Biological Basis Of Addiction

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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 rein-

forcers 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 mesocor-ticolimbic 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 cau-date-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 (Koob1992; 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 be-

Figure 4

Neuronal circuits involved in the reinforcing effects of stimulant drugs.

The major components of this system include the dopamine pathways from the ventral tegmental area to the nucleus accumbens caudate-putamen and frontal cortex. The limbic system inputs to the accumbens from the amygdala, frontal cortex, hippocampus and thalamus and the outputs from the nucleus accumbens to the ventral pallidum and substantia nigra. (Adapted from Koob, 1972, and Feldman et al., 1977)

Figure 4

Neuronal circuits involved in the reinforcing effects of stimulant drugs.

The major components of this system include the dopamine pathways from the ventral tegmental area to the nucleus accumbens caudate-putamen and frontal cortex. The limbic system inputs to the accumbens from the amygdala, frontal cortex, hippocampus and thalamus and the outputs from the nucleus accumbens to the ventral pallidum and substantia nigra. (Adapted from Koob, 1972, and Feldman et al., 1977)

havioral effects that are not the same in everybody and can even change in the same individual. For example, alcohol can produce feelings of euphoria in a social situation or depression when one is alone. Another example is cocaine, a very potent stimulant of brain systems involved in euphoria and feelings of well-being. However, when animals are given simultaneous infusions of cocaine without control of delivery, cocaine becomes a stressor that will lead to the animal s death much faster than animals controlling and self-administering the drug.

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 dopa-mine 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 (eth-anol) 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 psy-chomotor 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.

CONCLUSION

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.

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