway in the human brain which drugs of abuse stimulate, potentially leading to addiction (1,2,3,4,7). This reinforcement pathway, which is composed of both central nervous system structures and endogenous neurotransmitters communicating between these structures, has been termed the “reward pathway”(1). The reward pathway evolved to promote activities that are essential to the survival of the human race as well as other mammals.
One may compare the mechanism of drugs of abuse with that of viruses. Viruses and drugs of abuse are both foreign to humans. Viruses enter an animal’s cells and use the pre-existing cell “machinery” to synthesize more viruses, thus promoting their own survival. As the viruses infect more and more cells, the organism may become ill. Illicit drugs can take advantage of an organism in a similar fashion. Just as viruses take over cell function throughout the body, drugs of abuse modify cell function in these important brain structures leading to modifications in behavior. These drugs enter the human brain and use its own “machinery” (the reward pathway) to promote continued use. Just as the cell’s survival is dependent on its “machinery” so is the survival of the organism dependent on an intact brain reward pathway. Drugs of abuse, although harmful to the organism, are able to capture this “machinery “ in some individuals driving further drug use.
Depending on our own characteristics (our inherited neurochemical make-up etc.) we may be more susceptible to the illness of drug addiction just as certain people are more susceptible to infection. Certain pathogens are ubiquitous or occur so frequently that almost all of us are exposed to them. Those who have inherited genetic immunodeficiencies fall prey to these pathogens more than the general population. Similarly, individuals who have a genetic predisposition, may be more vulnerable to addiction after exposure to the drug.
As noted earlier, substances of abuse affect the brain reward pathway, which is made of neurons that release chemicals when they are stimulated. This release leads to subjective feelings of well being (1,2). This brain reward system evolved to subserve activities essential to species survival, such as sexual activity and feeding behaviors. Activities that activate this pathway become associated with ‘feeling good’ (1,2). For example, sexual intercourse causes release of chemicals activating this pathway, and the result is a feeling of well being. Thus, the reward pathway serves to promote survival of the species by rewarding behaviors necessary for continued survival (seeking food, reproduction, shelter, drink, etc). Drugs of abuse stimulate this “brain reward” pathway in a similar fashion, and this is why substance users experience feelings of pleasure or “high” when they use them (1,2). When drugs of abuse are repeatedly used, they may “commandeer” the brain reward system, driving compulsory drug use to the exclusion of other adaptive activities. Thus, “addiction” can be partially explained by the action of drugs of abuse on this common reward pathway, in which drug use stimulates further use and drug seeking behavior (1,2,3,4).
In the following paragraphs, the basic anatomy of the reward pathway and brain structures that interact with this pathway will be discussed. Next, the molecular physiology of the reward pathway will be delineated. After laying the foundation of the anatomy and physiology of brain reward, the specific interactions of drugs of abuse will be examined. Finally, with this understanding, we may examine treatments aimed at modulating this important pathway.
II. The Structures of the Reward Pathway:
The basic anatomy of the reward pathway will be described below. However, it must be remembered that the anatomical structures involved have complex interrelationships, and are modulated by other parts of the brain and other neurochemicals. Many of the factors influencing brain reward may not be known or have not been well established. Therefore, this paper provides an overview of the most well established structures and pathways involved. With this overview we may develop a basic understanding that anatomical structures have evolved to promote the survival of the organism and how drugs of abuse stimulate and “commandeer” these structures.
Core Structures of the Reward System
The core structures of the brain reward pathway is located in the limbic system, a set of primitive structures in the human brain (1,2,3,7,9). Conceptually, the function of the limbic system is to monitor internal homeostasis, mediate memory, mediate learning, and experience emotion. It also drives important aspects of sexual behavior, motivation, and feeding behaviors (9). The primary nuclei (or parts) of the limbic system include the hypothalamus, amygdala, hippocampus, septal nuclei, and anterior cingulate gyrus (9). Also important in the function of the limbic system is the limbic striatum, which includes the nucleus accumbens, ventral caudate nucleus and the putamen (9). The nucleus accumbens (NA) has been implicated as an especially important structure of the brain reward pathway because drugs of abuse target it. (1,2,3,5,7). Other structures important in brain reward include the amygdala and the ventral tegmental area (VTA). (1,2,3). The majority of this paper will concentrate on the NA and the VTA.
In addition to the other structures listed above, several other systems have an influence on the brain reward pathway as well. The endocrine and the autonomic nervous systems interact via the hypothalamus, an integral part of the limbic system, and the pituitary (1). These structures modulate the reward pathway. The hypothalamus is involved in every aspect of endocrine, visceral, and autonomic functions, and it is able to influence eating, drinking, sexual activity, aversion, rage, and pleasure (1,9). Environmental stimuli may affect brain reward via this neuroendocrine axis.
