January 25, 2025	PSY 340 Brain and Behavior Class 09: Substance Abuse and Addiction

• Jimi Hendrix (1942-1970). Musician. Alcohol & barbiturate overdose. Inhalation of vomit.
  
• Heath Ledger (1979-2008). Actor. Accidental. "died of the combined effects of five (5) prescription & one (1) over-the-counter medications: oxycodone, hydrocodone, diazepam, temazepam, alprazolam, and doxylamine (Unisom®)
• Michael Jackson (1958-2009). Singer. Homicide. MD administration of propofol, lorazepam, diazepam, & midazolam.
• Whitney Houston (1963-2012). Singer, actress. Accidental drowning. Cocaine + Benadryl, Flexeril, Xanax.
• Philip Seymour Hoffman (1967-2014). Actor. Heroin overdose.
• Prince Rogers Nelson (1958-2016) Accidental overdose of fentanyl
• Lil Peep (Gustav Ahr; 1996-2017). Rapper and singer. Multiple Xanax (alprozalam) pills. Blood showed traces of cannabis, cocaine, tramadol, hydrocodone, hydromorphone, oxycodone, & oxymorphon.
• Tom Petty (1950-2017) Singer, songwriter, musician. Accidental overdose of opioids including fentanyl & oxycocode, two sedatives, and an antidepressant.
• Mac Miller (1992-2018). Rapper, songwriter. Accidental overdose of fentanyl, cocaine & alcohol
• DMX (1970-2021). Rapper. Drug-induced (cocaine) heart attack.
  
• Taylor Hawkins (1972-2022). Drummer for Foo Fighters. Apparent heart disease/attack. Multiple drugs found in his system at the time of death included opioids, benzodiazepines, tricyclic antidepressants, and THC (active ingredient in marijuana, see below).
  

Surging Rates of Opioid Deaths in the US

   I. Drug Mechanisms

• Animals generally all use the same set of neurotransmitters. The plants they eat use many of these same chemicals.
   
  
• Drugs with behavioral effects share or oppose the actions of neurotransmitters.

Types of Drug Effects

• Antagonist: a drug that blocks the effect of a neurotransmitter
• Agonist: a drug that increases or mimics the effects of a neurotransmitter
• Some drugs are mixed agonist-antagonists, that is, they prompt some behaviors of the neurotransmitter they mimic while blocking other behaviors.
  

Other Qualities of Drugs

• Affinity: tendency of a drug to bind to a receptor (strong to weak)
• Efficacy: tendency of a drug to activate a receptor (high to low)
• Note that some drugs may bind to a receptor but do nothing else. This drug can be described as having a high affinity, but low efficacy.

• Synaptic activity is affected in a lot of different ways. These include
• increasing release of neurotransmitters
• blocking re-uptake
• blocking the effects of enzymes that breakdown the neurotransmitters
• affecting the post-synaptic receptors (stimulating or blocking them), etc.
  

James Olds & Peter Milner (1954) found areas in rat's brain which leads to continual self-stimulation. Pressing the lever in the experimental situation (see diagram on left) appears to have been very reinforcing for the rats. All of these areas associated with reinforcement eventually were seen to increase the release of dopamine in the nucleus accumbens (see diagram). 

Most drugs of abuse are likely to increase the release of dopamine and norepinephrine with effects on the n. accumbens. Some have labeled this area "the pleasure area" and dopamine as "the pleasure chemical." But, this label is very misleading.

B. Dopamine & Prediction Error Theory

Research in the last several decades points to dopamine as involved in more than the reinforcement Olds & Milner found in 1954. As the National Institute of Drug Abuse (NIDA, 2020) reported "The neurotransmitter dopamine helps people remember the pleasurable effects of drugs and reinforces the desire to seek them out again, making it centrally involved in addiction.

In a similar fashion, dopamine neurons are theorized to function according to “prediction errors,” responding when the value of a reward is more or less than expected...[R]esearch suggests that dopamine neurons are carrying much more information than previously thought…”  According to this theory, whenever we experience more of something than we expected, more dopamine is released (e.g., we expected a boring party, but actually it was a lot of fun. Or, we didn't quite know what to expect when we consumed a drug and it made us feel very happy.)


