PSYC 360 Term 2 - Drugs

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What are the basic principles of drug action?
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What are the basic principles of drug action?
needs to access the brain and cross the blood brain barrier (BBB)

drugs must be either small or soluble to cross, since the capillaries are very tight at the barrier

most drugs are ligands acting on specific receptor molecules; target one or a few specific receptor types
- e.g. serotonin has 6 classes with subdivisions but LSD only works on receptors 3 and 4; affects certain functions
What is drug tolerance?
drug tolerance: decreased sensitivity to a drug as a consequence of exposure to it
- shifts the dose-response curve to the right
- needs more concentration for the same effect

*contingent (drug tolerance): only develops for the effects you experience
What is drug withdrawal?
observed when drug use is terminated; withdrawal symptoms are usually the opposite of the drug's effect
- body makes changes to compensate for presence of drugs to facilitate normal functioning
- severity depends on drug and pattern of use
What is contingence drug tolerance?
contingent (drug tolerance): only develops for the effects you experience
What is conditioned drug tolerance?
conditioned drug tolerance: Maximal tolerance effects are seen in the environment in which a drug is usually taken
- situational; more likely to OD in unfamiliar places

cues: can be exteroceptive or interoceptive; become conditioned stimuli that are associated with the drug and elicit conditioned compensatory responses that produce tolerance prior to drug use
What is the difference between drug addiction and drug abuse?
drug abuse: realising that their actions and drug use have consequences and are willing to stop; maladaptive pattern of legal and illegal drug use

drug addiction: if they are caught and don't believe that their actions are problematic; use drugs despite negative social and health impacts

addiction and physical dependence are different - can experience cravings (addition) without the dependence
What are the biopsychological theories of addiction?
physical dependence theory

