These experiments demonstrate that powerful instinctive survival behaviors can be overcome by activating the brain’s reward pathway through the release of dopamine. Since rats do not have well-developed dorsolateral prefrontal cortices, the results of these tests also refute the idea that addiction is a behavioral problem originating in this area of the brain.
Other than the cortex and size, the rat brain is nearly identical to the human brain. Both use the same neurotransmitters and receptors, the same proteins for synaptic vesicle release and recycling, and similar signaling mechanisms. The reward circuitry is virtually identical as well, and both use dopamine as the principle neurotransmitter responsible for the sensation of pleasure.
The midbrain area is the brain’s survival and pleasure center and is sometimes referred to as “the lizard brain” because it generates such primitive behaviors as eating, drinking, and the fight-or-flight reaction. These behaviors are necessary for survival and are linked to the sensation of pleasure and the release of dopamine.
In the addicted patient, drug use becomes the most important behavior, which partially explains why addicted persons continue to take drugs despite such consequences as jail or divorce.
To understand drug cravings, think about situations in which survival is threatened, like dying of thirst or starvation. In these situations, the brain is preoccupied with getting food or water, and the mood becomes dysphoric, marked by depression, anxiety, hopelessness, and fear. These symptoms are relieved instantly as soon as food or water is obtained.
The role of dopamine in addiction
Produced in the substantia nigra and VTA, dopamine is a catecholamine neurotransmitter and the biosynthetic precursor to norepinephrine and epinephrine. Additional functions of dopamine include motivational stimuli, sexual arousal, thought, and the learning of new behaviors.
Dopamine also inhibits release of the hormone prolactin, which is involved in the sensation of sexual gratification. Dopamine administered in IV or oral form cannot cross the blood-brain barrier and has no direct effect on the central nervous system.
Opioids travel to the brain through the bloodstream and bind to opioid receptors in the cortex, VTA, thalamus, nucleus accumbens, brainstem, and spinal cord. Opioids bind to areas involved in the pain pathway (including the thalamus, brainstem, and spinal cord), which leads to analgesia. When opioids bind to opioid receptors in the reward pathway, dopamine is released, and the reward pathway is activated. Supernormal concentrations of dopamine are released with drugs of abuse.
To illustrate, consider the effect of cocaine on the release of dopamine from brain cells. Cocaine acts by blocking the removal of dopamine from the synapse, which results in an accumulation of dopamine and an amplified signal to the receiving neurons. This is what causes the initial euphoria commonly reported by cocaine users. However, although cocaine will increase the dopamine level of anyone who ingests the drug, the majority of users do not become addicted. The reason for this is only partially understood.
According to the National Institute on Drug Abuse (NIDA), the increase in dopamine release in the brains of addicted patients is often variable and is actually lower than in those who are not addicted. This comparatively smaller increase in dopamine levels in the addicted patient leads to drug-seeking and drug-craving behavior and helps to explain why people who become addicted can often remember their first experience of substance-induced euphoria in great detail.
Data show that people with novelty-seeking personality traits (thrill-seekers) have decreased numbers of dopamine autoreceptors.15 Dopamine autoreceptors reside on the presynaptic neuron and regulate the release of dopamine. The density of dopamine autoreceptors is inversely proportional to an individual’s desire for novel experiences and thrill-seeking behaviors.
The fewer available dopamine autoreceptors an individual has, the less his or her brain is able to regulate how much dopamine is released. Because of this, novelty and other potentially rewarding experiences will produce greater dopamine release in individuals with decreased dopamine autoreceptors. Hence, thrill-seekers are chemically wired to take chances. Not surprisingly, patients with addictive disorders are likely to have fewer dopamine autoreceptors.
The disease of addiction
Addiction is a primary disease and not merely a symptom of some other underlying disorder. Although addiction is treatable, it is also permanent. Addiction is progressive, can be fatal, and typically causes tremendous suffering in the addicted person as well as among his or her family and friends.
Clinicians should be aware of the abnormal yet predictable patterns of behavior that are displayed among individuals with substance use disorders. Cognitive distortion and poor judgment related to continued use of the substance and denial of negative consequences of addiction should be expected in such patients.
