Neuroscience C177: Midterm Study Guide PDF

Introduction On Drug - “Intoxicated” Drug Withdrawal - “Abstinent” Opioids/Depressants Relaxed, mellow Anxious, agitated Psychostimulants Energized, mo...

Introduction On Drug - “Intoxicated” Drug Withdrawal - “Abstinent” Opioids/Depressants Relaxed, mellow Anxious, agitated Psychostimulants Energized, motivated Down/crash, unmotivated ​ Mild SUD: 2 or 3 symptoms in the DSM-5 ​ Theories of addiction ○​ Biological/disease model ​ Treatment: rebalance with drugs or CRISPR ​ Cause: neurotransmitter imbalance or genetics ○​ Psychodynamic model ​ Treatment: therapy (CBT) ​ Cause: self-medicating for psychological issue ○​ Moral/spiritual model ​ Treatment: find the meaning of life ​ Cause: weak minded ○​ Environmental model ​ Treatment: good peers, eliminate trauma ​ Cause: troubled upbringing, trauma, poor parenting, peer pressure ○​ Biopsychosocial model ​ Treatment: wholistic, individual ​ Cause: bit of everything above ​ Drug targets ○​ Opioids and THC → G-protein coupled receptors ○​ Inhalants → voltage gated ion channels ○​ Nicotine and benzos → ligand gated ion channels ○​ Steroids → nuclear receptors ​ Increasing USA drug overdose deaths, exacerbated by COVID ​ Drug issues ○​ Accidents (acute) ○​ Overdose (acute) ○​ Cell death (acute or chronic)  ○​ Cancer or circulatory disease (chronic) ○​ Opponent processes (chronic, withdrawal) ○​ Disease transfer from needle sharing (acute) ○​ Use disorder behaviors ​ Comorbidity with psychiatric disorders ​ Licit drugs directly contribute to most preventable deaths ​ 18-25 year olds most frequently use drugs ​ Drug usage differs based on location, sex, ethnicity, crises, policies, attitudes, and age ​ Black people are disproportionately incarcerated for drugs Phenotypes of Addiction (Eydie) ​ Availability of drug, genetics, personality, and socioeconomic status predispose a person to addiction ​ Psychiatric disease is common in people with SUDs ​ Addictive personality - impulsivity and sensation-seeking in SUDs ○​ Barratt Impulsiveness Scale ​ Impulsivity mediates risk for stimulant dependence ​ Siblings of drug users are more impulsive than healthy controls ​ Stimulant users are more impulsive, especially with chronic exposure ○​ Sensation-seeking Scale (SSSV) ​ High sensation-seeking is likely an effect of stimulant drug use ​ Direct and indirect pathway: D1 and D2 receptors ○​ DA binding to D1 → disinhibits thalamus → go ​ D1 has low affinity to DA ​ Need a lot of DA to activate D1 (want many people on a D1 team) ○​ D2 inhibits GPe → disinhibited STN, which activates GPi/SNr → inhibits thalamus → no go ​ People with drug use disorders or a family history of drug or alcohol problems perform worse on cognition tests ○​ Stop-signal task tests motor response inhibition ​ SUD (meth) participants and siblings have slow response inhibition (high stop-signal reaction time) ○​ Stroop color-word test tests selective attention and inhibitory control ​ People with meth use disorder perform worse  ○​ Reversal learning tasks test cognitive flexibility ​ Much harder for people with METH use disorder to go against something they already know ○​ Decision-making ​ Delay discounting ​ Less reward now or more reward later ​ People with a family history of drug or alcohol problems discount delayed rewards more than those with no family history ​ Balloon analogue risk task ​ With each pump, you get higher reward but more risk of popping ​ Gambling tasks ​ People with drug use or family history of it do not learn about the disadvantageous choice of picking cards A and B ​ Brain imaging modalities ○​ MRI - structural and functional imaging using H protons and radiofrequency pulses ○​ PET - traces radioactive substances ​ Smaller gray matter volume in addiction ​ Damage of insula (involved in craving) disrupts addiction to cigarettes ​ D2 dopamine (DA) receptors ○​ Lower D2 DA receptor availability and binding potential in addiction, including meth use disorder ​ Fewer D2 receptors → take more cocaine ​ Take more cocaine → decrease D2 receptors ○​ More striatal D2-type receptor binding → less impulsivity ○​ Link to the balloon analogue risk task ○​ D2 striatal receptor availability correlated with prefrontal cortex (PFC) function ○​ D2 dopamine receptor gene (DRD2) Taq1A allele confers risk for AUD ○​ Less receptors → less BOLD signal ​ Physiology vs environment ○​ Physiology: genes, health, other drugs ​ Genes control: ​ Drug metabolism ​ Brain chemistry and function ​ Positive vs aversive responses ​ Temperament  ​ Risk for psychiatric disease ○​ Environment: stress, trauma, substance use and addiction in family or among peers, drug exposure, pop culture references ​ Risk factors increase the odds of addiction ​ SUDs are moderately to highly heritable ○​ Use is modulated by genes and environment ○​ Heritability is lowest for hallucinogens and highest for cocaine ○​ AUD is heritable ○​ Children of parents with an SUD have a much higher change of developing an SUD ​ Alcohol metabolism in the liver ○​ Acetaldehyde concentrations in hepatocytes depend on the rate of generation (ethanol oxidation by alcohol dehydrogenase - ADH) and the rate of removal (acetaldehyde oxidation by aldehyde dehydrogenase - ALDH) ○​ ADH and ALDH2*2 variants that produce the alcohol flushing syndrome reduce risk of AUD ​ More efficient metabolism of ethanol → more acetaldehyde ​ Genetics of nicotine metabolism ○​ Enzyme gene variations alter the rate of nicotine metabolism and smoking behaviors ​ Faster metabolism associated with: ​ More cigarette consumption ​ Greater nicotine dependence ​ Lower quit rates ​ Candidate gene vs genome-wide association (GWAS) studies ○​ Candidate gene approach - tests the effects of selected genetic variants, limited by what is known of the biology of the disease being studied ○​ GWAS - microarray technology to identify associations between phenotypes and genetic variants across the entire genome, rather than in a specific gene ​ GWAS identified the first susceptibility genes in tobacco addiction (more than genetics involved though) ○​ The genes, CHRNA5, CHRNA3, and CHRNB4, in the ɑ5 gene cluster on chromosome 15 encode the subunits involved in formation of nicotinic receptors ​ Key polymorphisms in nAChR genes show associations with:  ​ Nicotine dependence ​ Lung cancer ​ Chronic obstructive pulmonary disease ​ Cardiovascular diseases ​ ɑ5* nAChR in medial habenula and IP nucleus determines nicotine intake ​ Knocking out ɑ5 gene in medial habenula pathway → animals began self-administering more nicotine, which was not aversive anymore ​ White matter (WM) difference ○​ SUD participants and siblings have lower fractional anisotropy in the inferior frontal gyrus (IFG) and pre-supplementary motor area (deficit in white matter organization) ​ FA in right IFG is correlated with response inhibition ​ Gray-matter difference in SUD participants and siblings - preexisting neurocognitive phenotype ​ Larger volumes ​ Putamen (habit formation) ​ Amygdala (emotion) ​ Smaller volumes ​ Somesthetic cortex in the postcentral gyrus (processing touch) ​ Insula (decision-making, internal states) ​ Superior temporal gyrus (auditory, speech) Reward Path (Chris) ​ Memory circuitry is a critical component of addiction ○​ Drugs release dopamine, which enhance memory of what just happened ​ High comorbidity of those with opioid use disorder and those with anxiety and depression ​ Discomfort in the PNS can stimulate the brain to crave drugs ​ Drug craving can be initiated at any point in the addiction stages ​ Opioid dependence creates addiction vulnerability ○​ Drug dependence - the highs get lower as you take more opioids ○​ Withdrawal - anxiety, panic