positive-incentive theory

incentive-sensitisation theory
What is the physical dependence theory? What are some problems with it?
physical dependence theory: drugs are taken to avoid negative withdrawal effects
- doesn't explain relapse after long detoxification
- drug taking usually has cycles of binging and detoxification
- some drugs do not produce negative withdrawal effects but are still addictive
What is the positive-incentive theory?
positive-incentive theory: drugs are taken for the positive pleasurable effects
What is the incentive-sensitisation theory?
incentive-sensitisation theory: positive-incentive value increases from the memory of early drug experiences, but the hedonic value decreases due to tolerance; crave more but get reduced effect
- hedonic value: actual pleasure experienced
- positive-incentive value: anticipated pleasure associated with the action/drug
What are psychoactive drugs?Psychoactive drugs: drugs that influence subjective experience and behavior by acting on the nervous systemWhat does the route of administration influence? What are the four routes?Route of drug administration influences the *rate* and the *degree* to which the drug reaches its site of action fastest to slowest (also shortest to longest duration): inhalation: capillaries in lungs, rapid absorption; only available for some drugs (cannabis, tobacco, asthma meds, anesthetics) injection: direct to systemic circulation (no lost concentration); strong, fast, and predictable; dangerous (already in blood, can't remove); - subcutaneously: under skin - intramuscularly: into large muscles - intravenously: into veins, direct to brain (common with addicts) absorption through mucus membranes: nose/mouth/rectum; can harm membranes after prolonged use ingestion: oral, easy (no equip.) and safe; slow and unpredictable (indiv. differences)What is drug metabolism? How are drugs excreted?actions of drugs are broken down by drug metabolism: enzymes break down the drugs and excrete them can also be excreted via urine, sweat, feces, breath, mother's breast milk (drugs consumed after birth can still impact child!)What is cross-tolerance?Cross tolerance: exposure to one drug can produce tolerance to similar drugs - often occurs for drugs in the same class (affect the same receptors) or same modes of action - eg opioids, alcohol and benzodiazepines, some amphetaminesWhat kinds of drug tolerance are there?*metabolic*: less drug gets to the site of action *functional*: decreased responsiveness at the site of action, fewer receptors, decreased efficiency of binding at receptors; receptors less responsiveWhat is drug sensitisation?drug sensitisation: increased effect of drug following repeated exposure to the same doseWhat factors increase vulnerability to drug abuse/addiction?*biological factors:* - sex (males > females) - genetic predisposition *family situation:* - family breakup - poor relationship with parents *personal characteristics:* - aggressiveness - poor emotional control *environmental factors:* - high prevalence of drug use in community, esp peer groupWhat is relapse? What may cause it?relapse: return to drug-taking patterns possible causes: - *stress* (coping mechanism) - *drug priming*: single exposure leads to relapse - *environmental cues*: conditioned drug tolerance (conditioned compensatory responses, craving, and relapse from return to previous location or thinking about them); eg Vietnam veterans and heroinList some classes of drugsnarcotics/opoids: heroin, fentanyl, opium, morphine - used for pain relief stimulants: tobacco, caffeine, amphetamines, cocaine, metamphetamine - speed up CNS depressants: alcohol, benzodiazepine, rohypnol (date drugs) - slow down CNS hallucinogens: ecstasy, ketamine, LSD, psilocybin, marijuana, steroids, inhalants - induce hallucinationsHow does alcohol (ethanol) work?uptake via mucous membranes (rapid) and acts as a *positive allosteric modulator on GABA(A) receptors* in the CNS (binds to allosteric site to induce conformational change) - GABA is an inhibitory NT - alcohol also inhibits glutamate (excitatory) - releases other inhibitors to increase dopamine in the *ventral tegmental area (VTA)* and *nucleus accumbens* for drug-induced reward depressant - lower doses, stimulates neuronal firing for a euphoric state - higher doses, reduces neuronal firing ~ 50% heritabilityWhat are the effects of alcohol (acute and chronic)? Health risks?acute: - decreases in attention and executive decision-making - alterations in memory - changes in mood - drowsiness chronic: - induces lethargy, confusion, amnesia, loss of sensation, difficulty in breathing - enhanced excitatory NMDA signaling, discouraged GABA signaling, hyperexcitablenervous system that requires the depressant effects of ethanol *health risks* chronic use: - brain damage - cirrhosis (damaged and scarred liver) - erodes heart