Electrical Stimulation of the Brain Reward Pathway
The link between the brain reward system and the hypothalamic-pituitary axis may be seen through experiments on animals where electrodes are placed into the nucleus accumbens (part of the brain’s reward system) under conditions of imposed environmental stress. Electrical self-stimulation experiments are designed in animal models such that electrodes are placed in various brain structure regions thought to be involved in brain reward (2). The animal then performs an activity (i.e. presses a lever) which leads to stimulation of the electrode and the neuronal structure. If the electrode is placed in a structure in the reward pathway, the resulting stimulation is pleasurable and self-stimulation is therefore encouraged. In models of addiction hungry animals will demonstrate a preference for self-stimulation over food and drink to the point of starvation (2). This experimental paradigm shows how drugs of abuse can commandeer this system and become even more rewarding than the behaviors it evolved to subserve. Other techniques allow the animal to press a lever and the drug is injected into specific areas of the brain as illustrated below. If the point of injection is not within the brain reward pathway, reinforcement will not occur. Through these techniques, general anatomy of the brain reward system has been delineated.
Experimental Self-Stimulation of the Brain Reward Pathway
Core Structures of the Reward System
As discussed before the reward pathway, located in the limbic system, is primarily made up of core structures that are connected by the median forebrain bundle (MFB): the nucleus accumbens (NA), the ventral tegmental area (VTA), the ventromedial and lateral nuclei of the hypothalamus, and the amygdala (1,2,3,7). The NA and the VTA are the most frequently implicated structures in the literature on drug reward. The MFB is composed of nerves that connect the septum, amygdala, the NA and the olfactory tubercle with the hypothalamus and the VTA (1,9). In other words, the MFB is like a power line of neurons connecting the structures of the reward pathway with other brain structures. Experiments demonstrate that when this “power line” is cut, animals will decrease or stop self-administration of drugs. Thus, an intact MFB appears to be necessary for the “brain reward” system to function properly. Below are slides that show the anatomy of neurons and the electrical activity that occurs between them.
NEURON AND NEURON FUNCTION
ELECTRICAL ACTIVITY BETWEEN TWO NEURONS
Dopaminergic neurons making up the MFB or “power line” of the brain reward system run from the VTA to other structures involved in brain reward. The neurotransmitter they release is called dopamine. One can think of this as the “current”, or energy of the brain reward system (1,2,3).
2.2 Communicating Brain Structures
The central reward pathway of the brain sends information to and receives input from many other brain structures: the reticular activating system (RAS), the central gray around the aqueduct of Sylvius, limbic regions, and the basal ganglia and cerebellum. Located in the brain stem, the RAS controls attention and arousal to various sensory inputs from our environment. Limbic regions such as the amygdala, the septum and the thalamus provide input to the reward pathway concerning motivational and emotional variables. Next, the reward pathway interacts with the basal ganglia and cerebellum to modify motor activity. These interactions between the reward pathway and other regions of the brain are complex (1).
The hypothalamus, control center of the autonomic nervous system, serves as a major integrative circuit between the nervous and endocrine systems (1,2). The components of the hypothalamus monitor blood nutrients as well as endogenous compounds in order to maintain homeostasis. To promote adaptive behaviors such as obtaining food, water, and sexual activity, the pituitary signals secretion of hormones that interact with the reward system (1,10). Thus, the hypothalamus is the command center interconnecting the reward pathway with the body and environmental stimuli. These stimuli are analogous to a complex array of music each a melody of summation in the form of endocrine hormones, blood temperature, blood osmolarity, blood volume, and neurotransmitters are deciphered and directed by the hypothalamus. This command center then sends out signals in the form of neurotransmitters (chemical signals) to various parts of the brain including the brain reward system.
Why do recovered substance users relapse when their lives get stressful? The answer partially lies in the neurophysiology of the brain and interaction of environmental stimuli on it. Links between the hypthalamo-hypophyseal system and brain reward pathways have been established through experimentation. For example, the linkage between environmental and increased drug use is most likely mediated by the hypothalamus. Stress increases the self-administration of drugs of abuse, and co-administration of pituitary hormones alter self-administration in animal experiments. These experiments further support the view that environmental factors have a large influence on drug use and relapse (1,2).
