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Drug Addiction

  1. George F. Koob

Published Online: 30 JAN 2010

DOI: 10.1002/9780470479216.corpsy0290

Corsini Encyclopedia of Psychology

Corsini Encyclopedia of Psychology

How to Cite

Koob, G. F. 2010. Drug Addiction. Corsini Encyclopedia of Psychology. 1–4.

Author Information

  1. Scripps Research Institute, La Jolla, CA

Publication History

  1. Published Online: 30 JAN 2010

Substance dependence can be defined as a chronically relapsing disorder characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented (defined here as withdrawal). Addiction and substance dependence, as currently defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association, 2000), are used interchangeably in this article to refer to a final stage of a usage process that moves from drug use to abuse to addiction. The term dependence has two meanings: (1) an acute withdrawal syndrome (defined here as dependence with a little “d”), and (2) a syndrome in which a subject meets the criteria for substance dependence. In addiction, drug-taking behavior progresses from impulsivity to compulsivity in a three-stage cycle consisting of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

Two sources of reinforcement can be found in drug-taking behavior associated with the use, abuse, and addiction to drugs: positive and negative reinforcement. Positive reinforcement occurs when presentation of a drug increases the probability of a response to obtain the drug. Reward is defined as positive reinforcement with an added positive emotional valence usually associated with pleasure. Positive reinforcement is most often associated with the impulsivity construct that is a key element of the binge/intoxication and preoccupation/anticipation (craving) stages of the addiction cycle. Animal models of the positive reinforcing or rewarding effects of drugs are extensive and well validated and include intravenous drug self-administration, conditioned place preference, and brain stimulation reward. Drugs of abuse are readily self-administered by animals that are not dependent; therefore, positive reinforcement and intravenous drug self-administration have been used to predict abuse liability.

Negative reinforcement occurs when presentation of the drug prevents the aversive consequences of removal of the drug, usually in the context of drug dependence. Negative reinforcement is often associated with the compulsivity construct that is a key element of the withdrawal/negative affect stage and preoccupation/anticipation stage (protracted abstinence) of the addiction cycle. Animal models of the negative reinforcement associated with drug dependence include measures of conditioned place aversion (rather than preference) to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug, increases in reward thresholds using brain stimulation reward, and dependence-induced increases in drug-taking and drug-seeking behavior. Such increased self-administration in dependent animals has been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol.

A key element of drug addiction is how the brain reward system changes with the development of addiction, and one must understand the neurobiological bases for acute drug reward to understand how the reward systems change with the development of addiction. A principle focus of research on the neurobiology of the positive reinforcing effects of drugs with dependence potential has been on the activation of the circuitry related to the origins and terminals of the mesocorticolimbic dopamine system. Compelling evidence suggests a critical role of this system in drug reward associated with psychostimulant drugs, and all major drugs of abuse activate this system, as measured either by increased extracellular levels of dopamine in the terminal areas (such as the nucleus accumbens) or by activation of the firing of neurons in the ventral tegmental area. However, although selective neurotoxin-induced lesions of the mesolimbic dopamine system block cocaine, amphetamine, and nicotine self-administration, rats continue to self-administer heroin and alcohol in the absence of the mesocorticolimbic dopamine system. Place preference studies also show robust place preferences to morphine and nicotine in the presence of major dopamine receptor blockade. Together these results suggest that activation of the mesolimbic dopamine system is a component of drug-seeking in general, but it is only critical for the rewarding effects of stimulant drugs.

Specific components of the basal forebrain associated with the amygdala have also been identified with drug reward. The reinforcing effects of alcohol in nondependent animals are blocked by administration of γ-aminobutyric acid-A (GABAA) receptor antagonists and opioid antagonists into the nucleus accumbens and central nucleus of the amygdala. As the neural circuits for the reinforcing effects of drugs with dependence potential have evolved, the role of neurotransmitters/neuromodulators also has evolved, and multiple neurotransmitter systems, including mesolimbic dopamine, opioid peptide, γ-aminobutyric acid (GABA), glutamate, endocannabinoids, and serotonin, have been identified to have a role in mediating the acute reinforcing effects of drugs of abuse in these basal forebrain areas.

1 Neurocircuitry of the Binge/Intoxication Stage of the Addiction Cycle

  1. Top of page
  2. Neurocircuitry of the Binge/Intoxication Stage of the Addiction Cycle
  3. Neurocircuitry of the Withdrawal/Negative Affect Stage of the Addiction Cycle
  4. Neurocircuitry of the Preoccupation/Anticipation (Craving) Stage of the Addiction Cycle
  5. References

Electrical brain stimulation reward (or intracranial self-stimulation) has a long history as a measure of activity of the brain reward system and the acute reinforcing effects of drugs of abuse. Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest thresholds involve the trajectory of the medial forebrain bundle connecting the ventral tegmental area with the basal forebrain (Olds & Milner, 1954). Much emphasis was focused initially on the role of the ascending monoamine systems in the medial forebrain bundle, but other descending, nondopaminergic systems in the medial forebrain bundle clearly have a key role (Hernandez et al., 2006). Activity in brain reward pathways measured by brain stimulation reward have provided key validation in animal models of the subjective reward changes reported by humans during the addiction cycle and forms the basis for exploring the underlying neuroadaptive changes in reward systems that occur during the progression to addiction.

All drugs of abuse, when administered acutely to nondependent animals, decrease brain stimulation reward thresholds (Kornetsky & Esposito, 1979). In contrast, measures of brain reward function during acute abstinence from all major drugs with dependence potential have revealed increases in brain reward thresholds measured by direct brain stimulation reward. These increases in reward thresholds may reflect decreases in the activity of reward neurotransmitter systems in the midbrain and forebrain implicated in the positive reinforcing effects of drugs (Koob et al., 2004).

The acute reinforcing effects of drugs of abuse are mediated by the activation of dopamine, serotonin, opioid peptides, and GABA systems, either by direct actions in the basal forebrain (notably the nucleus accumbens and central nucleus of the amygdala) or by indirect actions in the ventral tegmental area (Koob & Le Moal, 2001). Much evidence supports the hypothesis that the mesolimbic dopamine system is dramatically activated by psychostimulant drugs during limited-access self-administration and to some extent by all drugs of abuse. Serotonin systems, particularly those involving 5-hydroxytryptamine-1B (5-HT1B) receptor activation in the nucleus accumbens, also have been implicated in the acute reinforcing effects of psychostimulant drugs. μ Opioid receptors in both the nucleus accumbens and ventral tegmental area mediate the reinforcing effects of alcohol and opioid drugs. GABAergic systems are activated pre- and postsynaptically in the amygdala by ethanol at intoxicating doses, and GABA antagonists administered into the nucleus accumbens and central nucleus of the amygdala block ethanol self-administration (Koob, 2006; Nestler, 2005).

2 Neurocircuitry of the Withdrawal/Negative Affect Stage of the Addiction Cycle

  1. Top of page
  2. Neurocircuitry of the Binge/Intoxication Stage of the Addiction Cycle
  3. Neurocircuitry of the Withdrawal/Negative Affect Stage of the Addiction Cycle
  4. Neurocircuitry of the Preoccupation/Anticipation (Craving) Stage of the Addiction Cycle
  5. References

The neural substrates and neuropharmacological mechanisms for the negative motivational effects of drug withdrawal may involve disruption of the same neural systems implicated in the positive reinforcing effects of drugs. These decreases in the activity of reward neurotransmitter systems in the midbrain and forebrain implicated in the positive reinforcing effects of drugs represent what has been termed a “within-system” neuroadaptation. Examples of such changes at the neurochemical level include decreases in dopaminergic transmission in the nucleus accumbens during drug withdrawal measured by in vivo microdialysis, decreases in firing of ventral tegmental area dopamine neurons, and changes in signal transduction mechanisms associated with dopamine neurotransmission in the nucleus accumbens during drug withdrawal. The decreases in reward neurotransmitter function have been hypothesized to contribute significantly to the negative motivational state associated with acute drug abstinence and also the long-term biochemical changes that contribute to the clinical syndrome of protracted abstinence and vulnerability to relapse.

Different neurochemical systems involved in arousal and stress modulation also may be engaged within the neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and to restore normal function despite the presence of drug and have been termed “between-system” neuroadaptations. Glutamate, an excitatory neurotransmitter, has been implicated in neuroadaptation to repeated exposure to drugs of abuse. Glutamate hyperactivity in the basal forebrain has been linked to the hyperexcitability associated with ethanol withdrawal, and this hyperexcitability has been observed in slices of the hippocampus, nucleus accumbens, and amygdala. The hyperexcitability is linked to the protracted abstinence state in alcohol dependence and is hypothesized to be a neural substrate for the anti-relapse effects of acamprosate, a medication for the treatment of alcoholism.

Chronic administration of drugs with dependence potential also dysregulate both the hypothalamic-pituitary-adrenal axis and the brain stress system mediated by corticotropin-releasing factor (CRF). Common responses include an activated pituitary adrenal stress response, elevated adrenocorticotropic hormone and corticosteroids, and an activated brain stress response with activated amygdala CRF during acute withdrawal from all major drugs of abuse. Acute withdrawal from drugs of abuse also may increase the release of norepinephrine in the bed nucleus of the stria terminalis and decrease levels of neuropeptide Y in the central and medial nuclei of the amygdala.

