L16 - Drug Use and Addiction

• Drug abuse is defined as the self-administration of a drug in a chronically excessive quantity, deviating from approved medical or social norms, and resulting in physical or psychological harm.

• Forms of drug abuse:

  • Experimental: Exploratory drug use, which may or may not continue.

  • Social/Recreational: Common with substances like alcohol, nicotine, caffeine, marijuana, and MDMA.

  • Compulsive: An irrational, irresistible dependence on a drug.

  • Self-Medication: Seeking relief from physical, psychological, social, or financial problems.

  • Ritualistic: Related to religious practices with psychomimetic/hallucinogenic drugs.

  • Poly-drug/Multi-drug Use: Combining drugs, such as marijuana, alcohol, and other depressants.

  • Abuse in Sports: Use of anabolic steroids, stimulants, narcotic analgesics, and diuretics.

Cycle of Compulsive Drug Use

• A three-step recurring cycle:

  • Frequent drug taking leading to a rewarding experience.

  • Dependence associated with acute or prolonged withdrawal (physical withdrawal vs. lowered mood and anxiety, respectively).

  • Craving (cue-induced, stress-induced) leading to relapse.

• Three stages:

  • Intoxication.

  • Withdrawal (negative effects).

  • Preoccupation/Anticipation (craving).

Addiction as a Chronic Relapsing Disorder

• Addiction is a chronic, relapsing disorder characterized by:

  • Behavioral pattern of drug use.

  • Overwhelming involvement in procuring and using the drug.

  • High tendency to relapse.

• Progression:

  • Recreational or therapeutic use evolves into excessive consumption, then compulsive drug seeking.

• Dopamine's Role:

  • Dopamine is central to the drug reward pathway.

  • Many psychoactive drugs increase dopamine levels.

• D2 Receptor Availability:

  • Imaging studies show reduced striatal dopamine receptor availability in chronic abusers of cocaine, methamphetamine, heroin, and alcohol.

  • Animal studies suggest low dopamine D2 receptor availability promotes self-administration of drugs to relieve reward feeling.

Drug Reward Pathway

• Dopamine's Central Role:

  • Most psychoactive drugs increase dopamine levels in the brain, particularly in the reward pathway.

• Reward Pathway (simplified):

  • Drug intake leads to dopamine release from the ventral tegmental area (VTA) to the nucleus accumbens.

  • This causes pleasure.

  • The prefrontal cortex partially controls this.

  • The amygdala maintains association of drug reward.

  • Cues develop, resulting in craving.

  • This causes drug-seeking behavior, restarting the cycle.

• Drugs Involved:

  • Opioids, nicotine, amphetamines, ethanol, and cocaine activate the reward pathway.

  • They have direct or indirect effects on dopaminergic neurons in the VTA, releasing dopamine in the nucleus accumbens.

  • Dopamine is the primary driver, mediating the reinforcing effects of these substances.

Brain Reward System Pathways

• Dopaminergic Functions (in blue):

  • Reward, pleasure, compulsive drug-taking, motor function.

• Glutamatergic Functions (in green):

  • Anticipation (cravings), emotions.

• Key Pathways:

  • VTA activating the dopaminergic pathway in the nucleus accumbens.

  • Glutamatergic pathway from cortex to amygdala.

• Repeated exposure to drugs may alter the structure and function of these pathways, leading to long-term changes in behavior.

Recap of Psychoactive Drug Mechanisms

• Opioids:

  • Receptor: Mu opioid receptor.

  • Effects: Decrease GABAergic signaling, increase dopaminergic signaling. Opioids bind to mu opioid receptors, reducing the release of GABA, an inhibitory neurotransmitter. This disinhibition leads to increased dopamine release.

• Alcohol:

  • Receptor: NMDA receptor.

  • Effects: Decreased glutaminergic signaling, increased dopaminergic and GABAergic signaling. Alcohol inhibits NMDA receptors, reducing glutamate's excitatory effects. It also enhances GABAergic transmission, contributing to its sedative effects. The increased dopamine release is a key factor in alcohol's reinforcing properties.

• Nicotine:

  • Receptor: Nicotinic acetylcholine receptors.

  • Effects: Increased dopamine release. Nicotine binds to nicotinic acetylcholine receptors in the VTA, stimulating dopaminergic neurons and increasing dopamine release in the nucleus accumbens.