Substance use disorders
According to criteria from The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), substance use disorders represent a maladaptive pattern of substance use leading to clinically significant impairment or distress. This impairment or distress is manifested by the presence of at least two of the following symptoms during a 12-month period:16
- The substance is often taken in larger amounts or over a longer period than was intended
- There is a persistent desire or unsuccessful efforts to reduce or control substance use
- A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from the substance’s effects
- Craving, or a strong desire or urge to use the substance
- Recurrent substance use resulting in a failure to fulfill major obligations at work, school, or home
- Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance
- Important social, occupational, or recreational activities are given up or reduced because of substance use
- Recurrent substance use in situations in which it is physically hazardous
- Substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
- Tolerance, as defined by either a need for markedly increased amounts of the substance to achieve intoxication or desired effect or a markedly diminished effect with continued use of the same amount of substance
- Withdrawal, as manifested by either the characteristic withdrawal syndrome for the substance or when the substance (or a closely related substance) is taken to relieve or avoid withdrawal symptoms
The severity of substance use disorders is classified as mild (presence of two to three of the symptoms described in this list), moderate (presence of four to five symptoms), or severe (presence of six or more symptoms).
Opioid and alcohol withdrawal
Clinicians must be aware of the most common signs and symptoms related to opioid and alcohol withdrawal. The signs and symptoms of opioid withdrawal typically include three or more of the following:
- Dysphoric mood
- Nausea or vomiting
- Muscle aches
- Lacrimation or rhinorrhea
- Pupillary dilation, piloerection, or sweating
- Crampy abdominal pains
Alcohol withdrawal includes two or more of the following signs and symptoms:
- Autonomic hyperactivity (e.g., sweating or pulse >100 beats per minute)
- Increased hand tremor
- Nausea or vomiting
- Transient visual, tactile, or auditory hallucinations or illusions
- Psychomotor agitation
- Generalized tonic-clonic seizures
Cognitive distortion refers to the impaired executive functioning that occurs in every addict. The dorsolateral prefrontal cortex primarily directs executive function. Examples of executive function include planning complex activities, moderating social behavior, differentiating conflicting thoughts, and evaluating risk versus reward.
Impaired executive function in the addicted patient is manifested as denial of negative consequences, poor judgment, and ineffective impulse control related to use of the substance. The addict becomes unable to adequately process information that is related to the addictive behavior or substance.
Negative consequences and harmful behaviors are minimized. It is common to hear an addict rationalize that “things are not that bad yet.” An addicted individual may explain a suspended driver’s license as bad luck or the loss of a job as the result of a difference of opinion.
NIDA classifies cognitive distortion as impaired response inhibition and salience attribution (iRISA) and describes an integrated model of drug addiction that encompasses intoxication, craving, binge use, and withdrawal (Figure 2).17 The relationship between inhibitory control and reward processing becomes dysfunctional in a drug-addicted individual.
Figure 2. Impaired response inhibition and salience attribution (iRISA) syndrome of drug abuse
Addiction features ineffective willed-control over automatic processes combined with attribution of high relative reward value to the experience of pleasure. Inhibitory control would be especially disturbed under conditions of high drug salience. For example, a cocaine addict would likely be unable to avoid using cocaine if he or she were in a crack house; the motivation to procure drugs would overpower every other goal.
Primary-care clinicians need to be knowledgeable about the various evidence-based screening tools and practices that are available to determine the presence of a substance use disorder. If a substance use disorder is suspected, screening allows for early detection and intervention.
An extremely valuable practice model for the primary-care setting is Screening, Brief Intervention, and Referral to Treatment (SBIRT).18 SBIRT is a model of practice that allows for the identification, reduction, and prevention of the harmful use, abuse, and dependence related to alcohol and illicit drugs and can be used in any community setting. As is evident by its name, the model is made up of three major components:
- Screening. The clinician assesses the individual for risky substance use behaviors using standardized screening tools.
- Brief intervention. The clinician describes risky substance use behaviors in a brief conversation, providing feedback and advice.
- Referral to treatment. The clinician provides patients who screen positively with a referral to therapy or additional treatment.
A second useful screening tool is the World Health Organization (WHO) Alcohol Use Disorders Identification Test (AUDIT), which is a questionnaire comprised of 10 items that screens for the presence of harmful alcohol consumption.19 The questionnaire has the ability to correctly classify 95% of patients as alcoholic or nonalcoholic.
The AUDIT is easy to administer in the primary-care setting and may be utilized in a wide variety of patient populations and cultural groups. A copy of the questionnaire is available on the WHO website.
The CAGE questionnaire is a quick and easy screening tool that primary-care clinicians can use when they suspect a potential substance use disorder.20 CAGE consists of four questions designed to help the clinician determine whether a further assessment for alcohol abuse is warranted.
Have you ever felt you should Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (Eye-opener)?
Responses are scored 0 or 1, and a higher score should be seen as an indication of alcohol problems. A total score of 2 or greater is considered clinically significant.
