Psychoactive or behaviorally active drugs are substances that alter internal and external behavioral processes including activity levels, moods and feelings. As a result of these changes, while some of these substances can lead to compulsive drug use and drug addiction, others are used to manage neuropsychological disorders. In both cases these drugs do not produce unique behavioral or neurological effects. Their behavioral activity results from modifying existing neuronal systems. To understand the actions of abused drugs on the brain, one must have an understanding of the functions that brain cells serve in the expression of behavior in general. This article focuses on information that will assist readers in understanding the biological basis of drug actions on the brain, and particularly the actions of commonly abused drugs. First, the general classification of brain cells will be discussed, followed by a discussion of brain structure as it relates to function and drug action. The classification of brain cells based on the chemical nature of communication between cells will then be discussed as it relates to the actions of abused drugs.
CLASSIFICATION OF BRAIN CELLS
The brain is a complex structure that has many different types of cells. Brain cells are subdivided into groups based on a number of criteria that include whether they serve as (1) structural support cells (glia) or (2) cells that receive and transmit information (called neurons or nerve cells). If cells are the latter, then additional criteria are: (a) shape or size; (b) their connections; (c) the distance over which they transmit information; and (d) which chemicals are released to transmit information to other cells. Most of the effects that drugs produce, which are related to abuse potential, are situated on brain cells that process or transmit information. For that reason, the discussions to follow will consider only actions on interneurons (nerve cells that connect to other nerve cells). The actions of drugs on the brain are complex and seldom involve only one type of brain cell. Nerve cells have a high level of connectivity between one another. Cells in one brain region send inputs to and receive outputs from other regions. These factors make the identification of cells in the brain responsible for a given drug effect difficult to distinguish. This is true of even the most simple behaviors, which involve complex interactions between millions of cells. For these reasons, the understanding of the processes underlying addiction is incomplete; however, significant progress has been made during the past 20 years. For example, it is generally believed that there are brain systems that are dedicated to the processes underlying euphoria and feelings of well-being that are stimulated by abused drugs.
ORGANIZATION OF THE BRAIN: BRAIN REGIONS
The Cerebral Cortex.
A number of experimental approaches have developed to study the basis of behavior in the brain. One of these has been to study the role of brain regions in behavior. The brain is composed of distinct substructures. The most general categorization scheme separates the brain into five segments called lobes (Figure 1). From front to back these include the frontal, parietal and occipital lobes and the cerebellum. The temporal lobe is on the lateral surface of the brain. The outermost surface of the brain is called the cortex; this part of the brain has expanded in size the most in higher animals and is thought to be responsible for the high level of intelligence in nonhuman and human primates. Areas of the cortex are specialized so that specific physiological functions are mediated by cells in defined cortical regions. For example, visual processes occur in cells located on the surface of the back of the brain in the occipital lobe. In front of this region, on the border between the parietal and frontal lobes, is the area that controls movement, which is called the motor cortex. The area of the brain that controls sensation, the sensory cortex, is just in front of the motor cortex. The area in front of
Information processing includes sensory information that comes in from sense organs (for example, eyes, ears, tongue) to the brain through the spinal cord or directly through cranial nerves (nerve cells connected directly to the brain). This in-coming information from sense organs goes to a central relay station called the thalamus. The thalamus is specialized, much like the cerebral cortex, in that defined areas receive input that is specific to a sensory modality. For example, input from the eyes through the optic nerve goes to a region of the thalamus called the dorsal lateral geniculate nucleus. This area of the thalamus, in turn, sends the information transmitted from sense organs to the appropriate area of the cortex. For example, the lateral geniculate sends visual information to the area of the cortex specialized for vision, which is located in the occipital lobe. Similarly, the cerebral cortex sends commands to the effector systems (usually muscles) that act on the environment through the same relay system. As one can easily see, the thalamus is a very important structure for the coordination of inputs and outputs from the brain. Thus, degenerative diseases of this structure are very debilitating, as would be drugs that specifically altered the function of this structure.
The Brain Stem.
Other areas of the brain are responsible for life processes of which we are not usually aware. These processes are generally controlled by the part of the brain called the brain stem, which is located between the spinal cord and the cerebral hemispheres of the brain. The brain stem contains the cell bodies for centers that maintain heart rate, blood pressure, breathing, and other involuntary or unconscious life-sustaining processes. A number of psychoactive agents have actions on NEURONS located in the brain stem. For example, OPIATES such as morphine or heroin have a direct inhibitory effect on the brain stem respiration (breathing) centers. This is why heroin OVER-DOSES are often fatalince the breathing centers stop working. Drugs that do not affect neurons in this area, such as marijuana, are seldom life-threatening. A significant part of the reticular formation is also located in the brain stem. This system sends outputs into the brain and down the spinal cord. It regulates arousal by increasing or decreasing the brain's responses to environmental events. Thus, morphine decreases pain by altering the sensitivity of brain cells involved in pain perception. The brain stem is important in the control of pain and also contains the cell bodies for some important nerve cells involved in the euphoric and depressant actions of drugs.
The Limbic System.
Another important anatomical brain system through which abused drugs act is the LIMBIC SYSTEM. This system is a collection of structures that lie between the brain stem and the cerebral cortex. It includes the olfactory bulb, frontal and cingulate cortices, NUCLEUS ACCUM-BENS, amygdala, hypothalamus, hippocampus and septum, all of which have direct connections with one another. The limbic system is involved in the control of motivated behaviors such as eating, drinking and sexual behaviors and in the expression of emotional behaviors including anxiety and aggression. Tumors or lesions of these structures often lead to abnormal emotional expression. Drugs that directly affect this system can produce changes in goal-directed behaviors, mood (euphoriadysphoria) and emotions.
The Motor System.
Motor function (movement) involves a number of brain structures that include the caudate nucleus-putamen, which sits above and in front of the thalamus, the premotor cortex, and the motor cortex as previously described. Drugs that increase (stimulants) or decrease (depressants such as alcohol) activity levels may do so by affecting the activity of these structures. Although the basic mechanisms may differ for drugs of different classes, the overall effect may be the same.
Besides categorizing the parts of the brain by structure, the brain can also be separated into systems based on the distribution of the chemicals that nerve cells use to communicate with one another. Thus, cell bodies for some important nerve cells are localized in specific brain nuclei (collection of nerve cell bodies). Some drugs of abuse have specific actions on subsets of cells that use or release a specific chemical to communicate with other cells. For example, ALCOHOL (ethanol) is believed to act on at least three systems in the brain-the ones containing the nerve cells that release SEROTONIN, GLUTAMATE, and GAMMAAMINOBUTYRIC ACID (GABA). The cell bodies of serotonin-releasing nerve cells are localized in the brain-stem region called the raphe' nuclei, while glutamate-releasing and GABA-releasing cells are distributed widely throughout the brain (see figure 2).
What about the different actions of drugs of abuse, where do they act in the brain? As stated previously, it is still not fully understood how the actions of drugs on the brain eventually affect behavior. Our knowledge at this time (2000), however, indicates some specific actions on some de-fined sites and cell systems. The so-called stimulant drugs (e.g., AMPHETAMINE, COCAINE, METH-AMPHETAMINE) produce overall effects on the brain resulting in increased activity, faster speech and thought patterns, and euphoria. This overall effect results from changes in a number of specific behavioral patterns and represents a complex action of these drugs on several important neuronal systems in the brain. Neurochemical studies of the brain have shown that these stimulant drugs enhance and/or prolong the action of the neurotransmitters DOPAMINE, NOREPINEPHRINE, and SEROTONIN that are released by cells that produce these chemicals to
BIOLOGICAL BASIS OF ADDICTION
Activation of Brain Reinforcement or Hedonic Systems.
One common effect of abused drugs is that they produce feelings of euphoria and pleasantness or they decrease unpleasantness. Abused drugs produce these reinforcing effects by activating brain-cell systems that are naturally involved in the reinforcing effects of non-drug reinforcers such as eating desirable foods, listening to pleasing music, sex, leaving unpleasant circumstances, and so on. Chemical stimulation by drugs can, however, produce activation of these systems far beyond that produced by these other natural reinforcers. The activation of the mesocorticolimbic dopaminergic system is believed to be critically involved in the neuronal processes that regulate the reinforcing effects of all environmental events. The major components of this system (see Figure 4) include the ventral tegmental area, nucleus accumbens, frontal cortex and ventral caudate-putamen. In addition, the nucleus accumbens is regulated by cells originating in the limbic system including the amygdala, frontal cortex, hippocampus, and thalamus. The nucleus accumbens alters activity in motor systems by the activation of cells in the ventral pallidum and ventral tegmental area (Koob 1992; Feldman et al., 1997). Many researchers believe that the ability to modulate these systems by chemical agents is the factor that leads to abuse. Such euphoric effects appear to pose a particular problem for those adolescents who have underdeveloped inhibitory systems, have limited experience with socially accepted forms of personal gratification, and have higher than average levels of aggression. Even without such characteristics, adolescence is one of the most confusing and stressful periods of human development. Ready access to simple chemical means of activating reward systems under these conditions can easily lead to abuse.
Drugs Do Not Have Intrinsic Hedonic Properties.The euphoria that occurs after chemical activation of these systems is not only the result of the direct actions of the drug on neurons but is also influenced by the expectations of the individual and the environment in which the drug is taken. Studies in laboratory animals have shown large differences in the effects of a drug on the brain depending on whether the drug is self-administered or administered to the animal passively (not under its control). It has become clear that the act of drug taking and control over when the drug is taken are perhaps the two most important factors in the pleasant feelings that follow drug intake. The drug itself has no consistent intrinsic hedonic properties. Why is it important for an individual to control the onset of drug action through self-administration? It suggests that the activation of these brain systems is also under behavioral influences. Drugs have behavioral
Dopamine Hypothesis of Drug Abuse.
It is widely accepted since the mid-1990s that the abuse potential of a wide variety of drugs, at least in part, is directly related to the direct actions of these chemical agents on brain mesocorticolimbic dopamine cells (see Figure 3 and 4). The dopamine cells in this system send inputs to the limbic system, including the limbic cortical regions. The dopamine hypothesis states that drugs that are abused directly activate these dopamine-releasing nerve cells, resulting in the production of reinforcement and/or feelings of euphoria and well-being. This may be correct for PSYCHOMOTOR STIMULANTS like amphetamine and cocaine, which have direct actions upon dopamine releasing nerve cells, but convincing evidence for dopamine being primarily responsible for the abuse of alcohol (ethanol) opiates, and particularly for BENZODIAZEPINES is lacking. Dopamine-releasing nerve cells clearly have an important function in the behavioral process and in the euphoria produced by psychomotor stimulants. To ascribe a universal role for these cells in all euphorogenic processes is, however, likely to be an oversimplification. Scientists initially focused on dopamine nerve cells often at the expense of exploring the involvement of other brain neurochemicals. However, more recent studies have demonstrated the involvement of additional neurochemicals and neuronal inputs. This research has increased knowledge that complex brain neuronal networks regulate behavioral effects that are called euphoria. It is likely that outputs of the cerebral cortex have a significant role in these processes. The roles of these neuronal systems have not been explored.
A drug may be subject to abuse if it directly activates the neuronal networks that are responsible for feelings of well-being and euphoria (positive reinforcement) or if it decreases the unpleasant or aversive nature of the environment in which the individual exists (negative REINFORCEMENT). Most scientific studies of the biological basis of addiction have focused upon the positive reinforcing effects of drugs, a focus which has led some to emphasize the role of dopamine in addiction. However, drug self-administration in humans and in laboratory animal models likely involves both positive and negative reinforcement. The act of taking the drug itself may result in circumstances that produce strain and pressures upon one's normal patterns of living. In addition, the drug itself may activate body and brain systems that are involved in stress, thus directly producing unpleasant circumstances. For these reasons, the research with animals that has implicated dopamine in the positive reinforcing effects of stimulant drugs is likely more the result of both positive and negative reinforcement. It could be that decreases in the unpleasant nature of one's existence may involve increases in the activity of dopamine-releasing nerve cells. It should also be noted that stressful situations can activate some of these same regions.
Neuronal Network Hypothesis of Drug Abuse.
In addition to dopamine, the nerve cells that appear to be involved in the euphoric properties of drugs include acetylcholine, glutamate, opioid, and serotonin-releasing cells. As of the very beginning of the 21st century, there is significantly less research data supporting the involvement of these cells; however, it is clear that the brain's opioid receptors are necessary for the reinforcing effects of opiates and that dopamine may not be the exclusive mediator of the euphoric effects of opiates. Serotonin and glutamate may have important roles in the euphoric properties of alcohol, while acetylcholine-releasing neurons may have a role in the general processes underlying euphoria.
Studies in laboratory animals have suggested that specific brain circuits are involved in the processes related to drug reinforcement. These include areas of the cortex, the midbrain, and the brain stem and involve acetylcholine, dopamine, glutamate, gammaaminobutyric acid, norepinephrine, opioid, and serotonin-releasing neurons. The frontal and cingulate cortices (nucleus accumbens, lateral hypothalamus, and amygdala) that are included in the limbic system are part of these circuits, as are the ventral pallidum and thalamus. Brain-stem dopamine, norepinephrine, and serotonin nerve-cell nuclei send projections to these fore-brain regions involved in such processes. In turn, these regions send output nerve cells to structures that utilize acetylcholine and glutamate primarily. Some of these forebrain structures are in turn connected to the brain-stem cell nuclei for dopamine, norepinephrine, and serotonin releasing nerve cells by GABA-releasing nerve cells.
This is a simplified description of complex neuronal networks that are believed to play a major role in the production of euphoric effects or reinforcement in the brain. It is likely that this complexity will increase as research continues to define and elucidate the basic biology of brain-behavior relationships. Investigations of drug self-administration continue to add significantly to this field of study in the early 2000s. This ongoing research will help us to understand the basic biology of drug abuse so that more efficient and effective forms of treatment and prevention can be developed.
The production of this discourse was funded in part by USPHS Grants.
KOOB, C. F. (1992). Drugs of abuse: Anatomy. pharmacology and function of reward pathways. Trends in Pharmacological Sciences, 13, 177-184.
KOOB, G.E, & BLOOM, F. E. (1988). Cellular and molecular mechanisms of drug dependence. Science, 242, 715-723.
FELDMAN, R. S., MEYER, J. S., & QUENZER, L. F. (1997) Principals of Neuropsychopharmacology. Sunderland, MA: Sinauer.
JAMES E. SMITH
STEVEN I. DWORKIN
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