Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Neurobiology of Addiction


GENERAL TERMS AND CONCEPTS

Following initiation of substance use, using is typically impulsive and a positively reinforcing experience. The chronic and repeated use of it leads to possible tolerance accompanied by diminishing returns on the substance’s positively reinforcing effects. In parallel, there is an increase in the negative reinforcing effects, such as using the substance to avoid withdrawal symptoms. Over time, substance use becomes less impulsive and rewarding and more compulsive and habitual. There is strong evidence of how the brain changes in substance use that explains long-term changes in behavior and motivation, the key points of which will be reviewed in this chapter.

Know This:

The following general terms and definitions are fundamental to know for the board examination.

  • ■

    Impulsivity: Tendency to perform actions without forethought or consideration of consequences. Impulsive actions are typically preceded by arousal, followed by gratification with the act’s performance, and then regret or guilt afterward. Impulsivity can be measured experimentally by tasks of delay-to-gratification (Go/No-Go Tasks and delayed discounting).

  • ■

    Compulsivity: Actions that persist despite not being pleasurable, not being related to an overall goal, often resulting in negative consequences. Compulsive actions are typically preceded by thoughts (obsessions) causing anxiety and stress. Following the performance of the compulsive act, one experiences relief. Compulsivity can be measured experimentally in animal models by pairing substance use with an adverse consequence or progressive-ratio reinforcement schedule.

  • ■

    Delayed discounting : It is the tendency to choose immediate, smaller rewards over larger, delayed rewards. Higher rates of discounting are associated with substance use disorders (SUDs) and many negative life outcomes.

    Positive reinforcement: A reward or punishment is paired with behavior in an additive fashion, making it more likely that the behavior will be repeated or extinguished. Example: Experiencing euphoria following heroin use, or withdrawal symptoms after substance use discontinuation.

  • ■

    Negative reinforcement: A stimulus is removed with a behavior, making it more likely that the behavior will be repeated or extinguished. Example: Removal of opioid withdrawal symptoms following resumption of heroin use or revoking social privileges following substance use.

    Operant conditioning: Behavior modification (e.g., decrease or increase in frequency) through positive and negative reinforcement by using punishing and rewarding consequences. Example: Contingency management (CM) treatment for SUDs.

  • ■

    Classical conditioning: A previously neutral (unconditioned) stimulus elicits a response after being paired with a biologically potent (conditioned) stimulus. Example: If someone always drinks alcohol while going to the bar, then that setting becomes the conditioned stimulus and can produce cravings.

THE ADDICTION CYCLE AND RELATION TO ANIMAL MODELS

The current body of human and animal research provides robust support for a conceptual model of addiction, first described by Dr. George Koob that involves three recurring stages: (1) binge/intoxication, (2) withdrawal/negative affect, and (3) preoccupation/anticipation. The addiction cycle is an organizing principle to understand the neurochemical and neurobiological changes that a person undergoes as their SUD intensifies, for example, as they move from impulsive to compulsive substance use. Definitions of these stages are as follows:

  • 1

    Binge/intoxication: The stage in which a person uses an intoxicant and experiences pleasure and reward (positively reinforcing effect). For example, a person experiences a pleasurable high from heroin or cocaine.

  • 2

    Withdrawal/negative affect: The stage in which a person experiences the negative emotional and physiological effects in the absence of the intoxicant and removes these negative effects on resumption of substance use (negatively reinforcing effect). For example, opioid or alcohol withdrawal.

  • 3

    Preoccupation/anticipation: The stage in which a person seeks out an intoxicant after a period of abstinence (stress-, cue-, or drug-induced reinstatement). For example, a relapse of alcohol after decades of abstinence following a stressful life event.

In the subsequent sections, we will describe each stage in more detail and the relevant animal models, neuroanatomy, neurocircuitry, and neurotransmitter systems that are frequently tested on in board examinations.