• Stimulants:

  • Cocaine: Inhibits dopamine transporter, blocking dopamine reuptake from the synapse, increasing dopamine concentration in synaptic cleft.

  • Amphetamines stimulate dopamine release.

• Cannabis:
  -THC binds to CB1 receptors in the brain, modulating the release of various neurotransmitters, including dopamine. Exact effects depend on dose, frequency, and individual.

• Classic Hallucigens:

  • Receptor: 5-HT2A receptors.

  • Activation of 5-HT2A receptors leads to altered sensory perception and cognition, but the mechanisms aren't fully understood. There are complex interactions with glutamate and dopamine systems.

Substance Dependence

• Definition: Recurrent drug use with two or more of the following:

  • Impaired control of use.

  • Continued/escalated use despite harms.

  • Physiological features: tolerance, withdrawal, or repeated use to prevent withdrawal.

• Neuroadaptations:

  • Excessive, repeated dopaminergic stimulation causes persistent neuroplastic adaptations in midbrain dopaminergic neurons projecting to the nucleus accumbens.

  • Enhanced incentive salience to drug use. This means that drug-related cues become highly salient and attention-grabbing.

  • Behavioral inflexibility.

  • These involve glutamatergic inputs on dopaminergic neurons, further reinforcing the addiction.

Drug-Induced Neuroplasticity

• Ventral tegmental area with dopaminergic and glutaminergic input to nucleus accumbens.

• Glutamatergic input from prefrontal cortex, amygdala, and hippocampus.

• Timeline of changes:

  • Short term (minutes to days): Changes in gene networks. This involves alterations in gene expression related to synaptic plasticity.

  • Medium term: Changes in neuronal signaling. This includes altered receptor expression and signaling pathways.

  • Long term: Neuronal adaptations. This results in structural changes in neurons and their connections.

  • Months to years: Persistent addictive behavior. These long-term changes contribute to the enduring nature of addiction.

Tolerance

• Definition: Successive doses have lesser effects.

  • May exist with or without psychological or physical dependence.

  • Increasing amounts of the drug are needed to produce the same effect.

• Mechanism:

  • Drug free state and administration of drug leads to acute drug effect: drug tips scales to desired effect.

  • Drug use and neuronal adaption: opposing neuronal adaption occurs to balance out effects.

  • Withdrawal of drug: withdrawal syndrome and symptoms associated with adaption.

  • Recovery from neuroadaption: normal central nervous system recurring.

  • Neuronal plasticity: Brain adapts to the acute effects over time, requiring more drug to produce the same effect.

Withdrawal

• Prolonged cessation of drug administration leads to withdrawal effects lasting days to weeks.

• Responses are characteristic of the drug.

• Intensity varies based on drug type and pharmacokinetic characteristics. Longer half-life drugs will result in longer withdrawal periods.

• Desire to avoid withdrawal symptoms incentivizes retaking the drug.

• Cues associated with drug taking: social situation, purchasing, preparing the drug.

• Drug administration is associated with positive reinforcement but that decreases overtime.

• Cues associated with withdrawal: social situation, suitable to taking drug, non availability of the drug.

• Agonist target abstinence syndrome or pysichal dependence.

• Antagonists/response modifiers target the reward pathway.

• Drug detox or drug withdrawal syndrome in the early days, early abstinence, and late abstinence. Understanding the stages of withdrawal is critical for effective management.

Pharmacological Options for Compulsive Drug Use

• Agonist therapies.

• Antagonist therapies.

• Aversive therapies.

• Medications to alleviate withdrawal symptom.

Agonist Therapy

• Medicinal-grade drug provided long-term to prevent withdrawal and reduce cravings.

  • Methadone: Mu opioid receptor full agonist.

  • Lessens opioid withdrawal symptoms by providing a controlled opioid effect.

  • Blocks euphoric effects of other opioids by occupying opioid receptors.

  • Effects last 24-36 hours, providing sustained relief.

  • Buprenorphine: Mu opioid receptor partial agonist.

  • Ceiling effect (effects plateau) reduces the risk of overdose and dependence.

  • Can be taken orally or as a six-month implant for long-term maintenance.

  • Nicotine Replacement Therapy:

  • Stimulates presynaptic acetylcholine receptors, enhancing acetylcholine release and metabolism, and also enhances the dopaminergic signalling associated with smoking.

