Wired for Addiction

United States

On June 22, 1998, Wired for Addiction was presented as part of NIDA's Frontiers in Neuroscience seminar series. The theme of these presentations centered on the neuronal remodeling that emerges after repeated substance use and withdrawal, with particular emphasis on the possibility of altered cognitive function as a consequence of the neural remodeling. Presentations were made by Drs. Ann Graybiel, Tony Grace, John Marshall, Janet Neisewander, and Regina Carelli, and a summary and discussion was presented by Dr. Steve Grant of NIDA. Brief summaries of their presentations follow.

Chronic exposure to psychomotor stimulants may rewire your brain

Ann Graybiel, Ph.D.,
Massachusetts Institute of Technology

Exposure to amphetamine and cocaine induces gene expression in cortico-basal ganglia circuits. Chronic intermittent exposure to the same drugs down-regulates some of the inducible change. After a course of chronic intermittent treatment and withdrawal of the drug, a subsequent challenge with the drug induces new patterns of gene expression in cortico-basal ganglia circuits. The repeated administration and withdrawal of cocaine induces both immediate early gene (IEG) expression after drug challenge in neurons that are not activated acutely, and an increase in the size of the area in which this response is observed. These findings raise the possibility that prolonged exposure to psychomotor stimulants produces enduring changes in brain wiring.

Neuronal interactions within the limbic system of rats: Alteration during amphetamine sensitization

Anthony Grace, Ph.D.
University of Pittsburgh

Amphetamine exerts differential actions on neurons in the nucleus accumbens when given acutely versus repeatedly. Our studies show that repeated amphetamine administration causes an increase in electrical coupling among nucleus accumbens neurons, which appears to be driven by an increase in prefrontal corticoaccumbens afferent activation. We propose that such a condition would lead to alteration of information flow within this system, resulting in a perseverance of behavioral action that may contribute to drug-seeking behavior in humans.

Cortical and striatal circuits influenced during repeated methamphetamine administration

John Marshall, Ph.D.
University of California at Irvine

Repeated administration of methamphetamine (m-AMPH) can induce long-lasting changes in brain function, including (I) regulatory events related to the phenomena of tolerance, sensitization, and craving, and (II) injurious effects associated with prolonged exposure to this stimulant drug. The ability of repeated m-AMPH administration to injure the dopamine terminals of the neostriatum is well characterized; this injury is a consequence of the drug-induced overflow of both glutamate and dopamine within the caudate-putamen.

The involvement of striatal glutamate in these effects of repeated m-AMPH treatments suggests a progressive recruitment of the corticostriatal projections during repeated drug exposure. Evidence that cerebral cortical neurons are activated, and that some of them degenerate, during the course of repeated m-AMPH administration is provided by studies of immediate early gene expression, quantification of glutamate receptors, and cellular markers for cortical neuron degeneration. Degenerating cortical neurons include pyramidal and stellate cells in layers III and IV of parietal cortex. As the neuronal degeneration occurs in concert with the intense stimulant-induced stereotypical behaviors, it is possible that the behavior itself may drive the circuits that trigger the injured neurons, promoting further damage. The implications of this progressive alteration in cortical and striatal circuits for the progress of amphetamine self-administration was discussed.

Neurochemical Correlates of Cocaine-Seeking Behavior

Janet Neisewander, Ph.D.
Arizona State University

Imaging studies in humans suggest that the amygdala plays an important role in craving elicited by cocaine and cocaine-conditioned environmental stimuli. Our research examined the relationship between neurochemical changes in the amygdala and cocaine-seeking behavior following exposure to a cocaine-paired environment or a cocaine priming injection. We measured cocaine-seeking behavior by assessing the persistence of lever-pressing in the absence of cocaine reinforcement in animals previously trained to press a lever for cocaine infusions. Lever-pressing under these conditions is thought to reflect the incentive motivational properties of cocaine and cocaine-associated stimuli. We first investigated whether the pattern of changes in cocaine-seeking behavior corresponded with changes in concentrations of dopamine in dialysates obtained from the amygdala during the course of cocaine withdrawal. There were concomitant changes in cocaine-seeking behavior and dialysate dopamine following the cocaine priming injection, but not following exposure alone to the cocaine self-administration environment. We next investigated changes in Fos protein expression as a general marker for neuronal activation. Exposure to the cocaine self-administration environment, but not the cocaine priming injection, elicited Fos expression in the basolateral nucleus of the amygdala, nucleus accumbens shell, and cingulate cortex. In contrast, the cocaine priming injection, but not the environmental stimuli, elicited Fos expression in the central nucleus of the amygdala and dorsolateral caudate-putamen. The findings suggest that different neural mechanisms mediate cocaine-seeking behavior elicited by cocaine-conditioned environmental stimuli and those elicited by a priming injection of cocaine. Increases in extracellular dopamine may be critical for the induction of cocaine-seeking behavior elicited by cocaine but may not be elicited by cocaine-conditioned environmental stimuli.

The Nucleus Accumbens and Reward: Electrophysiological Studies in Behaving Animals

Regina Carelli, Ph.D.
University of North Carolina

Numerous investigations indicate that the nucleus accumbens (NA) is a neural substrate crucially involved in mediating the reinforcing properties of "natural" rewards such as food and water, and drugs of abuse such as cocaine. Despite overwhelming evidence linking the NA with reinforcement-related events, we do not yet understand the underlying cellular mechanisms mediating this process in the behaving animal. We used multi-neuron recording procedure in which NA neurons (16-32 cells) are recorded simultaneously in rats trained to press a lever for water reinforcement, or for intravenous infusion of cocaine (ie, self-administration). The data show that although water and cocaine both activate cells that recognize reward, cocaine also uniquely activates a set of neurons that may be part of a specialized reward circuit. We found three types of activity patterns that occurred in response to presentation of either cocaine or water. Some neurons fired in anticipation of cocaine or water, others were activated only during the time the reinforcement was present, and a third group became quiescent in the period of time when the reinforcement was present. A fourth pattern in which the neuronal activity was increased just prior to and after the presentation of cocaine occurred. No similar responses to water reinforcement were observed. In addition, NA neurons exhibit very dynamic firing properties which are explicitly coupled to the behavioral state of the animal, and are markedly influenced by the environmental context in which the drug was self-administered. These studies provide insight into the neurobiological mechanisms underlying the rewarding properties of natural rewards such as water, and how drugs of abuse such as cocaine may affect this system and lead to drug addiction.

Summary and Discussion: Implications for Humans

Steve Grant, Ph.D.
National Institute on Drug Abuse:

How can we best exploit these advances to stimulate translational research in humans? The correspondences between data obtained in animals and man are striking. Presentation of drug-associated cues to humans and animals activates the similar regions in the brains of men and animals, exemplified by the convergence of the orbitofrontal projections to the basal ganglia. It may be fruitful to think of the brain as a collection of "modules" in which each module is more responsive to particular kinds of information.