Stage I: Binge/Intoxication

In this stage, an individual consumes a substance that is acutely experienced as rewarding and positively reinforcing. This stage’s neurobiological processes involve the acute effects of substances, activation of reward circuitry, development of incentive salience circuits, and drug-seeking habits. Key points to remember regarding this stage:

  • ■

    The “reward pathway” refers to the mesolimbic dopamine pathway, which includes dopaminergic cell bodies in the ventral tegmental area (VTA; midbrain) that project to the nucleus accumbens (NAc) in the ventral striatum (part of the basal ganglia).

    The acute effects of drugs are generally mediated through one of several mechanisms: they can directly increase extracellular dopamine release in the reward pathway (e.g., amphetamines, cocaine), activate or inhibit channels (e.g., phencyclidine, ketamine, or ethanol), or mimic neurotransmitters by activating receptors (opioids, cannabis, nicotine). Table 3.1 summarizes substances of abuse and affected neurotransmitter systems.

    Table 3.1
    Common Drugs of Abuse and Primary Receptor Signaling Mechanism
    Drug Molecular Target and Action Receptor Signaling Mechanism
    Nicotine Nicotinic acetylcholine receptor agonist Ligand-gated channel
    Alcohol GABA-A receptor agonist, NMDA receptor antagonist Ligand-gated channel
    Cannabinoids CB1 and CB2 receptor agonist G i a
    Opioids Mu-, delta- and kappa-opioid receptor agonist G i
    Cocaine Inhibits dopamine transporter, increasing extrasynaptic DA G i and G s
    Amphetamine Stimulates dopamine release, increasing extrasynaptic DA G i and G s
    Phencyclidine NMDA glutamate receptor antagonist Ligand-gated channels
    Ketamine NMDA glutamate receptor antagonist Ligand-gated channels
    Hallucinogens 5-HT2A agonist Ga q

    a G i receptors couple D 2 -like receptors and G s receptors couple D 1 -like receptors, both of which are important for their reinforcing effects. 5-HT2A, 5-Hydroxytryptamine 2A; DA, dopamine; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate.

  • ■

    “Incentive salience” refers to the phenomenon of cue learning, in which associated stimuli become conditioned with a substance’s rewarding effect to the point in which the associated stimuli alone can induce motivation to drug-seek and dopamine release. Incentive salience is regulated by glutamatergic projections from the prefrontal cortex (PFC) to dopamine neurons in the VTA, leading to dopaminergic cell excitation and dopamine release. Incentive salience is the principle behind the Alcoholics Anonymous aphorism of “people, places, and things,” referring to the environmental cues that can lead to urges and drug-like effects.

  • ■

    The dorsal striatum (part of the basal ganglia) is key for habit strengthening and development of compulsive substance use.

Know This:

Stimulants are the main drugs of abuse that directly increase dopaminergic neurotransmission in the NAc; other drugs of abuse increase dopaminergic neurotransmission indirectly. Fig. 3.1 summarizes the acute effects of substances on the reward pathway. These are some key features to remember regarding the specific biological effects of substances on the reward pathway:

  • ■

    Opioids inhibit γ-aminobutyric acid (GABA)-ergic interneurons in the VTA, which disinhibit VTA dopaminergic neurons, thus increasing dopaminergic neurotransmission. They also act on opioid receptors directly in the NAc.

  • ■

    Nicotine activates VTA dopamine neurons through stimulation of nicotinic acetylcholine receptors, stimulates glutamatergic nerve terminals that innervate VTA dopamine neurons and may also activate endogenous opioid pathways.

  • ■

    Alcohol increases GABA-A function, and is also believed to inhibit GABA-ergic nerve terminals in the VTA, thus disinhibiting VTA dopamine neurons and increasing dopaminergic neurotransmission. Alcohol also activates endogenous opioid pathways.

  • ■

    PCP and ketamine act by inhibiting postsynaptic N-methyl-D-aspartate (NMDA) glutamate receptors in the NAc.

  • ■

    Cannabis activates CB1 receptors on NAc cell bodies, as well as on glutamatergic and GABA ergic nerve terminals in the NAc.