C. Incentive Salience/Sensitivity Theory & Cravings
 
Research by Kent Berridge and his colleagues in the last twenty years (e.g., Berridge & Robinson, 2016) argues that there are actually two aspects of reinforcement that are different:

• Liking = experiencing pleasure
  
  
• Wanting, Desiring = motivation, grabbing your attention, "salience"

Though these seem similar, they are not. As Berridge & Robinson (2016) note:

Rewards are both “liked” and “wanted,” and those 2 words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of “wanting” a particular reward is dissociable from circuitry that mediates the degree to which it is “liked.” Incentive salience or “wanting,” a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, “liking,” or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. [Abstract]

In this theory, dopamine is NOT associated directly with liking or pleasure, but it IS centrally involved in making an individual desire or want something intensely. "Liking" comes from a variety of "hot spots" in the brain (NOT the nucleus accumbens) which do respond to the molecules of a substance which is addictive (see diagram to right).

Recent studies suggest that dopamine and the nucleus accumbens actually play an important role in attention-getting or arousal. Addiction seems to have a quality of demanding attention (increasing your craving or wanting something = salience) and this may be the link (rather than via the "pleasure" effects of chemicals)

Note that individuals with addiction show an overwhelming urge to get the drug even after the pleasure has stopped.

D. Tolerance and Withdrawal.

Over time as addiction develops, the enjoyable effects of the drug tends to decrease. This is called tolerance. The addicted individual must use more of the drug to achieve the same level of reward. A great deal of the phenomenon of tolerance involves learning, i.e., conditioned and strengthening associations between the setting and mechanisms of drug ingestion and the body's response to the drug. Indeed, repeated exposure to typical drug use settings without actual drug use will weaken the association.

However, whenever an addict is exposed to settings in which he/she has typically used the drug, there can be a very strong reaction even if no drug is ingested. This reaction is called withdrawal. Symptoms of withdrawal include anxiety, sweating, vomiting, and diarrhea for opioids and tiredness, shaking, sweating, nausea, convulsions, and hallucinations for chronic alcohol abuse.  

Is all drug use in chronic drug users an attempt to avoid withdrawal symptoms?

• For some addicts, there are very strong cravings even after many years of abstinence (no use).
  
• However, it appears that cravings are highest in those who use a drug while they are experiencing strong withdrawal symptoms, i.e., the relief they feel conditions them to turn to the drug more frequently in the future.
  

Some Drugs of Abuse (not in book) 

   1. Stimulant drugs (e.g., amphetamines, cocaine, etc.)

• produce excitement, alertness, elevated mood, decreased fatigue, and sometimes motor activity. Each of these drugs increases activity at dopamine receptors, especially at D2, D3, and D4 receptors. Stimulant drugs are often highly addictive.

a. Amphetamine increases dopamine (DA) release from presynaptic terminals and also reverses the direction of the dopamine transporter (reuptake gate) which makes more DA available.

b. Cocaine ("coke") blocks the reuptake of DA, NE, and serotonin at the synapse. The behavioral effects of cocaine are believed to be mediated primarily by dopamine and secondarily by serotonin.

c. The effects of amphetamine and cocaine are both short-lived, because of the depletion of dopamine stores and tolerance.

d. Methylphenidate (Ritalin®): Stimulant currently prescribed for Attention Deficit Disorder (ADD); works like cocaine by blocking reuptake of dopamine at presynaptic terminals. The effects of methylphenidate are much longer lasting and less intense as compared to cocaine.

--> the use of Ritalin® when used as prescribed does not lead to the use of other drugs in later life.

e. MDMA (methylenedioxymethamphetamine or "Ecstasy") at low doses is a stimulant which increases the levels of dopamine. At higher doses it releases serotonin and may have hallucinogenic effects.

   2. Nicotine

Nicotinic receptor stimulation leads to increased responsiveness and activity levels in novel settings

• morphine
  
• "Morphine was first isolated between 1803 and 1805 by Friedrich Sertürner," a German pharmacist. It is derived from opium, a dried latex (a sticky fluid) produced by the poppy plant.
  
• "Merck began marketing it commercially in 1827. Morphine was more widely used after the invention of the hypodermic syringe in 1853–1855." Before 1906 medications containing morphine and other opioids were available for purchase at drug stores without prescription.
  
• "Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep." [Wikipedia]
  

• heroin
  • Synthesized 1874 by English chemist, C. R. Wright
  • Commercial use recognized by Bayer's physiologist, Heinrich Dresser, in 1898. Sold in US & Europe as a treatment for cough and other conditions. Eventually, the use of Heroin was outlawed in the US and elsewhere.
    

• methadone, a synthetic ("man made") drug rather than derived from the poppy plant

• Oxycodone [OxyContin®] & hydrocodone [Zohydro ER, Vicodin, Norco] These are semi-synthetic opioids (see above). Note that Vicodin is a mixture of acetaminophen [Tylenol] & hydrocodone.