attacks, dysphoria​ ​ Learned association between taking opioids and relieving withdrawal symptoms  ○​ Life stressor - environmental stressors can trigger drug usage ○​ Relapse - the memory that opioids can relieve anxiety and dysphoria triggers craving ​ Susceptibility to drug addiction is individual, involving genetics and environmental factors ○​ There is a genetic contribution to SUD, but the assessment is complex ​ Genetic makeup is specific for specific drugs ○​ Environmental triggers can affect susceptibility for selective genotypes ​ Environment is more critical than genetic makeup ○​ Should analyze endophenotypes (response inhibition, impulsivity, stress adaptations, mood regulation, trauma coping, etc.) ○​ Cannot generalize addictions, because individuals have different perceptions of rewarding and aversive stimuli ​ Brain stimulation ○​ Can be very powerful and motivating in certain brain regions ​ Stimulated robo rat’s brain to make the rat do stuff ○​ Jim Olds’ experiment - rats will do anything, even avoid natural rewards, to get stimulation ○​ Results in “pleasure” in the septal area, nucleus accumbens (NAc), and ventral tegmental area (VTA) ​ VTA has the highest concentrations of DA neurons, which project to NAc ​ Increase in dopamine release to NAc when rats engaged in VTA stimulation ○​ DA agonists and antagonists have opposite effects on brain self-stimulation ○​ Intracranial self-stimulation (ICSS) or deep brain stimulation (DBS) as potential therapeutics for Parkinson’s, OCD, epilepsy, and more ​ Evidence for dopamine involvement in reward ○​ ICSS data ○​ Addictive drugs increase synaptic dopamine in the NAc ○​ The rewarding actions of many drugs and natural rewards are abolished by disruption of the DA system ​ Substantia nigra compacta (SNc) DA neuron ○​ Unusual type with branching axonal arbors ○​ Wimpy dendritic fibres are not as extensive as other neurons ​ Inhibitory opioids induce DA release via disinhibition  ○​ Opioids bind to receptors on GABAergic interneurons in the VTA → reduces the release of inhibitory GABA → removes inhibition from DA neurons, allowing them to fire ​ DA cells are not only linked to rewards ○​ DA release occurs with aversive stimuli, too ○​ DA cells eventually fail to respond to rewards but respond to novel stimuli and unexpected outcomes ○​ DA release not always required for reward ○​ DA important for learning ​ Wanting and liking are different circuits ​ Once habit systems take over during SUDs, prefrontal control is lost ○​ Addiction: goal directed → habit pathway ​ Functional connectivity ○​ Default mode network - activates when not performing a task ○​ Salience network - switching between the default mode network and the central executive network ​ Activated after a drug is taken intravenously but not when that same drug is taken orally ○​ Central executive network - engages your conscious brain to think and maintains attention on a prioritized task ​ Positive reinforcement ○​ First stage of the addiction cycle - binge/intoxication ○​ Reinforcing effects of drugs may engage reward NTs, such as DA and opioid peptides ○​ Involves the NAc, dorsal striatum, VTA, SNc, ventral globus pallidus (VGP), and dorsal globus pallidus (DGP) ​ Negative reinforcement ○​ A major motivation for drug taking ○​ Second and third stages of the addiction cycle ○​ Withdrawal/negative affect involves the extended amygdala ○​ Preoccupation/anticipation (craving) involves the basolateral amygdala (BLA), hippocampus, PFC, orbital and anterior cingulate cortices, and ventral striatum ○​ The circuitry driving dysphoric states and craving may be as significant for addiction as those driving reward ​ Much of the brain is involved in addiction  ○​ Mesolimbic DA neurons are critical and early responses but comprise just one element of complex interactive circuitry that is involved ​ Different drugs may engage the circuitry in different ways ○​ Ex: opioids may be more effective in triggering the withdrawal dysphoric circuitry than THC ​ The motivational circuitry driving reward and aversion overlap and are not completely understood Group One Presentation - Opiates ​ Opiates have taken many forms throughout history for recreational uses ​ Pro-drugs (codeine and heroin) are inactive until metabolized into morphine ​ Opiates provide temporary relief while causing dependence and brain changes, driving addiction ​ MOR, DOR, and KOR are G-protein coupled receptors (GPCRs) present through the brain and gut ​ Effects ○​ During: euphoria, analgesia, false sense of well-being, lethargy, relaxation ○​ After: anxiety, sadness, irritability, mental clouding ○​ Acute: reduced inhibitory inputs, enhanced DA activity in analgesia circuits ○​ Chronic ​ GPCR internalization or downregulation → tolerance ​ Increased DA neuron activity in disrupted VTA-NAc DA pathway ( drives reward-seeking behavior) ​ Heroin use can damage white matter in the brain ​ Brain craves the drug to feel norml or experience pleasure ○​ Decreased NA levels lead to overcompensation and a “new” homeostasis ○​ Heightened impulsivity and riskier decision-making ​ Krokodil derives from codeine ​ Kratom has strong affinity for MOR ​ Morphine mimics endogenous opioids, binding to the MOR to alter neural activity ​ Opioid agonist binds → decrease in GABA release → disinhibition of DA neurons in VTA → increased DA release ​ Absorption usually in the GI tract  ​ Bioavailability - the quantity of the drug that reaches the systemic circulation of the patient and is able to exert the desired action ​ Potency - the amount of drug required to produce a specific effect of a given magnitude ​ Half-life - time it takes to excrete half of the drug’s active component out of the system ​ MORs are abundant in the CNS, neuroendocrine tissue, ectodermal cells, immune cells, and GI tract ○​ Side effects outside of CNS: respiratory depression, decreased tone in veins, decreased peristalsis, urinary retention, nausea and vomiting ​ Continuous upward swing in usage of opioids ​ Decline in 21st century of plant-derived opioids in favor of synthetic alternatives GPCR Pharmacology Opioids (Chris) ​ Drugs of abuse that directly interact with GPCRs ○​ Opioids (morphine, heroin, fentanyl, salvinorin A) ○​ Cannabinoids (marijuana, spice) ○​ Hallucinogens (LSD, mescaline, ibogaine, salvinorin A) ○​ Gamma hydroxybutyrate (GHB) (date-rape drug interacting with GABAB receptors) ○​ Tranq ​ Drugs of abuse that indirectly interact with GPCRs by increasing synaptic DA, norepinephrine, and serotonin ○​ Cocaine ○​ Amphetamine ○​ MDMA (ecstasy) ​ GPCRs ○​ Signal via a large family of heterotrimeric G-proteins (ɑ, β, and Ɣ subunits) regulated by GTP binding to the ɑ subunit and GTP hydrolysis ​ Active state is GTP-bound ○​ Examples ​ Adrenergic receptors (tranq) ​ Serotonin receptors (MDMA, LSD) ​ DA receptors (cocaine) ​ Opioid receptors (heroin) ​ Acetyl choline receptors (muscarininc) ○​ Span the membrane 7 times (N-terminus on the outside, C-terminus on the inside) ​ Regulators of cannabinoid CB1 receptors ○​ Orthosteric site - primary binding site ○​ Allosteric site (PAM and NAM) ​ Potency vs efficacy ○​ Potency - amount of drug required for an effect (dose, concentration) ○​ Efficacy - the maximum drug effect ​ GPCR ligands ○​ (Full) agonists ​ Fully activate the receptor ​ Fentanyl - epidural, anesthesia companion ​ Morphine - surgery ​ Methadone - long lasting opioid used in maintenance therapy to treat addiction ​ Oxy/hydrocodone - pain ​ Loperamide - diarrhea relief ○​ Neutral antagonists ​ Block agonist activation of receptor ​ Naloxone/Narcan ​ Taken IV or intranasal ​ Short acting ​ Used for opioid overdose ​ Naltrexone/ReVia/Vivitrol ​ Taken orally or IM