Fig. 3.1, Scheme of acute effects of substances on the nucleus accumbens and ventral tegmental area. (From Nestler, E. J. ( 2005 ). Is there a common molecular pathway for addiction? Nature Neuroscience , 8 (11), 1445–1449. https://doi.org/10.1038/nn1578 ).

Binge/Intoxication: Animal Models

A summary of all animal models and their relation to specific stages of addiction is presented in Table 3.2 . The most important animal models related to the binge/intoxication stage are intracranial self-stimulation (ICSS), self-administration, and conditioned place preference.

  • ■

    ICSS: The landmark Olds and Milner ( )study was an ICSS animal study showing that animals would perform a response (lever pressing) to self-administer a stimulus delivered via implanted brain electrodes to brain reward circuits. ICSS provides a way to study substances’ effects on brain reward thresholds. Drugs and alcohol generally decrease ICSS threshold; the addictiveness of substance is correlated with its ability to lower ICSS threshold.

  • ■

    Self-administration: These studies differ from ICSS in that experimental animals will perform a response to self-administer a substance. Self-administration provides a reliable measure of the animal’s motivation to use a substance by measuring the amount of work an animal is willing to exert for the reward.

  • ■

    Conditioned place preference: This model provides a measure of the reinforcing effect of a substance. Administration of a drug is paired with a specific environment, whereas placebo is paired with another. Substances that are positive reinforcers will cause animals to prefer a drug-paired environment, whereas substances that have aversive effects will cause animals to prefer the placebo-paired environment.

Know This:

In the ICSS paradigm, rewarding drugs lower ICSS threshold, whereas substance withdrawal increases ICSS threshold.

Table 3.2
Summary of the Most Important Animal Models Used to Study Addiction, Categorized by Relevant Stage of the Addiction Cycle
Stage of Addiction Animal Models Description
I. Binge/intoxication Self-administration The animal receives a drug dose by performing a discrete response, such as pushing a lever. The pattern of response required for a dose depends on the reinforcement schedule (e.g., fixed or variable-interval schedule).
Conditioned place preference A drug is paired with one specific environment, whereas placebo is paired with another. The choice of the animal to spend time in one environment or another is a measure of conditioned place preference.
Brain stimulation reward ICSS, e.g., the classic Olds and Milner ( ) study in which animals pressed a lever to self-administer a stimulus delivered via brain-implanted electrode.
II. Withdrawal/negative affect Conditioned place aversion Animals are exposed to the effects of drug withdrawal in one environment and are not in withdrawal in another. The choice of the animal to spend time in one environment or another is a measure of conditioned place aversion.
Brain stimulation reward ICSS as described above; animals in withdrawal show increased ICSS thresholds (e.g., decreased ICSS reward).
Elevated maze test (anxiety) A maze is placed approximately 2 feet above ground and an animal is placed at the intersection of a cross, where two arms are dark and walled off, and the other two are open and well lit. An anxious animal will generally spend more time in the “safer” region (the dark, walled off arms), and an animal’s behavior in this paradigm is very sensitive to drug withdrawal.
Defensive burying (anxiety) An animal is placed in a box filled with woodchip bedding and an electrified probe protruding into the box. After touching the probe and receiving a mild shock, the active response is generally to bury the probe with the woodchips; observers will then measure the time to burying (latency), the height of the woodchip mound, total time spent burying, and number of burying acts.
III. Preoccupation/anticipation Drug-induced reinstatement Exposure to a reinforcing drug can reinstate drug use after the behavior has been extinguished.
Cue-induced reinstatement Cues previously paired to drug use act as a conditioned stimuli and lead to reinstatement of drug self-administration after the behavior has been extinguished.
Stress-induced reinstatement Reinstatement of drug self-administration provoked by stress; first shown with intermittent foot shock stressor in rats leading to reinstatement of substance use.
ICCC, Intracranial self-stimulation.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts