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Connection Between Behavioral Changes and Neuronal Plasticity in Specific Pathways

Addiction: Making the

The image evokes the alluring yet sinister nature of cocaine. By usurping neuronal pathways normally involved in motivated behavior, cocaine promotes "learning" of compulsive behavioral responses that underlie drug craving and addiction.

T

here is an emerging consensus that drugaddiction is a form of maladaptive learning. Drugs of abuse usurp the neuronal circuitry

involved in motivation and reward, leading to aberrant engagement of learning processes. As a result, drug-associated cues can trigger craving and compulsive drug-seeking behavior, and voluntary control over drug use is lost. Abused drugs can also modulate long-term potentiation (LTP) and long-term depression(LTD) in neuronal circuits associated with the addiction process, suggesting a way for the behavioral consequences of drug-taking to become reinforced by learning mechanisms. This review will assess progress in correlating these effects on LTP and LTD with behavioral changes in animal models of addiction, particularly behavioral sensitization.

Marina E. Wolf Department of Neuroscience, TheChicago Medical School, 3333 Green Bay Road North Chicago, IL 60064-3095
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Photo by Jay Justice

Addiction and Neuronal Plasticity

INTRODUCTION
Cocaine and amphetamines enter the brain and interfere with the function of cell membrane transporters that normally remove dopamine and other monoamines (serotonin and norepinephrine) from the synapse after these transmitters are released. Thisinterference produces a rapid elevation of dopamine levels that results in psychomotor stimulation: a feeling of being “high.” Although these interactions are becoming better understood, it remains a mystery how this initial elevation in dopamine levels leads, in some people, to a compulsive pattern of drug-seeking and drug-taking behavior. Even if abstinence is achieved, cocaine addicts remainvulnerable for years to episodes of craving and relapse triggered by stimuli previously associated with drugs (1, 2). This persistent vulnerability to drug-conditioned stimuli is also observed in animal models of addiction (3). These features of addiction suggest that it may be an exceptionally powerful form of neuronal plasticity, which can be broadly defined as the ability of the nervous system tomodify its response to a stimulus based on prior experience, and is believed to underlie learning and memory. Plasticity might also underlie addiction, because signaling through glutamate, the key neurotransmitter for producing and maintaining synaptic plasticity, is important for the formation of behavioral sensitization—a prominent animal model of addiction (4, 5). This role for glutamatereceives further support from imaging studies of the brains of human cocaine addicts: stimuli previously associated with drug use (e.g., drug paraphernalia) trigger intense drug craving, and at the same time, activate glutamate-rich neuronal circuits implicated in learning and memory (6). Animal studies implicate the same glutamate-rich circuits, and suggest that the progression to addiction is a formof habit-based learning (7). Parallels between addiction and learning are reflected in the striking similarities between the signal transduction cascades and molecular adaptations associated with both processes (8). For example, chronic administration of amphetamine or cocaine produces dramatic changes in the morphology of dendritic spines in addiction-related brain regions, which closely resemblethose associated with learning (9, 10).

ADDICTION AND LONG-TERM POTENTIATION
Learning and memory are thought to be encoded by changes in the usage of interneuronal connections (11). In other words, synapses that experience frequent use will be strengthened, whereas those that receive less use are weakened. In this way, an experience (which results in activation of pathways and increased...
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