Limbic System

LIMBIC SYSTEM COMPONENTS

The limbic system that surrounds the thalamus provides an interface between the midbrain and higher cortical structures. The general structure and components of the limbic system are shown in Figure 1. These include the AMYGDALA, the NUCLEUS ACCUMBENS, the olfactory tubercle, the septal nuclei, the hippocampus, the hypothalamus, the cingulate cortex, and the frontal cortex. As can be seen in the figure, these structures are positioned between the brain's major relay stationhe thalamusnd higher cortical structures. The separate components of the limbic system are interconnected such that activity initiated in one structure affects other components. One of the hypotheses about the basis of emotion speculated that reverberating neuronal activity in this system was responsible for affective behaviors. Initial animal studies using either direct electrical stimulation or lesions (loss) of various components of the limbic system substantiated the important role of this system in behavior.

THE ROLE OF THE LIMBIC SYSTEM IN BEHAVIOR

Electrical stimulation or the destruction (lesions) of components of the limbic system alter behavioral processes. Lesions of the hippocampus disrupt memory processes, whereas lesions or stimulation of the amygdala affect emotional behavior and feeding in a manner similar to manipulations of the medial and lateral hypothalamus. Stimulation of the lateral hypothalamus produces aggressive

responses, whereas lesions of this area produce a placid behavioral profile. In contrast, lesions of the medial hypothalamus produce a highly excitable and aggressive pattern of behavior, whereas lesions of the amygdala result in placid and nonaggressive behavior. Early studies found that lesions of the lateral hypothalamus can decrease feeding, whereas lesions of the ventromedial region produce excessive levels of feeding resulting in obesity. Recent experimental studies have demonstrated the complex nature of the involvement of hypothalamic cells in feeding and drinking; however, like most complex behaviors, the mechanisms that control hunger and satiety are not simply located in a single brain center.

Some structures of the limbic system are important in REINFORCEMENT processes. The term reinforcement applies to processes perceived as rewarding or good, which therefore are repeated, such as electrical self-stimulation. For example, animals will repeatedly emit a response that leads to the delivery of brief electrical stimulation of small electrodes that are implanted in selected brain structures. Humans will also choose to stimulate many of these same brain regions and report positive feelings of well-being and euphoria. The limbic system sites that produce these effects in animals include the lateral hypothalamus, nucleus accumbens, frontal cortex, cingulate cortex, and the brain-stem nuclei believed to be part of the limbic systemhese include the substantia nigra and ventral tegmental area, which both contain DOPAMINE neurons that send inputs to many limbic-system components. Measures of brain-glucose metabolism, which directly reflect brain-cell activity, have been used to determine the involvement of specific brain regions in animals electrically self-stimulating three of these brain regions. The stimulation of each of these regions produced significant activation of several limbic-system structures that included the nucleus accumbens, amygdala, hippo-campus, and the frontal and cingulate cortices. This area of investigation has led neuroscientists to propose that there are brain circuits dedicated to the behavioral processes related to reinforcement. Drugs of abuse likely produce their positive effects through the activation of these brain circuits.

THE ROLE OF THE LIMBIC SYSTEM IN DRUG ABUSE

A large number of experiments have focused on identifying the brain circuits that mediate the reinforcing effects of abused drugs, because the reinforcing effects are responsible for drug abuse. These experiments have included the use of drug self-administration techniques and sophisticated neurochemical procedures to measure the involvement of specific NEUROTRANSMITTER systems. As of the early 1990s, evidence indicates that limbic structures and brain cells that project to limbic structures play an important role in these processes. It is clear that dopamine-containing neurons that project from the ventral tegmental area to the nucleus accumbens have a critical role in the reinforcing actions of COCAINE and AMPHETAMINE. Removal of these inputs with toxic agents that selectively destroy dopamine-releasing brain cells disrupts intravenous self-administration of these drugs. Additional evidence of the importance of this region in drug abuse comes from glucose-utilization studies. The levels of glucose metabolism are significantly elevated in a number of limbic structures in animals self-administering cocaine intravenously. Other experiments have directly shown dopamine levels in the nucleus accumbens to be increased in animals intravenously self-administering cocaine. Collectively, these data imply an important role for the limbic system in general and specifically for dopamine neurons in the limbic system tied to the brain processes involved in stimulant abuse.

The brain circuits involved in OPIATE reinforcement appear to be very similar to those mediating cocaine self-administration. Limbic structures are clearly implicated in opiate reinforcement, but a central role for dopamine is less obvious. Significant changes in the utilization of some chemicals (neurotransmitters) involved in transmission between brain cells have been shown in the nucleus accumbens, amygdala, and the frontal and cingulate cortices of animals intravenously self-administering morphine. However, loss of dopaminergic inputs to the nucleus accumbens does not affect drug intake, whereas a similar loss of serotonergic inputs does. Similarly, nucleus-accumbens dopamine does not appear to be elevated in animals self-administering heroin as it is in animals self-administering cocaine. However, evidence does indicate an important role for limbic structures and chemicals used to communicate between cells of the limbic system in opiate reinforcement.

Limbic structures also appear to be important for ethanol (drinking ALCOHOL) reinforcement. The levels of dopamine appear to be elevated in the nucleus accumbens of rats orally self-administering alcohol. Injections of drugs that antagonize dopamine directly into the nucleus accumbens decrease alcohol self-administration, whereas drugs that enhance dopamine action increase alcohol intake. In addition, animals will self-administer alcohol directly into the ventral tegmental arean area that contains the cell bodies for the dopamine cells that send inputs to the nucleus accumbens. These data collectively indicate that the nucleus accumbens and dopamine-releasing inputs to the nucleus accumbens are important to alcohol reinforcement.

CONCLUSION

The limbic system plays an important role in behavior. These brain structures appear to be central to the processes that mediate the reinforcing effects of electrical-brain stimulation and of several highly abused drugs. The nucleus accumbens appears to be a structure central to the reinforcing properties of cocaine and amphetamine, but it appears less important to opiate and alcohol reinforcement. A more exact definition of specific neurochemicals and brain-cell pathways in the limbic system that are involved in drug abuse will become clearer as new methodologies are developed.

(SEE ALSO: Neuron; Neurotransmission; Research.)

ACKNOWLEDGEMENT

PREPARATION of this entry was supported in part by USPHS Grants DA 00114, DA 01999, DA 03628 and DA 06634.

JAMES E. SMITH

STEVEN I. DWORKIN