injection ​ Longer lasting (long half life) ​ Used for opioid and alcohol use disorders ○​ Partial agonists ​ Partially activate the receptor ​ Mitragynine in kratom (MOR) ​ Buprenorphine - maintenance ○​ Indirect agonists ​ Increase endogenous receptor ligands ○​ Positive allosteric modulators (PAMs) ​ Enhance agonist activation of receptor ○​ Negative allosteric modulators (NAMs) ​ Attenuate agonist activation of receptor  ○​ Inverse agonists ​ Block constitutive activity of receptor ​ Naloxone/Narcane ​ Naltrexone/ReVia/Vivitrol ​ Production pathways ○​ Opiates: dopamine → thebaine → codeine → morphine (demethylated codeine) → heroin ○​ Opioid receptors: opioid protein precursors → endorphins and enkephalins (small peptides) → δ, μ, and 𝛋 opioid receptors (each mediate different behavioral effects) ​ Mu - most important in opioids ​ Agonists: analgesia, reward, antitussive, respiratory depression, constipation, nausea ​ Antagonists: aversive, prevent reward, block overdose ​ More rewarding side effects ​ Give rewarding dose of THC → rewarding effect ○​ KO MOR → give rewarding dose of THC → aversive effect ​ Kappa ​ Agonists: aversive, hallucinogenic, anxiogenic ​ Antagonists: potential antidepressants or anxyoltics ​ More aversive ​ Opioid receptors are Gi/Go coupled and inhibit neuronal firing → reduced NT release ○​ Inhibit calcium channels → inhibit presynaptic firing ○​ Activate potassium channels to cause hyperpolarization ○​ Inhibit adenylate cyclase → attenuates cAMP synthesis ​ Routes of Administration ○​ Smoking opium or heroin ​ Immediate effect ○​ Kraton (tea but can be vaped, smoked, or snorted) ​ Takes a long time to work ○​ IV injecting heroin, fentanyl, or buprenorphine ○​ Intransal morphine has fast onset ○​ Orally taken morphine is slow to work ​ Knockout (KO) opioid receptors in mice → lose morphine effects ○​ Mu receptor involved in circuitry for other drugs, too ​ Motivational effects of cannabinoids are mediated by MORs and KORs  ○​ Evidence of interaction between opioid and cannabinoid systems ○​ KO MORs → lose rewarding effects of THC but does not affect aversiveness ​ Mu circuitry is involved in rewarding effects of THC ○​ KO KORs → lose aversive effects of THC ​ Kappa circuitry is involved in aversive effects of THC ​ Deficit in attachment behavior in mice lacking the MOR gene ○​ Put pups in environment without mother’s smell → distress calls ​ KO MORs → pups no longer distressed ○​ MORs are important in bonding ​ Pain ○​ Drugs can target opioid receptors in many parts of the pain processing pathway, including the descending modulatory pathway ○​ Mu-agonists, injected in specific regions of the CNS and spinal cord, produce antinociception ​ Effects of acute use ○​ Analgesic, euphoric, anxiolytic, antidepressant, constipating, respiratory depression (opioids can target MORS in the ventral respiratory column’s preBotzinger complex to stop breathing) ​ Adaptations or compensatory changes ○​ Spiraling hedonic tone - reduced appreciation of natural rewards (ex: food) ○​ Causes of opioid tolerance ​ Opponent processes: adaptive responses at molecular/cellular level ​ E.g. cyclase supersensitivity after opiates ○​ Take away opiates → cAMP levels go off the roof ​ Hyperalgesia in methadone maintained patients (cold pressor test) ​ Dysphoria during abstinence ​ Opioid withdrawal symptoms are predominantly opposite of the acute actions ​ Diarrhea ​ Anxiety ​ Low mood ​ Receptor desensitization (receptors do not work as well) ​ Or receptor internalization (lose receptors from cells) ​ Upregulation of enzymes metabolizing the drug (alcohol) ​ Some adaptations remain after physical withdrawal  ○​ Ex: decreased D2 receptors in striatum, metabolic changes, cue-activated limbic system, dendritic spines in striatum/cortex (affects memory), dleep changes ○​ Different adaptations recover at different times ​ Some will be there forever, such as the memory of what the drug does Opioids (Cathy) ​ Opioids remain the best analgesic drugs to treat acute and chronic pain ○​ Alleviate the sensory and affective components of pain ○​ Risks associated with opioid misuse in chronic pain patients ​ High catastrophizing scores associated with craving ​ Distress intolerance ​ Neuro-inflammation → depression ○​ Should never be prescribed for mild pain ○​ No better alternative, because developments focus on the sensory aspect of pain ○​ Prescription opioids - oxycodone, hydrocodone, morphine, methadone ​ Methadone  ​ Longer half life than morphine (slowly binds to proteins in tissues) ​ Greater oral efficacy than morphine ​ Similar CNS effects as morphine ​ Commonly used to treat OUD, as it suppresses withdrawal symptoms ​ NMDA receptor antagonist - treats neuropathic pain ○​ Fentanyl ​ Potent synthetic opioid ​ Approved for treating severe pain ​ Rise of its illegal distribution ​ Commonly used as an anaesthetic ​ Used in transdermal patches or buccal formulations ​ Lower oral bioavailability ○​ Heroin ​ Illegal in the U.S. ​ Antidepressants ​ Meperidine ○​ May be a better option than morphine due to less constipation and neonatal respiratory depression during labor ○​ Inhibits P-glycoprotein, which is involved in cancer multidrug resistance ○​ Inhibits NMDA receptors to allow chemotherapy drugs to enter the brain ​ Potentially useful for treating glioblastomas ○​ Rarely prescribed for pain due to the build up of the toxic metabolite, normeperidine, which causes CNS excitation ​ Codeine ○​ Analgesic and antitussive ○​ Higher oral bioavailability than morphine ○​ Converted to morphine via CYP2D6 ​ Polymorphisms affect drug metabolism ​ Pharmacological effects and therapeutic uses ○​ Constipation → treating diarrhea ○​ Cough suppression ○​ Analgesia ○​ Sedation → anesthesia ​ Adverse effects: truncal rigidity, respiratory depression, increased sensitivity to pain ​ OUD and opioid misuse is associated with duration of treatment and daily dose  ○​ CDC opioid guidelines ​ Prescribe immediate-release opioids (minimize days of opioid use) ​ Prescribe the lowest effective dosage ​ Assess benefits vs risks ​ Medications for opioid overdose, withdrawal, and addiction ○​ Methadone (schedule II) ​ Opioid receptor agonist (long acting activation of opioid receptor) ​ Benefits: prevents withdrawal, reduces craving, reduces euphoria of other opioid use ​ Risk: possible overdose, misuse, hyperalgesia ○​ Buprenorphine (schedule III) ​ Opioid receptor partial agonist (partial activation, partial blockade) ​ Benefits: reduces craving, daily oral or long lasting implant, can be combined with naloxone to prevent misuse ​ Risks: may induce withdrawal, street value due to withdrawal aid ○​ Naltrexone (prescription) ​ Opioid receptor antagonist (no activation, blocks opioids) ​ Limitation: requires complete withdrawal from opioids or would precipitate withdrawal ​ Benefits: prevents opioid intoxication, no addiction potential ​ Risk: can change tolerance for future opioid overdose ○​ Lofexidine ​ Adrenergic receptor agonist ​ Helps alleviate withdrawal symptoms ​ Overactivity of noradrenergic system during withdrawal, because it was suppressed during opioid usage ○​ Naloxone ​ Opioid receptor antagonist ​ Prevents euphoric highs of opioids and reduces cravings ​ Reverses dangerous drug effects such as slowing or stopping breathing ​ Environmental stressors are triggers for opioid addictive behaviors ​ Scales to assess OUD ○​ Clinical opiate withdrawal scale (COWS) ​ Clinician-administered gold standard for assessing withdrawal severity ○​ Subjective opiate withdrawal scale (SOWS)  ​ Self-administered scale for grading opioid withdrawal symptoms ​ For physicians prescribing opioids ○​ Opioid risk tool (ORT) ​ Identifies individuals