PSYC/NEUR 2P37: Drug Action and Addiction

• Drug addiction is related to the brain's reward circuits
• The notes were prepared by Charlis Raineki, PhD for PSYC/NEUR 2P37 on March 6, 2025

Learning Objectives

• Identify anatomical areas and neurotransmitter systems involved in reward pathways.
• Discuss basic principles of drug action.
• Discuss drug tolerance and drug withdrawal.
• Explain contingent and conditioned drug tolerance

Basic Principles of Drug Action

• Psychoactive drugs affect subjective experience and behavior by acting on the nervous system

Drug Administration and Absorption

• The route of drug administration impacts the rate and degree to which the drug reaches its site of action
• Ingestion involves the oral route, is easy and safe, results in slow action, and has unpredictable absorption via the digestive tract.
• Inhalation involves absorption through capillaries in the lungs, has rapid absorption, and applies only to a few drugs, such as anesthetics, asthma medication, tobacco, and cannabis.
• Injection allows direct delivery into systemic circulation, bypassing the digestive tract
• Injection has strong, fast, and predictable effects
• Forms of injection include subcutaneously (under the skin) and intramuscularly (into large muscles).
• Intravenously, injection goes into veins, and the drug is delivered directly to the brain
• Drugs can be absorbed through mucous membranes like the nose, mouth, and rectum
• The route of drug administration determines how fast a drug will act in the brain

Mechanisms of Drug Action

• Psychoactive drugs must reach the brain and bypass the blood-brain barrier to have an effect
• Most drugs act as ligands that bind to specific receptor molecules.
• Drugs can target one or a few receptor subtypes.
• Drug actions can vary widely because receptor subtypes have different localizations and functions
• Drug actions are terminated by enzymes in the liver through drug metabolism
• Small amounts of drugs may be excreted in urine, sweat, feces, breath, and mother’s milk

Drug Tolerance

• Drug tolerance is a decreased sensitivity to a drug as a consequence of exposure to it
• Drug tolerance involves a shift in the dose response curve to the right
• Tolerance often develops to some effects and not others
• Cross-tolerance means that tolerence to one drug can produce tolerance to similar drugs
• Cross-tolerance is observed between members of the same drug class
• Examples of cross tolerence are all opioids, alcohol and benzodiazepines and several amphetamines
• There are two types of drug tolerance:
  • Metabolic, where less drug is getting to the site of action
  • Functional, where there is decreased responsiveness at the site of action,
    • Fewer receptors
    • Decreased efficiency of binding at receptors
  • Receptors that area less responsive

Drug Sensitization

• Drug sensitization is a progressive and persistent increase in a drug effect produced by repeated exposure to the same dose

Learning on Drug Tolerance

• Contingent drug tolerance means that tolerance only develops to drug effects that are experienced
• Conditioned drug tolerance: Maximal tolerance effects are seen in the environment where a drug is usually taken
• Addicts are more likely to overdose in unfamiliar surroundings
• Exteroceptive or interoceptive cues associated with drug taking become conditioned stimuli that elicit conditioned compensatory responses, producing tolerance prior to drug use

Drug Withdrawal

• Drug withdrawal is observed when drug use is terminated
• Withdrawal symptoms are the opposite of the drug's effects
• The body makes physical changes to compensate for the presence of the drug to facilitate normal functioning
• Severity of withdrawal symptoms vary according to the drug and the pattern of use

Drug Abuse vs. Drug Addiction

• Drug abuse is a maladaptive pattern of legal and illegal drug use
• This includes the repeated use of drugs to produce pleasure, alleviate stress, and/or alter or avoid reality
• Individuals with substance use disorder continue to use a drug despite its adverse effects on health and social life
• Addiction and physical dependence may occur together or separately
• Addicts may still crave the drug, even after withdrawal symptoms from physical dependence have subsided

Economic Costs of Drug Abuse and Addiction

• The estimated economic cost to society due to drug abuse and addiction in The USA totals $524 billion/year
• Illegal drugs cost $181 billion/year, alcohol costs $185 billion/year and tobacco costs $158 billion/year
• Economic costs include huge expenses for medical and social services
• Economic costs include Millions of hours lost in the workplace
• Economic costs include elevated rates of crime
• Economic costs include damage to many children from their parents' substance abuse behavior