muscles and increases heart attack risk - increased risk of oral and liver cancer, stomach ulcers, pancreatitis, gastritis drinking during pregnancy -> can cause fetal alcohol spectrum disorder (FASD)What are the three phases of alcohol withdrawal?1) after 5-6 hrs: tremors, agitation, headache, nausea, vomiting, abdominal cramps, profuse sweating, sometimes hallucinations 2) after 15-30 hrs: convulsive activity 3) after 1-2 d (lasts up to 4 d): delirium tremens; disturbing hallucinations, bizarre delusions, agitation, confusion, hyperthermia, tachycardiaHow can we treat alcoholism?naltrexone (oral or injection) - opiate antagonist: prevents feelings of relief/happiness acamprosate (oral) - thought to stabilise the chemical imbalances from alcohol withdrawal - can have side effects (most common is diarrhea) - works as well as naltrexone, but unclear how it works disulfiram/antabuse (oral) - produces unpleasant side effects with alcohol, makes people not want to drink to avoid this - inhibits enzyme to produce hangover effects - alcohol is usually converted to acetaldehyde, then broken down by enzyme; builds up if enzyme is inhibited that results in unpleasantness - no tolerance: the longer you take it, the worse the drug gets - poor compliance; there is no reduction in cravingWhat are some health risks with tobacco?cancer (lungs, mouth) chronic bronchitis stroke/heart disease also results in bad breath, stained teethHow does tobacco work?uptake via pulmonary circulation (rapid) *sympathomimetic drug*: stimulant, mimics effects of endogenous agonists of SNS - binds to nicotinic cholinergic receptors (nAChR), which are co-expressed with dopamine and respond to acetylcholine (motor) - has been reported as a stimulant at smaller doses, but then a sedative as doses increase releases dopamine at the *VTA* and *nucleus accumbens* releases noradrenaline, serotonin, and endorphins (amongst many others)What are some effects of tobacco? What are withdrawal symptoms?- stimulation and pleasure - reduced stress and anxiety - may improve concentration, reaction time, and performance of certain tasks withdrawal: - irritability, depressed mood, restlessness, anxiety - increased hunger and eating, difficulty concentrating - hedonic dysregulationHow can tobacco withdrawal be treated?nicotine replacement products (patch, gum, spray, inhaler, lozenge) - supply low dose of nicotine bupropion - nicotinic antagonist, also an atypical antidepressant (norepinephrnie-dopamine reuptake inhibitor NDRI) - reduces the severity of nicotine cravings and withdrawal symptoms - smoking cessation for those without history of depression - doubles chances of cessation varenicline - nicotinic receptor partial agonist: stimulates nicotine receptors more weakly - reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products ie less pleasurable effects = want to smoke lessWhat are some health risks associated with marijuana? What are its effects (low vs high doses)?low addiction potential with rare withdrawal symptoms tachycardic effects might result in heart attacks in susceptible individuals low doses: - increased sense of well-being: initial restlessness and hilarity followed by a dreamy, carefree state of relaxation - alteration of sensory perceptions including expansion of space and time; and a more vivid sense of touch, sight, smell, taste, and sound - a feeling of hunger, especially cravings for sweets - subtle changes in thought formation and expression. high doses: - impaired short-term memory - impaired psychological functioning - slurred speech; meaningful conversations become difficult - sense of unreality, emotional intensification, sensory distortion, feelings of paranoia - motor impairment *gets stronger and stronger over time as people learn to have more concentrated dosesHow does marijuana work?active component is THC (delta-9-tetrahydrocannabinol); acts mostly as a partial agonist on CB1 endocannabinoids act on CB1 (one of the most abundant GPCRs in the brain) and CB2 (found in CNS and immune system) endocannabinoids - Anandamide (AEA) - 2-Arachidonylglycerol (2-AG) - released by postsynapse and act on presynaptic receptorsHow may marijuana be used therapeutically?- suppresses nausea and vomiting in cancer patients - stimulates appetite in AIDS patients - blocks seizures - dilates bronchioles of asthmatics - decreases severity of glaucoma - reduces anxiety - alleviates symptoms in multiple sclerosis patientsWhat kinds of amphetamines/cocaine are available?cocaine - natural; most commonly abused stimulant - typically snorted or injected - crack: potent, cheap, smokeable form of cocaine amphetamines: - synthetic - typically snorted, smoked, or orally ingested - types: MDMA/ecstasy, crystal meth, speed (not as concentrated or addictive)What are some health risks of cocaine/amphetamines? What are its effects?- moderate to high addiction potential - tolerance builds up fast - high risk for depression, acute psychosis, schizophrenia-like symptoms - euphoric, energetic, talkative, mentally alert, and hypersensitive to sight, sound, and touch - physiological effects: constricted blood vessels, dilated pupils; increased body temperature, heart rate, and blood pressure - temporarily decreased need for food and sleep *health risks* acute: - itching, fast heart rate, hallucinations, and paranoid delusions - OD causes hyperthermia and a marked elevation of blood pressure, which can be life-threatening, arrhythmias, death chronic: - strong imbalances of transmitter levels in order to compensate extremes - coughing up blood, bronchospasm, itching, fever, diffuse alveolar infiltrates without effusions, pulmonary and systemic eosinophilia, chest pain, lung trauma, sore throat, asthma, hoarse voice, dyspnea (shortness of breath), and an aching flu-like syndromeHow do cocaine/amphetamines work?cocaine/amphetamines: dopamine reuptake is blocked, accumulates at the cleft and increases binding with receptors methamphetamine: also trigger dopamine release from presynapse - even more dopamine = more rewarding and addictiveCompare and contrast cocaine with methamphetaminemethamphetamine - stimulant - synthetic - long-lasting high - 50% removed from body in 12 hours - increase dopamine release and prevent reuptake - limited medical use for ADHD, narcolepsy, weight loss cocaine - stimulant and local anesthetic - plant-derived - brief high - 50% removed from body in 1 hour - blocks dopamine reuptake - limited medical use as a local anestheticWhat are the 7 stages of the 'meth experience'?1) The Rush: initial, immediate response; up to 30 min 2) The High: user feels aggressively smarter, becomes argumentative, interruptive, intense focus on simplest things; can last 4 -16 hrs 3) The Binge: urge to maintain the high; can last 3 -15 days until full tolerance reached 4) Tweaking: craving of initial high, frustration, intense itching, sensation of bugs crawling under skin 5) The Crash: body shuts down, long period of sleep; can last 1 -3 days 6) Meth hangover: deteriorated state, starved, dehydrated, utterly exhausted; 2 -14 days 7) Withdrawal: depression, no energy, anhedonia, strong cravingWhat kind of therapy can be used with cocaine/amphetamines?no medication available, CBT most commonly used clinical trials: - AV411 (Ibudilast): suppresses neuroinflammatory actions of glia cells; inhibits methamphetamine self administration in rats; reduces development of tolerance and enhances analgesia (relief from pain) - 'vaccines': injection of user with antiamphetamine/anticocaine antibodies or with vaccines that would stimulate the body to produce its own such antibodies; monoclonal antibody mAb7F9 in a clinical trial to treat meth addictionWhat are opioids?- extracted from the poppy seed - analgesics, e.g. oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, morphine, fentanyl - prescription drugs - heroin very high addiction potential can be smoked, snorted or injectedWhat are some health risks of cocaine/amphetamines? What are its effects?overdose can be lethal due to respiratory depression - extreme risk of overdose when mixed with fentanyl acute: - 'rush' - depressed respiration - clouded mental functioning - nausea/vomiting - suppression of pain - spontaneous abortion chronic: - addiction - infectious disease - collapsed veins - bacterial infections, abcesses - arthritis - liver/kidney diseaseHow do opioids work?endogenous opioids (endorphins, enkephalins, dynorphins): bind to opioid receptors (μ-, δ-, κ-receptor) - heroin converts to morphine in brain to bind to μ-opioid receptor inhibit GABA release in VTA, which inhibits firing of dopamine neurons (so there is a net increase of dopamine) - indirect stimulation of dopamine releaseWhat are the withdrawal symptoms like for opioids?- starts within a few hours and peaks 24-48 hrs after last administration; subsides after ~ 1 week - restlessness, limb pain, insomnia, diarrhea, vomiting, cold flashes with goose bumps ("cold turkey")What kind of treatment is available for opioids?pharmacological: slow-acting opioid agonist: Methadone (Dolophine® or Methadose®) - relieve cravings, suppress abstinence syndrome, block euphoric effects from opiates - gradually tapering off partial opioid agonist: Buprenorphine (Subutex®) - similar to methadone; partial agonist = less potential for life threatening side effects opioid antagonist: Naltrexone (Depade® or Revia®) - also used with alcohol (more frequent) - blocks effects of opioid druugs behavioural therapy: contingency management - operant conditioning - reward or punish behaviours for adhering to a plan - can use token economies, levels etc cognitive-behavioral therapyWhat are the effects of hallucinogens? What are some health risks?- alter perception (awareness of surrounding objects and conditions), thoughts, and feelings - cause hallucinations, or sensations and images that seem real though they are not e.g. lysergic acid diethylamide (LSD), 4-phosphoryloxy-N,N-dimethyltryptamine(psilocybin), peyote (mescaline) - various routes of administration: snorting, ingestion as liquid, or piece of paper common for LSD - elevated heart rate, increased blood pressure, and dilated pupils. - intense visual changes with alterations of mood *health risks* - relatively low addiction potential - bad trips, panic, paranoia - low risk of persistent psychosis - can improve overall mental healthHow do hallucinogens work?LSD - resembles serotonin, binds to serotonin receptors - 5-HT autoreceptoragonist on 5-HT1A receptors in the raphe nucleus, locus coeruleus, and the cortex -> inhibitory and excitatory effects - partial agonist on the postsynaptic 5-HT1A and 5-HT2A - increases functional connectivity within brainWhat could LSD/hallucinogens be used for?- tried on British marines; didn't really work - therapeutics: mood disorders (depression, PTSD, OCD), addiction, chronic pain, cluster headachesDiscuss decriminalization of drugsPortugal decriminalized drugs for personal use - decreased drug use, rates of drug-related deaths and STD Heroin-assisted treatment program in Switzerland, Germany, Netherlands, Denmark and UK - improved health and social situation - decreased drug use, rates of drug-related deaths and STDWhat kind of evidence is there for drug addiction in adolescence being significant?adolescence - period of brain maturation - maturation occurs back to front (frontal/temporal last to mature); ie the impulse control area is last - addiction onset usually occurs during adolescence *rats* - adolescent rats consume more alcohol than adults - cocaine conditioned place preference (at low doses) occurs only with early adolescent rats - adolescent rats only require 3 days of training to learn methamphetamine conditioned place preferenceDiscuss the effects of stress on drug addictionhumans: stress is a key risk factor rats: social stress increases responses for cocaine *nonhuman primates* - dominant socially housed monkeys have greater D2 receptor density - subordinate monkeys will rapidly develop self administration of cocaine - stress responses from confrontations?What is intracranial self-stimulation (ICSS)?- rats, humans, or other animals press levers to deliver electrical stimulation to specific brain areas - LH, septum, midbrain dopamine system - used to areas originally proposed to drive pleasure from natural rewardsWhat is the nigrostriatal pathway?- dopaminergic neurons that project from substantia nigra to the corpus striatum - important for control of movement, motor sequences, habits - degeneration of these neurons in Parkinson's disease - is a slow learning systemWhat is the mesocorticolimbic pathway?- dopaminergic neurons that project from the ventral tegmental area to the cortex and limbic system - important for experiencing pleasure and obtaining reward - neurons that project to nucleus accumbens most implicated in reward and addiction - ICSS often occurs on this pathway, increases the dopamine release - dopamine agonists increase stimulation and lesions disrupt itHow can we test drug-induced reinforcement?drug self-administration paradigm - self-administered via cannulas to bloodstream or area of brain conditioned place preference - choose to spend more time in the cage compartments where drugs were administeredWhat NT is implicated strongly in the reward effects of drugs? What brain area(s)?*dopamine* antagonists block self administration and conditioned place preferences for many drugs; reduce reinforcement with food addicted brains have reduced D2 receptors *nucleus accumbens* - self administer addictive drugs to nucleus accumbens - microstimulations will result in conditioned place preference - lesions here *or* VTA result in no ICSS or conditioned place preference - increase in dopamine after self administration - administration of cocaine results in increased dendritic spines in the nucleus accumbensExplain the rat park experimentHypothesis: Apparent addiction to opiate drugs not just due to addictive properties of the drug itself. Impoverished, stressful living conditions play a role in addiction - lack of social contact and environmental stimulation (enrichment) appear to facilitate drug addiction and its associated behavior - enrichment can eliminate addiction-related behaviours, prevent relapse, reduce activation of addiction-related brain areasWhat are some concerns about the drug self-administration paradigm?Unnatural housing and testing conditions - Rodents in enriched environments are less likely to consume drugs Excessive focus on stimulants - Less is know about non-stimulants - The dopamine hypothesis may be limited to only certain classes of drugs