These results suggest not only a change in function of neurotransmitters associated with the acute reinforcing effects of drugs (dopamine, opioid peptides, serotonin, and GABA) during the development of dependence, but also recruitment of the brain arousal and stress systems (glutamate, CRF, and norepinephrine) and dysregulation of the neuropeptide Y brain anti-stress system. Thus, reward mechanisms in dependence are compromised by disruption of neurochemical systems involved in processing natural rewards and by recruitment of the anti-reward systems that represent neuroadaptation to the chronic exposure of the brain reward neurocircuitry to drugs of abuse.

The neuroanatomical entity termed the extended amygdala thus may represent a common anatomical substrate for acute drug reward and a common neuroanatomical substrate for the negative effects on reward function produced by stress that help drive compulsive drug administration. The extended amygdala receives numerous afferents from limbic structures such as the basolateral amygdala and hippocampus and sends efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the extrapyramidal motor system. The decreases in neurotransmitter function are paralleled by molecular changes in signal transduction factors such as adenylate cyclase and gene transcription factors such as c-fos.

3 Neurocircuitry of the Preoccupation/Anticipation (Craving) Stage of the Addiction Cycle

  1. Top of page
  2. Neurocircuitry of the Binge/Intoxication Stage of the Addiction Cycle
  3. Neurocircuitry of the Withdrawal/Negative Affect Stage of the Addiction Cycle
  4. Neurocircuitry of the Preoccupation/Anticipation (Craving) Stage of the Addiction Cycle
  5. References

Parallel to dysregulation of reward systems are decreases in reward system function and increases in anti-reward system function (Koob, 2008). Shifts in striatal-pallidal-thalamic-cortical function have been hypothesized. Here, drug-seeking moves from corticostriatal loops operating from the ventral striatum to corticostriatal loops operating from the dorsal striatum (Everitt & Wolf, 2002).

Animal models of “craving” involve the use of drug-primed reinstatement, cue-induced reinstatement, or stress-induced reinstatement in animals that have acquired drug self-administration and then have been subjected to extinction of responding for the drug. Most evidence from animal studies suggests that drug-induced reinstatement is localized to a medial prefrontal cortex/nucleus accumbens/ventral pallidum circuit mediated by the neurotransmitter glutamate. For example, glutamate neuroplasticity has been implicated in cocaine-induced reinstatement in which increased glutamate release combined with reduced basal glutamate function in the prefrontal cortex-to-nucleus accumbens core pathway has been hypothesized to explain increased glutamate release in response to repeated cocaine administration. In both models, increased glutamatergic function contributes to increased drug-seeking in addiction. In contrast, neuropharmacological and neurobiological studies using animal models for cue-induced reinstatement involve the basolateral amygdala as a critical substrate with a possible feed-forward mechanism through the prefrontal cortex system involved in drug-induced reinstatement. Stress-induced reinstatement of drug-related responding in animal models appears to depend on activation of both CRF and norepinephrine in elements of the extended amygdala (central nucleus of the amygdala and bed nucleus of the stria terminalis). Again, molecular changes in these circuits that persist into protracted abstinence involve changes that range from cystine glutamate exchange function to gene transcription factors such as ΔFosB that remain increased long past acute abstinence.

In summary, three neurobiological circuits have been identified that have heuristic value for the study of the neurobiological changes associated with the development and persistence of drug dependence. The acute reinforcing effects of drugs of abuse that comprise the binge/intoxication stage of the addiction cycle most likely involve actions localized to a nucleus accumbens-amygdala reward system, dopamine inputs from the ventral tegmental area, and local opioid peptide and GABAergic circuits. In contrast, the symptoms of acute withdrawal important for addiction, such as dysphoria and increased anxiety associated with the withdrawal/negative affect stage, most likely involve decreases in function of the extended amygdala reward system and recruitment of brain stress neurocircuitry. The preoccupation/anticipation (or craving) stage involves key afferent projections to the nucleus accumbens and extended amygdala, specifically the prefrontal cortex (for drug-induced reinstatement) and the basolateral amygdala (for cue-induced reinstatement). Compulsive drug-seeking behavior is hypothesized to engage a transition from ventral striatal-ventral pallidal-thalamic-cortical loops to dorsal striatal-pallidal-thalamic-cortical loops. Molecular neuroadaptations begin with the binge/intoxication stage and transition through the addiction cycle with long-term changes in gene transcription that may convey vulnerability for relapse.

References

  1. Top of page
  2. Neurocircuitry of the Binge/Intoxication Stage of the Addiction Cycle
  3. Neurocircuitry of the Withdrawal/Negative Affect Stage of the Addiction Cycle
  4. Neurocircuitry of the Preoccupation/Anticipation (Craving) Stage of the Addiction Cycle
  5. References