• Fentanyl "is a short-acting synthetic opioid that is often used to treat chronic pain [e.g., with patients in end-stage cancer]. It is 25 to 40 times more potent than heroin and 50 to 100 times more potent than morphine by weight." (NDEWS Special Report Fentanyl 20151207). "Other fentanyl analogues include sufentanil, which is approximately eight times more potent than fentanyl, and carfentanil, which is about 100 times more potent than fentanyl and 10,000 times more potent than morphine." (HuffPost, 20170109)
• However, the overdose deaths due to fentanyl are often the result of illegally-manufactured versions of the drug which are added to other addictive drugs. The user is unaware that they are consuming a lethal dose of fentanyl.
  

Opioid Receptors (= inhibitory G protein-coupled receptors)

• Opioid family of receptors. There are multiple places within the brain, spinal cord, and peripheral nervous system (as well as the digestive track) that are populated by opioid receptors. However, different types of opioid receptors are activated by different types of opioid molecules. There are four general classes of opioid receptors including the μ (mu) receptors which have a high affinity for morphine-like molecules [the other types are δ (delta), κ (kappa), and NOP (noiceptin/orphanin) receptors/]. Each of these types of receptors have a number of subtypes.

• Opioid receptors can be found on both the presynaptic terminal button and the postsynaptic membrane (see figure). Thus they are able to affect both the release of neurotransmitters from the presynaptic neuron and the effects of neurotransmitters on the postsynaptic neuron (Reeves et al., 2022).
  

• Opioid receptors within the central nervous system cause hyperpolarization in GABA neurons. Many of these GABA neurons normally restrain or inhibit the release of dopamine neurons.  As a result, opiate receptors overall have the net effect of increasing the release of dopamine in the brain (Reeves et al., 2022).
  

• Opiates decrease (inhibit) other opiate receptors & cause a range of effects such as analgesia (pain relief), decreased respiration, lowered motility of the GI system (anti-diarrhea), and physical dependence

4. Marijuana

• Contains the chemical delta-tetrahydrocannabionol (delta-THC) and other cannabinoids (chemicals related to delta-THC); Δ-THC works by attaching to cannabinoid receptors (particularly in hippocampus, basal ganglia, & cerebellum). These receptors are found only on the presynaptic membrane and form negative feedback loops with postsynaptic GABA or glutamate membranes. The cannabinoids tend to slow down or inhibit the release of both neurotransmitters.

• Lipid soluble (dissolves/stored in fatty tissue)
• which slows down withdrawal effects)
• can test positive for MJ for 4-6 weeks afterwards

• Relieves pain or nausea, combats glaucoma, increases appetite

• Psychological effect is to intensify sensory experience and to alter the sense of time (time slows down)

• Heavy use impairs memory significantly. Even short-term marijuana use interferes with memory in the time frame around the use of the MJ, i.e., don't use MJ when you're studying for a test.
  

• Adolescents with genetic vulnerability to develop schizophrenia are at greater risk when using marijuana in heavy doses

• Moderate use does seem to lead to some level of tolerance.

5. Alcohol and Alcoholism

A. Alcoholism or alcohol dependence: A common type of substance abuse that produces significant harm to people's lives, and those people often find themselves continuing to drink in excess even after deciding to quit or reduce their drinking.

B. Alcohol (ethanol, ETOH): Inhibits Na⁺ ion flow across the neuron membrane; decreases serotonin activity, facilitates transmission at the GABAA receptor, blocks glutamate receptors, and increases dopamine activity. Thus, alcohol is mostly an INHIBITORY substance.

C. There have been multiple attempts to classify subtypes of alcoholism. One important effort was undertaken by the researcher Robert Cloninger on the basis of adoption studies among Scandinavian alcoholics. The two subtypes in his classification scheme (Oreland et al, 2017) are:

• Type I Alcoholism: This type of alcoholism is less dependent on genetic factors and has a late onset, that is, it develops gradually over years (> 25 years old). It tends to affect men and women equally, and is generally less severe. It is often the result of years of leading a stressful life and using alcohol to cope with the stress.

• Type II Alcoholism: This type of alcoholism has a strong genetic basis and a rapid and early onset (< 25 years old), affects men primarily, is more severe, is associated with the use or abuse of other substances, and reflects others social problems, e.g., a family history of alcoholism, depression, and antisocial or criminal behavior (fighting & arrests)

D. Predispositions for Alcoholism & Substance Abuse

i. Alcoholism: Tends to be more likely among those who, as children, were described as impulsive, risk-taking, easily bored, sensation-seeking, & outgoing.