A variation on the CAGE questionnaire, the CAGE AID (Adapted to Include Drug use) screening tool consists of the same four questions but with slight modifications to include illegal-drug use and the use of prescription drugs other than as prescribed. The advantage of the CAGE AID is that it allows clinicians to screen for potential alcohol and drug abuse simultaneously.
The Drug Abuse Screen Test (DAST) is a self-reporting questionnaire for patients that consists of 28 yes-or-no questions.21 A condensed 10-question version (DAST-10) is also available and may be more appropriate for the primary-care setting. Patients can complete the DAST-10 in less than eight minutes.
A list of additional screening tools can be found on the SAMHSA website. The list includes a description of each tool and printable copies that can be used immediately in the clinical setting.
Recovery from substance use disorders involves brain “healing” and recalibration of the hedonic set point so that such natural pleasures as food, music, or art are once again perceived as enjoyable. People successful in recovery are able to develop effective impulse control to enable the realization of long-term abstinence and stability.
A study involving PET-scan imaging showed that the brain can recover after total abstinence, even in methamphetamine abusers.22 In this study, the concentration of dopamine transporters actually increased after 24 months of abstinence.
The next installment of this two-part series will focus on the potential for abuse among the various classes of controlled substances and will include evidence-based recommendations regarding the prescription of opioids for the treatment of pain.
Mary Atkinson Smith, DNP, FNP-BC, is a nurse practitioner at Starkville Orthopedic Clinic in Starkville, Miss., and an adjunct faculty at Capstone College of Nursing, University of Alabama, in Tuscaloosa.
Scott Hambleton, MD, FASAM, is the medical director of the Mississippi Professionals Health Program in Ridgeland.
- CASAColumbia. Addiction medicine: Closing the gap between science and practice. Available at www.casacolumbia.org/addiction-research/reports/addiction-medicine.
- Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Rockville, Md.: Substance Abuse and Mental Health Services Administration, 2011.
- National Drug Intelligence Center. The Economic Impact of Illicit Drug Use on American Society. Available at www.justice.gov/archive/ndic/pubs44/44731/44731p.pdf.
- Substance Abuse and Mental Health Services Administration. Drug abuse warning network, 2010: National estimates of drug-related emergency department visits. Available at www.samhsa.gov/data/2k13/DAWN2k10ED/DAWN2k10ED.htm.
- Centers for Disease Control and Prevention. CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep. 2012;61:10-13. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm.
- U.S. Census Bureau. Historical national population estimates: July 1, 1900 to July 1, 1999. Available at www.census.gov/population/estimates/nation/popclockest.txt.
- Kochanek KD, Xu J, Murphy SL, et al . Deaths: preliminary data for 2009. Natl Vital Stat Rep. 2011;59:1-51.
- Glover S, Girion L. Legal drugs, deadly outcomes. Los Angeles Times. November 11, 2012. Available at www.latimes.com/news/science/prescription/la-me-prescription-deaths-20121111-html.
- Nestler EJ, Malenka RC. The addicted brain. Sci Am. 2004;290:78-85.
- Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol. 1954;47:419-427.
- Headlee CP, Coppock HW, Nichols JR. Apparatus and technique involved in a laboratory method of detecting the addictiveness of drugs. J Am Pharm Assoc Am Pharm Assoc (Baltim.). 1955;44:229-231.
- Thompson T, Schuster CR. Morphine self-administration, food-reinforced, and avoidance behaviors in rhesus monkeys. Psychopharmacologia. 1964;5:87-94.
- Bozarth MA, Wise RA. Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat. JAMA. 1985;254:81-83.
- R&D Magazine. Tiny “wearable” PET scanner ready for use. Available at www.rdmag.com/news/2011/03/tiny-wearable-pet-scanner-ready-use.
- Zald DH, Cowan RL, Riccardi P, et al. Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans. J Neurosci. 2008;28:14372-14378. Available at www.jneurosci.org/content/28/53/14372.long.
- Hasin DS, O’Brien CP, Auriacombe M, et al. DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry. 2013;170:834-851.
- Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159:1642-1652; available at ajp.psychiatryonline.org/article.aspx?articleid=175797.
- SAMHSA-HRSA Center for Integrated Health Solutions. SBIRT: Screening, Brief Intervention, and Referral to Treatment. Available at www.integration.samhsa.gov/clinical-practice/sbirt.
- Saunders JB, Aasland OG, Babor TF, et al. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption. Addiction. 1993;88:791-804.
- Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974;131:1121-1123.
- Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.
- Volkow ND, Chang L, Wang GJ, et al. Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci. 2001;21:9414-9418. Available at www.jneurosci.org/content/21/23/9414.long.
All electronic documents accessed March 7, 2014.