III. Genetic and Biological evidence for a Common Reward Pathway
3.1 Evolution of the Pathway
As noted earlier, the intrinsic purpose of an endogenous reward center is to reinforce behaviors that promote the survival of a species. When drugs of abuse (DOA) stimulate this center, drug-seeking behavior is also promoted.
3.2 Genetics and Population Studies
Why do studies show that many individuals experiment with DOA but only some become addicted? Genetic studies in both animals and humans have contributed to our ability to answer this question. Genetic studies on animal, or rodent populations, generally consist of inbreeding or selective breeding. Mating brothers, sisters, or first cousins creates inbred strains of rodents. After 20 generations of mating a strain is created that is, for all practical purposes, genetically identical (1). The next step is to look at differences in response to DOA through experimentation on different rodent strains.
In selective breeding, a desirable trait is chosen. For example, researchers may breed for a high response to EtOH. Rodents who have the desirable trait are then mated. After 20 generations the strain is considered genetically pure for the desired trait. Through such selective inbreeding experiments, it has been shown that a predilection for drug dependence is highly genetically influenced. Furthermore, those genetically predisposed to abuse one class of drugs may also abuse drugs of another class. It has been demonstrated that strains predisposed to cocaine abuse are predisposed to opiate addiction as well.
Human studies investigating the genetics of drug abuse consist of either adoption or twin studies (1). Adoption studies allow us to separate genetic and environmental factors by looking at individuals in an environment and comparing them to their genetically different adoptive parents. The individuals are then compared to their biological parents. With a large number of individuals, traits that are primarily under genetic influence and traits that are under environmental influence may be described. In twin studies, identical and fraternal twins are compared. Identical twins share 100% of their genes while fraternal twins share 50% of their genes. The relative agreement of behavioral traits to these percentages suggests the proportion of genetic and environmental influences. Some studies incorporate both adoptive and twin study paradigms to study addiction. Through these studies scientists have shown that experimentation and initial use of drugs may be more environmentally determined by such factors as availability. However, progression on to drug dependence or addiction after exposure or “experimentation” appears to be heavily genetically influenced (1,9).
IV. Molecular Physiology of the Reward Pathway
Dopamine Binding at the Neuron Level
The primary neurotransmitter of the reward pathway is dopamine (1,2,3,4). Although drugs of abuse often act through separate mechanisms and on various locations in the brain reward system, they share a final common action in that they increase dopamine levels in the brain reward system. However, neurotransmitter systems are inextricably intertwined. Thus serotonin, endogenous opiates, as well as GABA also modulate dopamine levels in the brain reward pathway (1,2,3). In the following paragraphs the major neurotransmitters involved in brain reward will be discussed.
Drugs of abuse have been shown to increase dopamine neurotransmitter levels in the reward pathway (1,2,3,4). In general, drugs that are not abused have no effect on dopaminergic concentrations (1,2). Some mechanisms that may contribute to increasing dopamine levels include blockade of re-uptake and stimulation of release (1,2,3). The specific mechanisms of action of various substances of abuse in increasing dopamine levels in the brain reward pathway will be described below.
Neurotransmitter Release and Re-uptake
4.2 Other Neurotransmitters and Brain Reward
Even though increased dopamine in the brain reward system is generally thought to be the final common pathway for the reinforcing properties of drugs, other neurotransmitters such as serotonin are involved in the modulation of both drug self-administration and dopamine levels. Serotonin may be important in modulating motivational factors, or the amount of work and individual is willing to perform to obtain a drug (1). Serotonergic neurons project both to the NA and VTA and appear to regulate dopamine release at the NA. However the relationship between serotonin and dopamine release is complex in that, serotonin has numerous receptor types and its regulation of dopamine release is at times inhibitory and at other times excitatory (1,2). Thus, serotonin modulates the reward pathway through various mechanisms by interacting with different receptors throughout the brain.
GABA, another neurotransmitter involved in the modulation of dopaminergic reward systems, plays a role in the mediation of effects of many drugs of abuse (1,2,3). GABA is an inhibitory neurotransmitter located diffusely throughout the brain. Drugs of abuse (DOA) act on the GABA receptor to hyperpolarize neurons. When a neuron is hyperpolarized, it is inhibited from firing. An analogy may be applying brakes to a car. Just as greater amounts of gas are required to cause the car to move while stepping on the brakes, greater amounts of stimuli are required to cause a neuron to fire that is hyperpolarized. When neurons fire they release neurotransmitter, and since drugs of abuse (DOA) inhibit these neurons, they release less GABA. When barbiturates, benzodiazapines or alcohol interact with the GABA receptor, they inhibit the release of GABA onto the dopaminergic neurons (1,2,3). Thus, this is like taking your foot off the brakes & allowing the car to go full speed ahead. The net result is disinhibition of dopaminergic neurons, making them fire more rapidly and releasing more dopamine in the reward system. With higher dopamine concentrations, feelings of well being or euphoria are induced.