at high risk for opioid abuse ○​ Screener and Opioid Assessment for Patient in Pain (SOAPP-R) ​ More comprehensive evaluation of more factors related to opiod use ​ Opioid withdrawal syndrome ○​ Key determinant of continued opioid use ○​ Difficult to differentiate chronic pain from withdrawal pain ○​ Use a taper slow enough to minimize withdrawal symptoms ○​ Prolonged use leads to activation of opponent processes ​ Tolerance - pain relieving effects of medication decrease over time, so you need to take more ○​ Increase in potency ○​ Extent ​ High - analgesia, euphoria, sedation ​ Moderate - bradycardia ​ Minimal or none - miosis, constipation ○​ Mechanisms ​ Receptor desensitization - receptor phosphorylation by G protein-coupled receptor kinases (GRKs) and uncoupling of G-proteins ​ Receptor down-regulation ​ Opponent processes ​ How opioids are different than other medications ○​ Changes in regimen cannot be done quickly ○​ Used across various practice specialties ○​ No maximum daily dose ○​ Opioid induced hyperalgesia = ongoing or worsening pain ​ Deadly epidemic - increasing drug overdose deaths ○​ Significant disparities (all drugs) ​ Black men had the highest death rate from drug overdoses ​ Terminology ○​ Opioid - all compounds that act on opioid receptors ○​ Opiate - drugs derived from opium (including morphine and codeine) ○​ Narcotic - substances of abuse in the legal context Group Two Presentation - Opioids ​ Key factors of opioid crisis deaths: overprescription, misuse, and illicit synthetic opioids ​ Primarily bind to the MOR → reduce NT release → hyperpolarize cell → analgesia ​ Associated synthetic opioid drugs and pharmacokinetics ○​ Oxycodone ​ More potent than hydrocodone ​ Moderate MOR affinity in CNS ○​ Hydrocodone ​ Oxidized form of oxycodone ​ Moderate MOR affinity in CNS ○​ Meperidine (Demerol) ​ Neurotoxic primary metabolite, normeperidine, that increases seizure risk ​ Not given as much anymore ​ Inhibits NMDA receptors ​ Can help with cancer ​ More efficacious than morphine ○​ Fentanyl ​ Surgical anesthesia ​ High potency → main agent driving the opioid epidemic ○​ Loperamide ​ Selective OTC MOR agonist used to treat diarrhea ​ Unique high MOR affinity in the GI tract ​ Minimal MOR affinity in the CNS (prevented from entering the brain by P-glycoprotein) ​ Have to take a larger dose to feel its effect ​ Self-treatment for opioid withdrawal ​ Used in chemotherapy ○​ Buprenorphine ​ Treats pain and OUD ​ Partial agonist ​ Long half life - makes withdrawal comedown much milder than fentanyl ○​ Methadone ​ Used in medication-assisted treatment (MAT) for OUD ​ Long half life ​ Antagonist of NMDA receptors  ○​ Naltrexone ​ MOR antagonist ​ Long acting for relapse prevention in rehabilitation ​ Have to be clean of opioids before you use it ○​ Naloxone ​ Rapidly reverses effects of opioid overdoses as a life saving medication ​ MOR antagonist ​ Short acting - often need repeated doses ​ Natural opioids ○​ Morphine ​ Gold standard opioid ​ Low lipophilicity (takes longer to cross the BBB and enter the system) ​ Minorities are overrepresented in the overall overdose death rate ​ Increasing U.S. overdose deaths involving prescription opioids in combination with synthetic opioids ​ Opioid receptors (DOR, MOR, and KOR) ○​ Endogenous ligand: enkephalin, endorphin, dynorphin ○​ Couple with Gi proteins ○​ Most commonly used opioid analgesics bind to more than one receptor but preferentially to MOR ​ Physiological effects and toxicity (receptors widely distributed throughout the body) ○​ CNS ​ Disinhibition of DA release in reward pathway ​ Analgesia, euphoria, respiratory depression, sedation ○​ PNS ​ Smooth muscle, skin, GI, cardiovascular, and immune system effects Transporters I (Eydie) ​ Transporters bind drugs that regulate the ability of NTs to reach their targets → behavioral effects ​ Monoamine uptake is a key factor in intensity and duration of monoamine signaling ​ Members of the soluble carrier superfamily with 12 transmembrane ɑ-helical domains Plasma Membrane VMATs Transporters Family SCL6 SCL18 (similar structure as SCL6) Subtypes DAT, NET, SERT VMAT1, VMAT2 (CNS, all monoaminergic cells) Distribution Presynaptic and extrasynaptic Synaptic vesicles of presynaptic membrane of axon terminals terminals in all and dendrites monoaminergic cells (primarily works on the CNS) Driving Force -​ Na+ gradient across -​ Proton electrochemical plasma membrane (Na+ gradient across pump maintains a vesicular membrane higher concentration (ATPase maintains of Na+ outside the cell) higher concentration -​ Symporter mechanism: of protons inside the Na+ and NT go in same vesicle) direction into the cell -​ Antiporter mechanism couples the flow of protons out of the vesicle with the pumping of NTs into the vesicle Functions Reuptake - monoamine Storage of monoamines into removal from synaptic and synaptic vesicles, extrasynaptic space → neuroprotection: preventing terminate NT action, cytosolic DA accumulation replenishment of monoamines which can lead to oxidative for vesicular storage stress ​ DAT maintains DA homeostasis ○​ DAT brings DA back into cell so it can regulate activity of tyrosine hydroxylase (TH) ​ TH - rate limiting enzyme for DA synthesis ​ DAT KO → too much DA outside the cell and too little inside → decreased DA release in response to stimuli ​ Effects of MA transporter KO mutations in mice ○​ DAT KO → hyperactivity, stereotypy, insensitivity to cocaine ○​ NET KO → reduced locomotion, stress resistance, reduced seizure susceptibility ○​ SERT KO → anxiety-like syndrome​  ○​ VMAT2 KO → sensitivity to cocaine’s stimulant effects, vulnerability to neurotoxic effects of MPTP in DA neurons of SNC ​ Terminating NT action ○​ DA, NE, 5-HT → reuptake to presynaptic neuron by transporters ○​ Acetylcholine → degradation by cholinesterase, choline reuptake ○​ GABA → reuptake into neurons and glia (astrocytes) by GABA:Na+ symporters ○​ Glutamate → uptake into neurons and astrocytes ​ Medications acting on monoamine transporters include treatments for: ○​ ADHD → methylphenidate (Ritalin) blocks DA, NE reuptake ○​ Narcolepsy → modafinil blocks DA reuptake ○​ Depression, anxiety, epilepsy → SSRIs such as fluoxetine (Prozac) block 5-HT reuptake ​ Not abused, since they take a long time to work (no instant reward signal) ​ Drugs that block DAT → buildup of extracellular DA ○​ Cocaine (schedule II) ​ Much quicker action, especially if smoked ○​ Methylphenidate/Ritalin/Concerta (schedule II) ​ Lower abuse potential than amphetamines but does not work as well ○​ Bupropion (not a controlled substance) ○​ Amphetamine ​ Works better but is more abused, because it is an efflux agent ​ Efflux agents (methamphetamine, amphetamine, cathinone, MDMA) act at both plasma membrane and vesicular transporters, VMAT2 ○​ Block DAT by activating TAAR1 → NT stays in synapse ○​ Drugs bind to vesicle transporters, causing release of NT from the vesicle into cytosol ​ Increased cytosolic amine may increase efflux at the plasma membrane → even more NT in synapse ​ Psychostimulant drugs of abuse - amphetamine, methylphenidate, modafinil, cocaine, methamphetamine, MDMA ○​ Inhibit or reverse transport at DAT, NET, SERT, and produce internalization of transporters ○​ Indirect agonists (do not act directly at the receptor)  ○​ Block reuptake or promote efflux ○​ Effects on brain and behavior ​ Short term: euphoria, reward, intoxication, increased arousal ​ Long term: addiction, withdrawal, dysphoria ​ Cocaine and meth withdrawal is not as physiological as opioid withdrawal ​ Neurodegeneration ○​ METH ​ More lipophilic → gets into brain faster ​ Effects ​ Mitochondrial impairment ​ Oxidative stress - increased production of