Vulnerability to Drug Abuse and Addiction

• Biological factors:
  • Sex
  • Genetic predisposition
• Family situation:
  • Family breakup
  • Poor relationship with parents.
• Personal characteristics:
  • Aggressiveness
  • Poor emotional control
• Environmental factors include a high prevalence of drug use, especially within a peer group

Other factors related to Drug Abuse and Addiction

• Drug abuse/addiction is highly comorbid with other mental health disorders
• Self-medication happens when substance abuse begins to alleviate symptoms of mental illness
• Causal effects occur when substance abuse may increase vulnerability to mental illness
• Common or correlated causes occur when risk factors give rise to mental illness, and substance abuse may be related or overlap

Biopsychological Theories of Addiction

• Physical-dependence theory
  • states that dependence due to pain of withdrawal does not explain why addicts relapse long after detoxification
• The pattern of drug taking routinely displays periods of binges and detoxification
• Addictions develop to drugs that do not produce severe withdrawal symptoms
• Positive-incentive theories
  • Addicts take drugs not to escape unpleasant withdrawal
  • Addicts are driven to obtain the drugs' pleasurable effects
• Incentive-sensitization theory
  • states that it is not the hedonic value (liking) but the actual pleasure experienced
  • states that it is the positive-incentive value (wanting): the anticipated pleasure associated with the action (taking the drug)
  • As drug use increases, so does the positive-incentive value due to memory of the pleasure of early drug experience. The hedonic value decreases due to drug tolerance
  • People with substance use disorder crave drugs more but enjoy them less

Relapse Causes

• Stress as a drug use coping mechanism
• Drug priming, where a single exposure leads to relapse
• Environmental cues within conditioned drug tolerance like going back to places where drugs were taken causes conditioned compensating responses craving and relapse

Intracranial Self-Stimulation (ICSS)

• Rats, humans, and many other species stimulate levers that deliver electrical stimuli to specific brain regions.
• Electrical stimuli delivered to the lateral hypothalamic regions, septum, and midbrain dopamine system
• Activity in these brain regions is proposed drives the pleasure of natural rewards, such as food and sex

Mesotelencephalic Dopamine System

• Nigrostriatal pathway (green) Dopaminergic neurons project from substantia nigra to the striatum
• This pathway controls movement, motor sequences, and habits Degeneration of neurons in Parkinson's disease
• Mesocorticolimbic pathway (red) Dopaminergic neurons project from ventral tegmental area to the cortex and limbic system
• This pathway helps with experiencing pleasure and obtaining reward Neurons that project to the nucleus accumbens are most implicated in reward and addiction

Mesocorticolimbic Pathway and Reward

• Many brain sites that facilitate intracranial self-stimulation are part of the mesocorticolimbic pathway
• The pathway stimulates because it feels rewarding
• Intracranial self-stimulation increases dopamine release
• Dopamine agonists tend to increase self-stimulation; antagonists tend to decrease self-stimulation
• Lesions disrupt intracranial self stimulation and animals may no longer find the action rewarding

Measuring Drug-Produced Reinforcement

• The drug self-administration paradigm involves drugs being self-administered through cannulas to the bloodstream or into an area of the brain
• Conditioned place preference involves lab animals that
  choose to spend more time in cage compartments where drugs were administered than elsewhere

Dopamine and Drug Addiction

• Dopamine plays an important role in the rewarding effects of addictive drugs and natural reinforcers
• Dopamine antagonists block self-administration and conditioned place preference for several addictive drugs, reducing reinforcing effects of food
• The dopamine D2 receptors are decreased in an addicted brain
• Needing more pleasure is associated with the decrease

Nucleus Accumbens and Drug Addiction

• Animals self-administer microinjections of addictive drugs into the nucleus accumbens to feel the reward
• Microinjection of drugs into the nucleus accumbens produces conditioned placed preferences
• Condiitonal animals love the place because that's where they get pleasure
• Lesion of the nucleus accumbens or ventral tegmental area stops drug self-administration and drugs' related place preference
• The reward system being broken prevents the animal from wanting the drug
• Self-administration of addictive drugs and natural reinforcers result in increased dopamine in the nucleus accumbens.
• Self-administration of cocaine increases dendritic spines in the nucleus accumbens
• This strengthens the connection and increases craving over time