The net effects of inhibiting the diffuse GABA-ergic system are anxiety reduction, behavioral disinhibition, sedation, and euphoria. Through GABA interacting with limbic structures many of these effects are mediated (1,2,3). Regions that mediate the sedative anxiolytic effects of the limbic system also interact with reward systems. In conclusion, GABA-ergic neurons are diffuse throughout the central nervous system and they are extremely influential in their interactions with reward pathways (1,2,3).
4.2c The Endogenous Opiates
Endorphin Binding at the Synapse
Just as the structures of the brain reward system encourage adaptive behaviors such as seeking food and sex, endogenous proteins called endorphins also motivate behaviour (1,3). The “runner’s high” is thought to be related to the production of such endogenous opiate compounds or endorphins. In addition, place preference (animals prefer the environment where the drug is administered to other environments) is elicited when endorphins are applied to the NA (1,2). Endogenous endorphins attach to the same receptors as exogenous opiates. Through the same mechanism, they both increase dopamine in the brain reward pathway (1,2,3).
5. Drugs of Abuse and the Reward Pathway
Primary Location of Action for Drugs of Abuse
Experiments have shown that specific drugs of abuse affect receptors/neurochemical response act in different areas of the brain. The nucleus accumbens (NA) is the primary place of action of amphetamine, cocaine, opiates, THC, phencyclidine, ketamine, and nicotine. Opiates, alcohol, barbiturates and benzodiazapines (2,3,4) stimulate neurons in the ventral tegmental area (VTA). The final common action of most substances of abuse is stimulation of the brain reward pathway by increasing dopamine. The action of drugs of abuse on structures of the reward pathway at the gross anatomical level, followed by molecular actions of this system, will be discussed below.
The complete discussion of the anatomical and biochemical effects of alcohol is beyond the scope of this paper. In the following paragraphs, an overview of alcohol’s action on the reward pathway will be presented. Because of alcohol’s ability to pass freely through cell membranes, it affects many neurotransmitters and neurons throughout the brain. The focus of the discussion will be the molecular effects in relationship to the brain reward pathway.
Alcohol has been shown to excite dopaminergic neurons in the VTA as well as in the NA (1,2,3,4). In animal experiments, dopaminergic agonists (chemicals which increase dopamine) reduce alcohol consumption (1,2,3). For example, the dopamine agonist bromocriptine increases water intake and decreases consumption of alcohol in rodents(1). Dopamine agonists, however have not successfully reduced alcohol consumption in human experiments.
Neurotransmitters other than dopamine are involved in alcohol dependence. Studies demonstrated that serotonin re-uptake inhibitors (medications that are commonly prescribed for depression such as fluoxetine ) may decrease consumption of alcohol in both rodents and in humans (2). It is not known whether this is due to a direct or an indirect effect of serotonin on dopaminergic systems, or a combination effect. Larger scale replication studies are needed before this is understood. The effects of serotoninergic medications on drug self-administration may be due to their effects on motivational factors, as opposed to the specific reinforcing effects of the drug by modulating the reinforcing properties of other reinforcers such as food, water, alcohol and drugs of abuse (2).
Opiate Action in the Brain
Opiates influence dopamine levels and brain reward indirectly by inhibiting GABA neurons in the VTA (1). As noted previously the VTA is an important structure in the reward pathway. GABA neurons inhibit dopaminergic neurons in the VTA. Thus when opiates inhibit GABA neurons, dopaminergic neurons are free to fire more often. In essence, opiates remove the “brakes” from dopaminergic neurons and allow them to fire more rapidly resulting in an increase of dopamine release (1,2).
Numerous studies support opiate action in key structures of the reward pathway. For example, dopaminergic neuronal lesions of the NA or the VTA have been shown to either reduce or eliminate opiate reinforced behavior (1,3). Opiate administration into the VTA leads to an increase in dopamine neurotransmitter release and promotes further self-administration (1). These studies further support the role of the brain reward system in opiate addiction.
Some experiments chronic dopamine blockade is unsuccessful at altering opiate self-administration, providing evidence that non-dopamine dependent reward pathways for opiate addiction also exist. (1,3). However, most experiments demonstrate that opiates function by stimulating both the NA and the VTA, both of which are key structures in the reward pathway. However, as lesions to dopaminergic neurons do not completely eliminate self-administration of opiates in some experiments, indirect and dopamine independent mechanisms of opiate addiction and reinforcement also exist (3).
Like other drugs of abuse, stimulants increase dopamine concentrations in the brain reward pathway (1,2,3,4,7). Stimulants such as cocaine, amphetamines, caffeine and nicotine all stimulate the brain reward pathway through slightly different mechanisms and increase dopamine to different extents. Moreover, the route of administration of stimulants also influences the addictive properties of stimulants, by influencing the rate at which dopamine “spikes” in the brain. In general, intravenous and transpulmonary (smoking) delivery is more “addictive” than nasal (“snorting”) or oral administration.
Cocaine Binding at the Synapse
Cocaine, like other drugs of abuse, increases dopamine in the reward pathway. Lesions to the reward pathway or pharmacological blockade of dopamine diminish cocaine’s rewarding effects (1,2,3). Thus, dopaminergic neurons in the reward pathway have been shown to be important in the reinforcing effects of cocaine (2). This increase of dopamine in the brain reward centers is dose dependent (the more cocaine that is taken in, the higher the dopamine concentration in these areas). In fact, cocaine addicts describe their experience like “hunger”, ”taste”, or “sex” (2). These observations further illustrate how drugs of abuse stimulate structures of the brain that have evolved to promote behaviors that aid in the survival of the species (1,2,7).
Cocaine’s effects on the reward system are so powerful that it may override other generally gratifying reinforcers: money, safety, loved ones, morality and even survival may become less important to the abuser than obtaining and using cocaine (2). Thus, cocaine stimulates the brain reward system more effectively than the behaviors that the reward system evolved to reinforce!
Cocaine acts to increase dopamine levels by inhibiting monoamine (dopamine, serotonin, and norepinephrine) re-uptake from the synaptic cleft (1,2,3,4,6,7). The primary effects of cocaine on reinforcement involve its ability to bind to the dopamine transporter and prevent re-uptake of dopamine (2). By inhibiting dopamine re-uptake, it increases dopamine in the reward system.
Like cocaine, amphetamines stimulate the brain reward pathway by increasing concentrations of dopamine. 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. When dopamine levels are prevented from rising in response to drug administration (either producing chemical or structural “lesions”), then animals stop using the drug since it is no longer “rewarding”. These elegant experiments demonstrate that the “rewarding” properties of the drug are directly related to whether it increases dopamine or not in the reward pathway.
Nicotine is thought to affect the brain reward system by increasing dopamine concentrations through interacting with nicotinic acetylcholine receptors. It has been shown to mimic endogenous (or the body’s natural) acetylcholine neurotransmitter. 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).
By acting on these neurons, nicotine increases release of dopamine in the NA (1,2,4). 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 (11). Caffeine blocks the actions of adenosine, an inhibitory neurotransmitter, by binding to its receptor and preventing post binding changes from taking place (2). Caffeine is a “competitive antagonist” of adenosine. 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).
5.6 Treatment Implications of the Brain Reward System
Operating through different mechanisms drugs of abuse have a final common pathway by which they increase dopamine levels within the core structures of the so called “brain reward system” which includes the VTA and NA. 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). Generally the positive effects or “high” of using a drug occur immediately or shortly after use, by the action of increasing dopamine.
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). 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.
VI. 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).
6.1 Aversive Conditioning
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). 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 (12). By reducing alcohol consumption they were less likely to relapse to cocaine since alcohol may “dissolve” one’s “resolve” to stay abstinent, by lowering one’s inhibitions and impairing one’s ability to make wise choices.
6.2 Neurotransmitter Manipulation
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 (13). Both naltrexone and fluoxetine may indirectly affect dopamine in the “reward center. Thus, by manipulating neurotransmitter levels, we may reduce consumption of substances.
6.3 Pharmacological Substitution
By substituting one substance that stimulates the brain reward pathway with another less addictive/ less harmful substance, we may aid in relapse prevention. 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. 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. Thus, the gradual increase in nicotine that occurs with the nicotine patch will lead to more constant moderate levels of dopamine in the brain as opposed to the “spike and dip” pattern produced by most drugs of abuse. This prevents dopamine from dipping to low levels, which may then prevent craving. Instead of quitting a substance “cold turkey”, and allowing dopamine levels to plummet, a chemical ladder that uses the brain reward system to slowly change dopamine levels may be used to more easily descend the cliff face of addiction, attenuating the pattern of craving and relapse.
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! Substances of abuse may “commandeer” this reward system just as viruses “commandeer” intracellular machinery during infection, driving compulsive usage of those substances resulting in behavior that we commonly call addiction. 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.
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