Drug Addiction


Addiction is a loss of control over drug-taking behavior that occurs in vulnerable individuals after repeated exposure to a drug. The DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-5) uses the term substance use disorder, which encompasses a spectrum of disorders from mild misuse of drugs to full blown addiction. Severe substance use disorder is characterized by dependence on the drug, in which the individual experiences overwhelming craving for the drug, and a need to keep taking the drug to avoid withdrawal. Withdrawal is a syndrome of unpleasant symptoms that occur when drug taking stops. Withdrawal symptoms can be both psychological (anxiety, irritability, depression) and physical (tremors, sweating, headaches, nausea). For some drugs, withdrawal symptoms are quite severe (delirium and seizures).

Addictive drugs generally work to affect synaptic transmission in the brain. Some addictive drugs act as agonists for neurotransmitter receptors; for instance heroin is an opioid agonist and nicotine is a cholinergic agonist. Other drugs may increase the amount of neurotransmitter in the synaptic cleft. Cocaine blocks the dopamine transporter responsible for dopamine reuptake, while amphetamine increase norepinephrine release through a variety of mechanisms.

Addictive Drugs Affect the Reward Circuitry

mesocorticolimbic dopamine pathwayAlthough different drugs of abuse affect diverse neurotransmitter systems, what they all have in common is their ability to affect the brain circuitry underlying reward and motivation. The core of this circuitry is the mesocorticolimbic dopamine pathway. This consists of neurons whose cell bodies are located in a midbrain nucleus known as the ventral tegmental area (VTA). The neurons of the VTA project to the nucleus accumbens in the basal ganglia, and the prefrontal cortex, where they release the neurotransmitter dopamine. (In the name of the pathway, “meso-“ refers to midbrain, “-cortico-“ to the connection in the prefrontal cortex, and “-limbic” to the nucleus accumbens, which is part of the limbic system. The limbic system refers to the interconnected set of brain structures involved in emotional processing.)

Under normal circumstances, the mesocorticolimbic pathway is activated by stimuli that are pleasurable and reinforcing. The reward circuitry was originally identified in experiments in the 1950s and 1960s. Rats with electrodes implanted in certain regions of the brain could press a bar to deliver current to activate neurons in that region. This experimental paradigm is known as intracranial self-stimulation (ICSS). When electrodes were located in the ventral tegmental area, the nucleus accumbens, or in places along the axon tracts of the mesocorticolimbic pathway, rats would greatly increase the rate at which they pressed the bar. The experimenters hypothesized that when the rats increased ICSS, it was because electrodes activated regions associated with reward and reinforcement. Similar experiments have shown that rats will also press a bar to deliver a drug to various regions of the brain.

Another technique used to investigate the role of the mesocorticolimbic pathway is microdialysis. Microdialysis makes it possible to sample the extracellular fluid in a specific region of the brain. This technique shows that ICSS as well as naturally rewarding stimuli increase dopamine levels in the nucleus accumbens. Similarly, microdialysis has been used to show that certain drugs of abuse increase dopamine release at synapses in the nucleus accumbens and the prefrontal cortex.

Activation of the reward circuitry is a phenomenon that occurs initially when a drug is taken, and is presumably related to the feelings of intoxication and euphoria that drug users experience. With time chronic drug use causes long-lasting changes that affect behavior. One long-lasting change is tolerance, an adaptation that causes the user to need more of a drug to achieve the same effect. Another long-lasting change is the tendency for relapse. Even after a long period of abstinence, a former addict is at great risk to relapse into drug-taking behavior when prompted by certain environmental cues.

Scientists have developed animal models of addiction to explore how drugs of abuse alter neural function in the reward circuitry and other parts of the brain. The hope is to identify the long-lasting neural changes underlying the dysfunctional behaviors that occur with addition, with a goal toward developing new and better treatments.

Despite the fact that drugs of abuse can activate the mesocorticolimbic dopamine pathway, interfering with dopamine neurotransmission does not work as a treatment for addiction in humans. Instead, treatments are focused on the specific pharmacology of the substance that is being abuse. Below, we focus on the treatment for opioid addiction.

Opioid Addiction and Treatment

Opioids are drugs related to morphine that act at opioid receptors located in the brain and spinal cord. These drugs are used clinically as analgesics. The rate of opioid addiction has risen greatly since the 1990s when prescription opioids to treat chronic pain became more readily available. A recent U.S. survey found that 4.6 percent of individuals over the age of 12 reported misuse of an opioid drug in the previous year.

A particular danger of opioid drugs is the risk of overdose. Death occurs because opioids cause respiratory depression (insufficient breathing); this effect is exacerbated when individuals combine opioid drugs with other sedating drugs such as alcohol or benzodiazepines. Naloxone is an opioid antagonist that is used for emergency treatment of opioid overdose. Naloxone is now available in an easy-to-use injection device to help prevent overdose deaths.

Agonist Therapy

The most successful method of treatment for opioid addiction involves the use of opioid agonists methadone or buprenorphine (agonist therapy). These drugs are agonists so they bind and stimulate opioid receptors.  However, because of different dosing and pharmacokinetics, when taken properly they are not intoxicating. Importantly, because they are opioid agonists, they prevent the debilitating symptoms of withdrawal. Agonist therapy involves an initial stage of carefully managed withdrawal from the drug of abuse, followed by maintenance therapy where the agonist drug is taken long term. Maintenance therapy is more likely than abstinence to prevent relapse into substance abuse.

Methadone is a full opioid agonist that is given in a once-daily oral dose. Because the drug is given orally, it is absorbed slowly and so does not produce the intoxicating effects of injected opioids. When used for agonist therapy, methadone is only dispensed in specialized treatment clinics where dosing and administration is carefully monitored.
(Methadone may also be dispensed by prescription when used in the treatment of severe pain, although use of methadone to treat pain requires caution due to a higher risk for overdose.)

Buprenorphine is a partial opioid agonist (recall that a partial agonist is one that binds to a receptor but does not give the full biological activity). Buprenorphine has been available to treat opioid addiction since 2002, and its use has increased substantially in recent years. The advantage over methadone is that it can be prescribed by a physician, and so does not require the patient to make daily visits to a treatment clinic.

Other Drugs

Naltrexone is an opioid antagonist that is approved for addiction treatment in abstinence-based treatment programs. Because it is an antagonist, it prevents agonist binding and so is designed to prevent the intoxicating effects of abused opioids. The problem with abstinence in treatment of opioid addiction is that patients have trouble staying in treatment and are prone to relapse into substance abuse.

Quick Quiz

Fill in Answer Correct False Correct Answer
1. Name the specific region of the basal ganglia that is one target of the mesocorticolimbic pathway.
2. Name the technique used to show there is increased dopamine release by neurons of the mesocorticolimbic pathway in response to drugs of abuse.
3. Which of the following drugs is used for the emergency treatment of opioid overdose? [methadone, buprenorphine, naltrexone, naloxone]
4. Name the partial opioid agonist used to treat opioid addiction.  This drug is available by prescription.
5. Name the opioid antagonist used in abstinence-based treatment for opioid addiction.

(Spelling must be correct)