highly reactive free radicals from DA released into cytosol and synapse ​ Activation of astrocytes and microglia that lead to inflammation → sleep problems, depression, neurotoxicity ​ Loss of DAT and recovery with long-term abstinence from METH ○​ Chronic MDMA use → reduced binding to 5HTT Transporters II (Edyie) ​ Trends ○​ Increasing overdose deaths due to stimulants in the U.S. ○​ Increasing use of fentanyl with stimulants ​ Transporter blockers Cocaine Methylphenidate Bupropion Atomoxetine (MPH) Stimulant? yes yes yes no Medical ENT surgery, ADHD, narcolepsy Depression, ADHD Uses nosebleeds, smoking cessation anesthetic eye drops Trade Neurocaine, Ritalin, Concerta Wellbutrin, Xyban Strattera names Numbrino Scheduling II II Not scheduled Not scheduled Transporter DAT, NET, SERT DAT, NET DAT NET target Effects Rapid peak in Increased alertness plasma level (within and concentration minutes), reduced (people abuse it to brain activity, increase productivity) decreased glucose metabolism due to DAT blockade - correlation with negative affect ​ Why MPH has less abuse potential than amphetamine ○​ Amphetamine produces a great effect with a lose dose ○​ Amphetamine affects both the plasma transporter and VMAT2 ○​ Amphetaime has a faster onset of action (MPH has slow time course) ​ Adderall reaches its peak sooner than Concerta ○​ Amphetamine formulations - smoother plasma concentration over time ​ PET scanning to study DA dynamics ○​ MPH blocks DAT, increasing extracellular DA, which competes with [11C]raclopride to show less D2 binding of the tracer ○​ Ɑ-methylparatyrosine (AMPT) inhibits TH and reduces DA production → less extracellular DA to compete with [11C]raclopride → PET scan shows more D2 binding ○​ Cocaine increases extracellular DA → decreases [11C]raclopride binding in putamen (brain region with highest concentration of DA receptors) ​ More information from fMRI, which measures increased cerebral blood flow and oxygen with neuronal activity ○​ Evaluate resting-state functional connectivity ​ Cocaine reduces global brain connectivity ​ Efflux Agents *all stimulants Amphetamine, Lisdexamfetamine Phenterine dextroamphetamine Medical Uses ADHD, narcolepsy, ADHD obesity obesity Trade Names Adderall, Adzenys, Vivance, Elvance Adipex-P, Lomaira  Dyanavel Scheduling II II IV Target DAT, NET, VMAT2 Inactive prodrug that NET, VMAT2 turns into dextroamphetamine ​ Stimulant use disorder ○​ Diagnosis in DSM-5: clinically significant impairment or distress manifested by at least two symptoms (amount of use, craving, social problems, etc.) over a year ○​ Use of stimulant drugs including cocaine and amphetamines but not caffeine or nicotine ​ Effects of stimulants ○​ Acute ​ CNS: intoxication, rapid speech, behavioral/psychiatric symptoms, seizure ​ Outside CNS: hypertension, cardiac arrhythmia, vasoconstriction, platelet inhibition (associated with stroke), hyperthermia, respiratory distress) ​ Misdiagnosis → long-term antipsychotic medication ○​ Chronic ​ Structural brain changes ​ Grey-matter deficits in methamphetamine use ○​ Can induce or worsen cognitive deficits ○​ Cocaine or amphetamine withdrawal ​ Not as obvious as opioid withdrawal ​ Tired, miserable, combative, craving ​ Timing ○​ Speed of onset of action ​ Major determinant of abuse potential ○​ Duration of action ​ Short for cocaine, long for methamphetamine Group Three Presentation - Stimulants ​ Similar mechanisms of cocaine and amphetamines → stimulating effect on the brain and body (alert, awake, euphoric), chronic and acute health risks ○​ Very addictive Amphetamines Both Cocaine Disrupt storage of Block reuptake of DA, NE, and Does not inhibit VMAT or monoamines by inhibiting 5-HT → buildup of MAO VMAT2 protein → higher monoamines, particularly DA levels in cytoplasm → more and NE, in synaptic cleft DA released → higher highs Cause monoamine transport protein to run in reverse Inhibit monoamine oxidase B (MAO-B), preventing breakdown of monoamines ​ Stimulants have existed for centuries but started becoming tightly controlled and criminalized in the 70s ​ The different ways stimulants are taken affect their addictiveness and media portrayal ​ Treatment options for stimulant use disorder are not easy ​ Schedule II: high potential for abuse → severe psychological or physical dependence ○​ Dextroamphetamine in Adderall ○​ Methylphenidate ○​ Cocaine (powder and crack) ​ Crack has higher highs ​ Potent and illegal ○​ Crystal meth ○​ Methamphetamine ​ Potent and illegal ​ Effects - cocaine and amphetamines work similarly ○​ While using → euphoria, increased energy, increased blood pressure ○​ Comedown → opponent processes, damage to systems, dependency ○​ Withdrawal → depressive episodes, insomnia, chills ​ Uses ○​ Legitimate ​ Amphetamines are prescribed for ADHD and narcolepsy  ​ Cocaine is rarely medically used as an anaesthetic ​ Sometimes in eye drops to diagnose Horner’s Syndrome ○​ Illegitimate uses ​ People abuse ADHD meds to try to boost cognitive performance ​ The euphoria from cocaine makes it a popular party drug ​ People may turn to meth or cocaine to cope Amphetamine Methamphetamine Methylphenidate Cocaine salts Synaptic increase DA, NE, 5-HT in: Targets DA, NET, 5-HTT, VMAT-2, MAO DAT, NET, 5-HTT Half-life longest shortest Common routes Oral, smoking Oral, smoking, Oral Oral, of injecting smoking, administration snorting, injecting ​ Route of administration matters Smoking Snorting and swallowing Injecting -​ Pyrolysis of stimulant -​ Accidental digestion of -​ Dilution of stimulant -​ Damage to lungs stimulant in blood -​ Crack is more -​ Damage to nostrils -​ Risks from dirty criminalized than -​ Longer half life needles cocaine powder -​ Damage to skin and -​ More severe high and veins withdrawal -​ Higher duration of -​ Higher speed of onset effect and comedown -​ Greater acute health -​ Higher addictive risk potential -​ Higher bioavailbility -​ Higher magnitude of -​ Higher risk from effect adulterants -​ Difficult to tell what concentration and amount you are taking  ​ Trends ○​ Commonly co-used ○​ Cocaine use commonly associated with psychological distress ○​ Marijuana, tobacco, and alcohol SUDs co-occur with cocaine use ​ Meth users show similar trends ○​ Prescription stimulants are abused but not as destructive of people’s lives ○​ High relapse rates ○​ Increase in deaths from cocaine during COVID (correlated with social isolation) ​ Stimulant abuse disorders can be overcome ○​ No major maintenance medicine or FDA approved medication ○​ Cognitive behavioral therapy ○​ Vaccines in trial Group Four Presentation - Party Drugs ​ MDMA, cathinone, and synthetic cathinones are entactogens that enhance emotional connection and social bonding ​ Drug synthesizers alter the chemistry of illegal drugs to create “legal” substances, undetected by rapid drug-screening tools ​ Khat ○​ Contains cathinone, a naturally occurring stimulant that acts as a DAT substrate, inducing DA release ○​ Inhibits reuptake transporters and MAO ○​ Metabolism in the liver ○​ Cathine is an active metabolite of cathinone ○​ Effects and toxicity (affects nearly all organ systems) ​ Desired: cheerfulness, optimism, alertness ​ Adverse: delusions, liver failure, arrhythmias ​ Bath salts ○​ Synthetic cathinones (designer drugs) ○​ Routes of administration: sniff or snort, oral, smoke, inject as a solution ○​ Relatively new rise in abuse ○​ Not all are bad - bupropion is an anti-depressant ○​ Undetected on drug screening tools - “legal high” ○​ Cheap - appealing alternative to cocaine and amphetamines ○​ MDPV (derived from cathinone) has greater potency than cocaine  ○​ Effects and toxicity ​ Desired: euphoria, concentration, entactogen ​ Adverse: psychosis, aggression, self-harm ​ MDMA (ecstasy) ○​ Schedule I ○​ Routes of administration: swallowing, snorting, occasionally smoking ○​ Most users are ages 18-25 ​ Enhanced energy and dancing, availability, peer influence ○​ Pharmacokinetics ​ Metabolism mainly in liver ​ Active metabolite: MDA ​ Close chemical analog: MDEA ○​ Indirect monoaminergic agonist ○​ Primarily a substrate for the SERT, inhibiting reuptake and causing a flood of 5-HT to be released into the synaptic cleft ○​ Effects and toxicity ​ Desired: euphoria, energy, emotional closeness  ​ Mild: muscle tension, jaw clenching, restlessness ​ Severe: acute liver failure, serotonin syndrome, high HR (noradrenaline) ​ Serotonin syndrome due to excess 5-HT ○​ Reasons for occurrence: mixing drugs, MDMA overdose, SSRIs, MAO inhibitors ○​ Ways to treat (can be fatal otherwise): physical cooling, muscle relaxers, intubation, 5-HT blocking drugs ○​ MDMA is being studied for its potential to treat PTSD ○​ Popular in nightclubs and dance clubs Hallucinogens ​ Psychedelics ○​ Ergots: lysergic acid diethylamide (LSD, or “acid”) ​ Numbness → distortion of sensory perception → hallucinations → fatigue ○​ Indolealkylamines: psilocybin (“shrooms”), bufotenin (toad skin venom), dimethyltryptamine (DMT) ​ DMT ​ Fast high ​ Usually vaporized or smoked ​ Exists naturally in the rat brain with receptors for it ​ Made from tryptophan (AA) ​ Broken down by MAO ​ Active chemical in ayahusca ○​ Phenylethylamines: mescaline (the active ingredient in peyote) ○​ Dissociatives or others: ketamine ​ Evidence for serotonin association to LSD hallucinogenic activity ○​ Structural similarity to 5HT ○​ Classical hallucinogens partial agonists at many 5-HT receptors ○​ LSD raises brain levels of 5-HT and lowers those of its metabolite (decreases turnover of 5-HT) ○​ Profound tolerance and cross-tolerance to behavioral effects ​ Giving LSD to elders a second day in a row did not work or required a high dose ​ Mouse head twitches in response to drug but decreases in intensity with more days of exposure  ​ Tolerance is accompanied by downregulation of 5-HT2 binding sites but not other 5-HT receptors ○​ In humans, the effects of psilocybin can be blocked by a 5-HT2A-selective antagonist ○​ Caveats ​ LSD is very potent yet is a low affinity weak partial agonist at 5-HT-2A receptors ​ Drug discrimination - several non-hallucinogens that are 5-HT-2A are LSD-like in this model, such as quipazine and lisuride, while psilocybin is not ​ Transcriptome fingerprints distinguish hallucinogenic and non-hallucinogenic 5-HT-2A receptor agonist affects in mouse somatosensory cortex ○​ Block 5-HT-2A receptors to block hallucinations and mouse head twitches in hallucinogenic agonists (DOI and LSD) ​ Mechanism of action is still murky - biased agonist, heterodimers, …? ○​ Head-twitch behavior induced by hallucinogens is absent in 5-HT2A KO mice ○​ Head-twitch response induced by the psychedelics only slightly reduced in Gɑq KO mice ​ Questions the Gɑq-coupled 5-HT2A pathway ○​ Head twitches for 5HT but not DOI requires arrestin 2 ​ Different signaling requirements for different drugs to induce hallucinations ○​ Dimerization with metabotropic glutamate receptors ​ Antagonist suppresses the head-twitch behavior induced by DOI ○​ Psychedelics promote plasticity by directly binding to BDNF receptor TrkB ​ Where in the brain do psychedelics work? ○​ Emx1 transgene drives Cre in cortical but not thalamic Raphe neurons ​ Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior ​ Ibogaine ○​ Dirty drug - binds to numerous CNS targets at the micromolar range (nicotinic acetylcholine receptors, NMDA, kappa and mu opioid, 5HT2A and 5HT3 receptors, DA and 5HT transporters)  ○​ Tested as a therapy to cure drug craving ○​ Can be deadly with significant cardiac effects ○​ Other side effects: nausea and vomiting, ataxia, hallucinations ​ Psychedelics promote structural and functional neural plasticity by increasing the number of dendritic spines ​ Therapeutic potential ○​ Psychedelics reopen the social reward learning critical period ○​ Could help patients who have not improved from standard treatments ○​ Could help treat SUDs, OCD, depression, PTSD ○​ Can increase neuroplasticity to change patterns and break cycles of anxiety and depression ○​ Psychedelic assisted psychotherapy ​ Oral pill or injection (consistent dosages, unlike smoking) ​ SSRIs or MAO inhibitors decrease responses to hallucinogens ○​ MAO inhibitors will increase the acute activity of some drugs such as DMT ○​ Tricyclic antidepressants (NE uptake inhibitors) increase subjective response to hallucinogens ​ Hallucinogen persisting perception disorder (HPPD) ○​ Flashbacks of on-drug hallucinations due to heavy LSD use ○​ SSRI-induced flashbacks in prior LSD users ○​ Treated with benzodiazepines, alpha2 adrenergic agonists, and sometimes naltrexone ​ Hallucinogens have low addictive potential, but they change your brain ○​ Altered reality may become a desired state Group Five Presentation - Psychedelics ​ Because of their more mild physiological effects, psychedelics have lower addictive potential ​ Psychological effects include changes in sensory processing and cognitive functions ○​ Can have a long lasting effect on emotions ○​ CNS ​ Visual and auditory hallucinations ​ Altered sense of time and space ​ Enhanced sensory perception ○​ PNS ​ Tachycardia ​ Nausea and vomiting  ​ Increased body temperature ​ Many studies show promising results for the therapeutic potential of psychedelics in treating conditions such as PTSD, depression, and anxiety ​ Psychedelics originated in indigenous cultures and are widely used in their rituals ​ Psychedelics are 5-HT2A receptor agonists, which enhance glutamatergic transmission in the prefrontal cortex through Gq/11 signaling ○​ 5-HT2A receptors ​ GPCR primarily found in prefrontal cortex ​ Enhances glutamate release ​ Downregulates inflammatory cytokines ​ Increases DA in ventral striatum ​ Agonist trafficking of receptor signaling theory ​ Downstream effects of 5-HT2A from psychedelic drugs are different than non psychedelic drugs ​ Ayahuasca’s components ○​ DMT ​ Endogenously produced ​ A serotonergic psychedelic that is similar to psilocin and LSD ​ Mainly binds 5-HT2A ​ Not an effective ligand of DA receptors but could affect DA signaling through Sigma-1 binding ○​ β-carbolines ​ Selectively and reversibly inhibit MAO-A ​ Inhibits the main DMT metabolic pathway → allows for DMT to be orally active ​ Alkaline phosphatases and esterases dephosphorylate psilocybin to psilocin ○​ Unlike DMT, psilocybin must be chemically altered before becoming psychoactive ○​ Two mechanisms on the serotonergic system ​ 5-HT2A agonism ​ Inhibition of the SERT → decreased 5-HT reuptake → more 5-HT in synaptic cleft → increases in serotonergic neurotransmission ​ Very limited toxicity ○​ Physiological effects are mild and temporary compared to cognitive effects Drug class Characteristics Unique aspects Metabolism Psilocin Tryptamine (most -​ Strong partial Therapeutic for PTSD, Psilocybin (prodrug) (shrooms) similar to agonist for anxiety, depression → psilocin serotonin, so they 5-HT2A Bufotenine primarily activate activation -​ Greater Bufotenine → the serotonin -​ Low to moderate somatic effect 5HIAA pathways) arousal state -​ Hydrophilic -​ Inward-focused -​ Short half life emotions DMT purging Ayahuasca → DMT (ayahuasca) → IAA Mescaline Phenylethylamine -​ Full agonist for Grounded feelings Peyote → mescaline (peyote) (more similar to 5-HT2C activation with spitiual insights DA) (mood and N-bomb -​ Very Varies and not (synthetic) impulse control, dangerous - known very well; DA regulation) highest risk of LSD → -​ Activate 5-HT, overdose (very 2-oxo-3-hydroxy DA, and NE high and LSD via CYP2D pathways variable potency, -​ High arousal state narrow -​ Outward-focused therapeutic emotions index, -​ Schedule I​ hyperthermia, cardiovascular toxicity) -​ Serotonin syndrome → insomnia -​ Muscle tissue can break down and cause kidney issues -​ Constriction of blood vessels in the brain LSD ergoline -​ Very strong -​ More (synthetic) partial agonist for controlled 5-HT2A experience  activation -​ Less potent (psychedelic than N bomb effects) -​ Moderate to high arousal state -​ Inward- and outward- focused emotions -​ Schedule I Cannabis and Cannabinoids (Chris) ​ Medical cannabis used to treat seizures, nausea, and vomiting ​ Cannabis ○​ Many factors (water, age) can affect the plant’s cannabis content ○​ Chemovars classified by cannabinoid and terpenoid content ○​ Complicated mix of compounds ​ Different concentrations of each element in different parts of the plant make it an inconsistent drug ​ Cannabinoids derived from fatty acids ​ Terpenes and terpenoids give weed its smell ​ Flavonoids give the color ​ Many types of cannabinoids and terpenoids → maybe millions of different targets in body and brain ​ THC vs CBD ○​ THC (delta-9-tetrahydrocannabinol) - psychoactive and intoxicating ○​ CBD (cannabidiol) - psychoactive but not intoxicating ​ Cannabinoid receptors ○​ CB1 and CB2 have similar structures and signaling ​ Inhibit cAMP and Ca2+ channel, activate K+ channel → diminishes cell activity ○​ CB1 ​ Most abundant G protein receptor in the brain ​ THC binds to this to cause intoxication ​ Present in the periphery, too ​ Regulation by ligands ​ Full agonists bind to the orthosteric binding site  ○​ Spice, 2Ag endocannabinoid ​ Partial agonists partially activate the orthosteric site ○​ THC, AEA ​ Inverse agonists ○​ Rimonabant (potential to treat obesity and smoking) ​ Neutral antagonists block agonist activity but not constitutive activity ○​ O-2050 ​ Allosteric modulators ○​ Pregnenolone (NAM) - precursor of steroid hormones ○​ CB2 ​ More in microglia than neurons ○​ In many of the same brain regions as opioid receptors, involved in… ​ Driving or movement (ex: cerebellum)→ cannabis makes you slow ​ Hunger, stress, and homeostasis (hypothalamus) → munchies ​ Memory (ex: hippocampus) → cannabis makes you forgetful ​ Paranoia, fear, reward value (ex: amygdala) → weed makes you paranoid ​ Reward (ex: nuc. accumbens) → decreased feeling of pleasure ​ Analgesia (spinal cord) → pain relief ​ Breathing (brain stem) → cannabis does not stop these vital signs ​ Tylenol (acetaminophen) ○​ One of the most common analgesic drugs ○​ COX3 inhibitor ○​ Antagonist at serotonin receptors ○​ Inhibits nitric oxide synthase (NOS) ○​ When you take Tylenol, you are taking a cannabinoid ○​ Metabolized to AM404 ​ Anandamide reuptake inhibitor ​ CB1 agonist that likely works via CB receptors as an analgesic ​ CB1 receptor antagonists block Tylenol’s analgesia in rats ​ TRPV1 agonist ​ Cannabinoids ○​ Phytocannabinoids ​ Occur naturally in the cannabis plant ​ THC ​ Weak partial agonist at CB1 and CB2 receptors  ​ Many other targets ​ CBD ​ Negligible affinity for CB1 and CB2 receptors ​ At higher concentrations, it is a neutral antagonist at the CB1 receptor and may oppose actions of THC ​ Many other potential targets ​ Potential as an indirect agonist by increasing naturally occurring AEA through inhibiting FAAH ​ NAM at CB1 receptors ​ High doses → liver toxicity ○​ Endocannabinoids - anandamide (AEA) and 2-AG ​ Endogenous (occur naturally in humans and animals) ​ Anandamide (AEA) ​ Partial agonist at CB1 and CB2 receptors ​ Ligand at GPR18 ○​ Activates TRPV1, ligand-gated, and voltage gated ion channels ​ Broken down by fatty acid amide hydrolase (FAAH) ○​ FAAH inhibitors might help treat anxiety, chronic pain, or neurodegenerative disorders → BIA fatal clinical trial ​ 2-AG - full agonist at CB receptors ​ Agonists at another G-protein coupled receptor, GPR55 ​ Long hydrophobic/lipohilic part and hydrophilic part ​ Derived from phospholipid precursors ○​ Synthetic cannabinoids ​ Produced in the lab ​ Can be chemically identical to phytocannabinoids or act on the body’s endogenous cannabinoid system ​ Can be abused or used as medicine ​ K2 ​ Chemically unrelated to THC but has similar structural features ​ Activate receptors through the orthosteric site, similar to THC ​ Usually more potent than THC ​ Many chemical derivatives (some full agonists) ​ Cannabinoid therapeutics ○​ Cannabis  ​ Diverse mixture of cannabinoids, terpenes, and flavonoids ​ Schedule I ○​ Hemp ​ Diverse mixture of cannabinoids ​ Not scheduled ​ Has a THC threshold ​ The government wrongly thinks it is nonpsychoactive - legal in all 50 states ○​ Epidiolex ​ CBD extracted from cannabis ​ FDA approved for seizures, not scheduled ○​ Marinol/sandros ​ Synthetic THC ​ Schedule II or III ​ Treat anorexia, AIDS, nausea ​ Use in chemotherapy ○​ Cesamet (nabilone) ​ Synthetic THC analogue ​ Schedule II ​ Treat nausea, use in chemotherapy ○​ Sativax ​ Extracted from cannabis ​ Not FDA approved ​ Dangers of cannabinoids ○​ Oral: delayed effects, difficult dosing ○​ Smoking or hookah: respiratory disorders ○​ Vaping: propylene glycol, contaminants, lung injury ○​ Injection: needle sharing diseases ○​ Spice: off target effects or impurities ○​ Cannabis: contaminants in plants, mold, heavy metals (phytoremediation) ○​ Synthetics targeting endocannabinoid system: off target, potency ​ Marijuana is a gateway drug ​ Rare but possible to OD on marijuana Group Six Presentation - Cannabinoids ​ THC and CBD are the two most prevalent forms of cannabinoids  ○​ THC ​ The intoxicating component ​ Broken down into 11-OH-THC, the more potent and intoxicating form ​ Cannabinoids are the most trafficked, used, and cultivated illicit drug ​ Cannabis has one of the longest histories of medical and recreational use ​ Cannabinoids can be addictive ​ It is near impossible to overdose on natural cannabinoids ​ Many hybrid strains of cannabis plant with different concentrations of CBD vs THC ​ Cannabis is widely used for medicinal and recreational purposes around the world ○​ Used for seizures and nausea during chemotherapy ​ Reasons for cannabis popularity ○​ Legal in many countries and widely available ○​ Many forms of consumption ○​ Enjoyment of intoxication ○​ Changed culture and attitude ○​ Widely considered to be a less addictive illicit drug (makes people open to experimentation) ​ Higher rates of cannabis consumption in the U.S. among… ○​ Low-income people ○​ Young adults ○​ Less educated people ​ Chemical players Endocannabinoids Phytocannabinoids Synthetic cannabis -​ AEA -​ Cannabidiol (CBD) -​ K2/spice -​ 2-AG -​ Δ-9-tetrahydrocannabinol -​ More use because (THC) better high, legal, -​ Precursor: THCA cheaper, can pass -​ Δ-8-tetrahydrocannabinol drug tests (THC) -​ Mimic THC but -​ Less potent have unpredictable, dangerous, and potentially life-threatening effects ​ The endocannabinoid system  ○​ Cannabinoids target this - mainly the CB1 receptor ○​ CB1 receptor ​ CNS, peripheral tissue ​ Mood, memory, pain, appetite, motor function, time perception ○​ CB2 receptor ​ PNS, immune system ​ Inflammation, immune response, pain modulation ○​ Retrograde signaling ​ Endocannabinoids from postsynaptic neuron bind to cannabinoid receptors on presynaptic neuron to inhibit the release of NTs ​ Comparing cannabinoids CBD THC Synthetic (K2/spice) Intoxicating? no yes Yes (stronger than THC) Legality (US) Federally legal if Illegal federally but Illegal but caveats derived from hemp legal in some states Addiction risk very low Mild or moderate High Binding to ECs Weak binding, Binding more to CB1, Can be very strong modulates other NTs partial agonist binding as full agonists (higher highs and lower lows) Other Notes Not taking the counterpart of CBD, which usually helps control some negative effects in natural cannabis ​ Mechanism ○​ CB1 receptors are coupled with G proteins ○​ Suppress NT release ​ Inhibit Ca2+ influx ​ Promote K+ efflux ​ Inhibit adenyl cyclase (AC) ​ Pharmacokinetics  ○​ IV and smoking gives quicker and shorter lasting high ○​ Oral gives slower onset but longer lasting high ​ Effects ○​ Cannabis use can directly correlate with psychosis, especially in younger users ○​ Acute ​ THC and synthetics (intoxicating) → the high ​ Euphoria, relaxation, time distortion ​ Anxiety, panic, hunger (dose and individual dependent) ​ Possibility to overdose but not fatal ​ CBD (non-intoxicating) ​ “Counteracting” → anxiolytic ​ Anti-inflammation and pain relief, relaxed mood, seizure and neuro- protection ○​ Long term cannabis use and toxicity ​ Tolerance, withdrawal, addiction ​ Respiratory issues from smoking ​ Cognitive impairments ​ Psychiatric disorders (psychosis) ​ Cannabinoid hyperemesis syndrome ​ Decrease in gray matter volume ​ Contingency management - a form of therapy to help those with cannabis use disorder wean off of it slowly ​ Must consider CBD to THC ratio when using cannabis to treat anxiety GHB, Salvia, Caffeine, Xylazine ​ Salvia (divinorum) ○​ Magic mint ○​ Smoking or oral (longer lasting effect) ○​ Effects ​ “Dissociative” ​ Intense and bizarre hallucinations ​ Uncontrollable laughter ​ Panic, dysphoria, anxiety, fear ○​ Active constituent: salvinorin A ○​ No approved medical use in the U.S.  ○​ Not controlled under the Controlled Substances Act but illegal in some states ○​ Rats prefer kratom and have aversive responses to salvia ○​ Salvinorin A: the “magic mint” hallucinogen finds a molecular target in the KOR ​ High affinity and selective kappa agonist → hallucinatory effects ​ Naloxone and buprenorphine (kappa antagonist) → no hallucinations ​ Human opioid receptors ○​ Gi-coupled ○​ Same signaling cascades ○​ Produce very different effects due to their different distribution ​ Date rape (sedative) drugs ○​ Ketamine ​ NMDA antagonist ○​ Tranq/Xylazine ​ Potent ɑ2 adrenergic agonist ​ Inhibits NT release of noradrenaline ​ Non-opiate analgesic and muscle relaxant used in veterinary medicine ​ Derivative of clonidine ​ Concentrated on east coast (PA) ​ An adulterant in an increasing number of illicit drug mixtures, commonly with fentanyl ​ Anecdotal reports that users experience effects similar to opioids ​ Naloxone cannot reverse overdoses ○​ Gamma hydroxybutyrate (GHB) ​ High affinity at GHB receptor (GRP172A) in cortex, thalamus, and hippocampus → associated with convulsions ​ Direct GABAB partial agonist with low affinity → sedation ​ GABAB receptor ○​ Widely distributed throughout the brain ○​ Unusual GPCR as a heterodimer ○​ Produces slow inhibitory postsynaptic potentials via activating G-protein-coupled inwardly rectifying K+ channels (GIRKS) → inhibits NT release ​ Effects (dose dependent symptoms) ​ Euphoria ​ Heightened sexual awareness  ​ Short-term amnesia ​ Inhibits locomotor activity ​ Induces hypothermia ​ KO GABAB-R → no hypothermia or locomotor impairment ​ GABAB responsible for sedative effects ​ Leaves the body quickly - difficult to detect ​ Endogenous ​ Precursor to GABA ​ GHB can be an agonist at GABAA but controversial and can be metabolized to GABA to activate any GABA receptor ​ Prodrug: GBL ​ Uses ​ FDA approved treatment for narcolepsy and ethanol withdrawal ​ Body building for its growth-hormone releasing effects ​ Schedule 1 due to date rape and abuse ​ Caffeine ○​ Fast acting ○​ Adenosine receptor antagonist ○​ Can have nasty withdrawl syndrome Group Seven Presentation - Tranq, GHB, Caffeine ​ Mixing drugs does not negate the effects of an “opposite” drug such as caffeine and xylazine ​ Caffeine ○​ CNS stimulant ○​ Metabolism via CYP1A2: caffeine → paraxanthine, theobromine, theophylline → uric acid derivatives ○​ Mechanisms and drug action ​ Non-selective adenosine receptor antagonist ​ Prevents influx of Ca2+ → decreased glutamate release from presynaptic neuron → increased NT release from postsynaptic neuron ​ Caffeine binds to A2AR → disinhibits D2R → DA release → alertness, wakefulness ○​ IV, oral, or rectal ingestion ○​ 100% bioavailability  ○​ Absorption in the GI tract (mostly) and stomach ○​ Potency: moderate effect dependent on tolerance, body size, predispositions, and dose ○​ Distribution: A1 = HC, A2A = striatum ​ A1 - inhibitory modulatory effects ​ A2A - counters with excitatory effects in DAergic regions ​ Low doses only affect these two receptor types ○​ Toxic doses prevent cAMP breakdown and increase Ca2+ release ○​ Increased glutamatergic and intracellular calcium release → increased cardiac and skeletal strength ○​ Hit peak → sedative effects kick in ​ Magic mint ○​ Hallucinogen (+ out of body experiences) ○​ Metabolism: magic mint → salvinorin A (diterpenoid) → salvinorin B ○​ Mechanisms and drug action ​ Salvinorin A - highly selective KOR agonist binds ​ → dissociation of beta-gamma complex goes on to cause K+ efflux and lower Ca2+ influx, inducing hyperpolarization ​ → Gi subunit dissociates and activates → inhibit adenylate cyclase and downregulate signaling cascade ​ Overall: suppressed DA release ○​ Highly lipophilic (unique compared to other hallucinogens) ○​ Fast onset (low Tmax) and short duration (short half-life) ○​ Distribution: hypothalamus, HC, striatum, amygdala ○​ Adverse effect: fear ○​ Withdrawal effect: nausea ○​ Similar effects in a class of drugs can be mediated by entirely different pathways ○​ Smoke ○​ Clinical trials to treat type two diabetes ○​ Not very toxic ​ Tranq/xylazine ○​ Sedative (sleepiness and disorientation) ○​ Metabolism: tranq → Xylazine → excreted through the kidneys as 2,6-xylidine ​ Primarily occurs in the liver via CYP450 ​ Mostly eliminated this way (unique) ○​ Powerful euphoric effect  ○​ Stigmatized due to media labeling as “zombie drug” ○​ Mechanism of clonidine ​ Least selective, prototypical alpha-2 adrenergic agonist → inhibits release of NE (usually activates sympathetic nervous system) from presynaptic neuron →sedation, analgesia, hypotension, paradoxical blood pressure ○​ Potent but more potent with other drugs ​ Used to boost the effects of opioids - often used with fentanyl or heroin ​ Dual effect overdose ○​ Xylazine can reduce the amount of fentantyl needed to overdose ○​ Distribution: dorsal horn, locus coeruleus ○​ Physiological effect: paradoxical blood pressure ○​ Adverse effects: hyperglycemia, skin wounds ○​ Narcane will not react exclusively to tranq overdoses ​ Alpha 2 antagonist can reverse xylazine ○​ Not a controlled substance - very accessible online ​ GHB ○​ CNS depressant ○​ Metabolism: GHB → SSA → succinic acid ○​ Prodrug: GBL, BD ○​ GHV - ‘legal’ but deadlier alternative ​ Prodrug: GVL ○​ Euphoric and calming effects ○​ Supplements for bodybuilding, baldness reversal, eyesight ○​ GHB receptor ​ Full agonist ​ High-affinity ​ Increases DA and glu release in striatum and cortex ​ High density in cerebellum, thalamus, IPN, frontal cortex ○​ GABAB receptor ​ Weak, partial agonist ​ Low-affinity - requires high dosage to activate ​ Inhibits DA release ​ High density in hippocampus, septum, PFC, amygdala ​ Heterodimer  ​ One part increases K+ efflux out of the GIRK channel ​ The other part decreases Ca2+ influx ○​ Mostly metabolic elimination ○​ Dose dependent symptoms ​ Euphoria ​ Disinhibition ​ ‘Rebound’ effect ○​ GHB is not inherently harmful ○​ Designer drugs produced to bypass legal restrictions although they turn into GHB upon entering the bloodstream