Associated with genes causing

• "long form" dopamine type 4 receptors: these receptors tend to be less sensitive to ETOH and, thus, people tend to consume more, and
  
• more active form of COMT (enzyme breading down DA) leading to lower levels of reinforcement & higher levels of impulsiveness.

ii. Among sons of alcoholics, alcoholism is associated with

• less than average intoxication after drinking a moderate amount of alcohol.
• experiencing more than average relief from tension after drinking alcohol.
• having a smaller than normal amygdala in the right hemisphere

iii. Genetic influences on drug abuse

• Strong evidence for polygenetic influences on alcoholism, cocaine use, and some other drugs. NO individual genes, but many genes contribute toward this vulnerability.
  
• The same genes that create an addiction vulnerability to substances like alcohol are associated with bipolar disorder, conduct disorders, and antisocial personality disorder.

iv. Environmental Influences

• Mothers who drink alcohol during pregnancy have children with a greater risk of alcoholism in later life
• Children with a variant gene for a less sensitive GABA receptor tend to have impulse control problems (including drug use) unless they grow up in families which clear parental supervision.
  

• Medications to Combat Opioid Abuse

• The most effective medical treatment for opioid (heroin, etc.) abuse in patients who have failed to "kick their habit" by more traditional treatment methods is the use of suboxone or methadone.
  

• Suboxone is a prescription medicine that contains the active ingredients buprenorphine (an opioid which has a slow onset, has a mild effect, and is very long acting with a half-life of 24 to 60 hours) and naloxone (a drug that blocks the effects of opioids). Suboxone is very effective in preventing accidental overdoses which lead to death.

• Methadone as noted above is a synthetic ("man made") opioid which is taken orally once a day. It does not lead to heroin "highs" but does relieve the cravings for heroin. Methadone is usually used with individuals who have failed multiple times in other treatment approaches. In the form of methadone maintenance therapy, it is taken for long periods of time (even for a lifetime) as a way of preventing the use of heroin. In methadone reduction therapy, it is taken over a period of time, but tapered down until the individual no longer feels the need to consume an opioid.
  

• Note that our textbook says, "these drugs do not end the addiction. They merely satisfy the craving in a less dangerous way" (p. 472). I inserted a bold-faced italics for the word "merely" because it can be interpreted as a moral judgment by the author and, certainly, many others object to "substituting" one opioid for another since, in some fashion or another, the addict is not only medically-impaired, but considered to be a moral failure. As Maia Szalavitz and others point out, however, physicians and other treatment givers should not be in the business of condemning people, but saving their lives. When the alternative to suboxone and methadone is so frequently death, it would seem that keeping people alive ought to be the principal goal of health care providers.  

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References

Active/Lethal Dose Ratio and Dependence Potential of Psychoactive Drugs. Data source: Gable, R. S. (2006). Acute toxicity of drugs versus regulatory status. In J. M. Fish (Ed.),Drugs and Society: U.S. Public Policy, pp.149-162, Lanham, MD: Rowman & Littlefield Publishers. Image retrieved from http://en.wikipedia.org/wiki/File:Drug_danger_and_dependence.svg

Berridge, K. C., & Robinson, T. E. (2016). Liking, wanting, and the incentive-sensitization theory of addiction. American Psychologist, 71(8), 670-679. https://dx.doi.org/10.1037/amp0000059

Case, A., & Deaton, A. (2017, Spring). Mortality and morbidity in the 21st century (Brookings Papers on Economic Activity). Washington, DC: Brookings Institution. Retrieved from https://www.brookings.edu/wp-content/uploads/2017/08/casetextsp17bpea.pdf

NIDA (2020, March 27). Dopamine neurons signal rich information about unexpected events. https://www.drugabuse.gov/news-events/science-highlight/dopamine-neurons-signal-rich-information-about-unexpected-events

Oreland, L., Lagravinese, G., et al (2017). Personality as an intermediate phenotype for genetic dissection of alcohol use disorder. Journal of Neural Transmission. doi:10.1007/s00702-016-1672-9

Reeves, K. C., Shan, N., Muñoz, B., & Atwood, B. K. (2022). Opioid receptor-mediated regulation of neurotransmission in the brain. Frontiers in Molecular Neuroscience, 15. https://doi.org/10.3389/fnmol.2022.919773

Torregrossa, M. M., & Taylor, J. R. (2016). Neuroscience of learning and memory for addiction medicine: From habit formation to memory reconsolidation. Progress in Brain Research, 223. https://doi.org/10.1016/bs.pbr.2015.07.006

The first version of this page was posted January 18, 2005.