  • Alleviates withdrawal symptoms and reduces cravings by providing a controlled dose of nicotine without the harmful effects of smoking.

Antagonist Therapy

• Blocks the effects of a drug by prior administration of an antagonist.

  • Naltrexone: Non-selective opioid antagonist.

  • Blocks opioid effects in drug-withdrawn patients addicted to opioids, preventing them from experiencing the rewarding effects of opioid use.

  • Nalmefene can be administered with naltrexone to reduce ethonal use by blocking effects of endogenous opioids released by ethanol.

  • Nicotinic Antagonist:

  • Blocks the positive effects of nicotine, reducing the incentive to smoke.

Agonist vs Antagonist Therapies

• Full Agonist: Generates the full effect, mimicking the action of the abused drug.

  • Eliminate peaks and troughs associated with drug seeking and withdrawal by providing a stable level of receptor activation.

• Partial Agonist: Generates a more limited effect with that ceiling effect limitation, reducing the risk of overdose.

• Complete Antagonist (Naltrexone): No effect taken within the patient system prior to them relapsing.

  • No pleasurable effect associated with taking drug, discouraging further drug use.

Aversive Therapies

• Make the drug experience unpleasant, creating a deterrent effect.

  • Disulfiram (for alcohol addiction):

  • Aldehyde dehydrogenase inhibitor, blocking the metabolism of acetaldehyde.

  • Induces unpleasant response to ethanol:

    • Inhibits second step in alcohol metabolism, causing buildup of acetaldehyde.

    • Results in flushing, headache, nausea, vomiting, chest pain, blurred vision, mental confusion, sweating, breathing difficulty, anxiety, making alcohol consumption highly unpleasant.

Therapies Alleviating Withdrawal Symptoms

• Facilitate drug withdrawal/detox by substituting a drug in the same class (but with less intense withdrawal) or by administering drugs that reduce withdrawal intensity.

  • Methadone/Buprenorphine: Mu receptor agonists.

  • Short-term use to blunt opioid withdrawal effects by providing a controlled opioid effect.

  • Alpha-Two Adrenoreceptor Agonists (e.g., clonidine).

  • Alleviate opioid, alcohol, and nicotine withdrawal symptoms by reducing autonomic overactivity.

  • Reduce autonomic symptoms (elevated pulse and blood pressure).

  • Limit noradrenergic detoxification storm (opioid withdrawal).

  • Used in alcohol withdrawal to diminish the autonomic symptoms by reducing elevated pulse and blood pressure.

  • Used in opioids to lessen the effects of the detoxification storm associated with noradrenaline following addiction to opioids.

Mechanisms of Action: Alleviating Withdrawal Symptoms

• Mu Receptor Agonists:

  • Induce less intense effects of withdrawal from opioids of addiction such as heroin by providing a stabilized opioid effect.

  • To reduce the intensity of the withdrawal symptoms substitute opioid receptor with other opioids such as methadone.

• Alpha-Two Adrenergic Receptor Agonists:

  • Bind to alpha-two adrenergic receptor and reduce the effects associated with withdrawal by decreasing sympathetic nervous system activity.

Other Drugs for Withdrawal

• Drugs that target the α4β2 subunit of nicotinic acetylcholine receptors.

  • α4β2 nicotinic receptor partial agonist to alleviate nicotine withdrawal symptoms. These drugs provide a moderate level of nicotinic receptor activation, reducing cravings without the full reinforcing effects of nicotine.

• Smoking vs. Nicotine Withdrawal vs. Partial Agonist

  • When person smokes, nicotine receptors activated by nicotine, leading to rapid dopamine release.

  • If person in nicotine withdrawal, there is no activation, leading to very little dopamine release.

  • Partial agonists help to stimulate moderate dopamine release, easing withdrawal symptoms.

• Benzodiazepines (for Alcohol Withdrawal):

  • Positive allosteric modulators of GABA receptors, enhancing GABAergic transmission.

  • Enhance GABA receptor activation, decrease glutamate excitatory signaling, reducing central nervous system excitation.

  • Reduce withdrawal symptom severity, risk of seizures and delirium by restoring balance in neurotransmitter activity.

  • Alcohol is a depressant, when patients suddenly stop there is central nervous system excitation due to the removal of alcohol.

  • This leads to autonomic overactivity, which benzodiazepines help to restore balance.

Summary

• Substance abuse is a chronic illness leading to altered cognitive