Psychomotor stimulants.pdf

STC PHILLY EVENTS Tuesday (Today) we are volunteering with Savage Sisters for outreach from 5:30 to 6:30pm. If anyone is interested in, please email us at [email protected]. 12 Psychomotor Stimulants: Cocaine and the Amphetamines Psychomotor Stimulants: Cocaine and the Amphetamine...

STC PHILLY EVENTS Tuesday (Today) we are volunteering with Savage Sisters for outreach from 5:30 to 6:30pm. If anyone is interested in, please email us at [email protected]. 12 Psychomotor Stimulants: Cocaine and the Amphetamines Psychomotor Stimulants: Cocaine and the Amphetamines Cocaine Amphetamines • Background • Background • Pharmacology • Pharmacology • Mechanisms of Action • Mechanisms of Action • Acute Effects • Behavioral and Neural Effects • Chronic Effects • Treatment Options for Cocaine Abuse • Stimulant Withdrawal Psychomotor Stimulants: Cocaine and the Amphetamines Past Year Central Nervous System (CNS) Stimulant Misuse: Among People Aged 12 or Older; 2020 https://www.samhsa.gov/data/report/2020-nsduh-annual-national-report Cocaine: Background and History !!!!!! Cocaine: Background and History “If you got that lose, you want to kick them blues, cocaine When your day is done, and you want to ride on cocaine She don't lie, she don't lie, she don't lie, Cocaine” Eric Clapton, Cocaine Cocaine: Background and History Erythroxylon coca plant • Cocaine is an alkaloid found in the leaves Cocaine: Background and History • Sigmund Freud § recommended it for many ailments § declared it was non-addictive tamed was thou (PO) about ant erect local benericial anaesthetic • In 1886, Coca-Cola: introduced by John Pemberton § contained caffeine and cocaine (until 1903) § marketed as an alternative to alcohol during the temperance movement § ~2 million “current users”; ~900,000 cocaine-dependent Basic Pharmacology and Mechanisms of Action Basic Pharmacology of Cocaine • Cocaine alkaloid § extracted from coca leaves (0.6% -1.8% cocaine) § converted to a hydrochloride (HCl) salt and crystallized § water-soluble: can be taken orally, intranasally (insufflation), or by IV—not heat stable cantbesmokedit breaks downnine at Basic Pharmacology of Cocaine How to make crack: §smokable cocaine (e.g., “rock”, freebase form): •Mix dissolved cocaine HCl with baking soda, heat the mixture, then dry it §freebase crystals “crackle” when heated almost p §Produces profound euphoria §Far less expensive than cocaine powder §Antidrug Abuse Act of 1986: 1:100 rule crack : cocaine •Fair Sentencing Act of 2010 reduced it to 1:18 instantaneously Basic Pharmacology of Cocaine On a humid Saturday afternoon in West Philadelphia, near 40th Street and Lancaster Avenue, a group of middle-aged Black men swapped grapevine stories about acquaintances who had recently “fallen out” after taking a hit of what they thought was their everyday crack cocaine. Little did they know it contained fentanyl, the deadly synthetic opioid that has spurred an overdose crisis across the country, attributing to more than two-thirds of Philadelphia’s 1,217 unintentional drug overdose fatalities last year. Over the last two weeks, at least 20 people in the Powelton Village and Mantua neighborhoods landed in the hospital with fentanyl overdoses, the Philadelphia Department of Health confirmed. Two of the overdoses proved fatal, officials wrote in a memo. The victims were predominantly African American, two-thirds male, most between 40 to 50 years old. And according to health officials, many of them had more in common: they were adamantly cocaine users – not opioids. “But you don’t know what you’re smoking anymore,” said one crack cocaine user, who declined to give his name. http://www.philadelphiaweekly.com/news/what-we-know-about-the-crack-fentanyl-outbreak-in-philly/article_f3dbf71c-7ad5-11e8-b6c0-3373982f1dda.html Basic Pharmacology of Cocaine crack • • Smoking crack cocaine results in a large surge of cocaine in the brain that is not reflected in peripheral blood concentrations Rapid entry into the brain is an important factor in the strong addictive properties of crack cocaine Basic Pharmacology of Cocaine • Lipophilic • readily passes through blood– brain barrier § broken down by enzymes in the blood and liver (non-CYP) § Rapidly eliminated • half-life ranging from 0.5 to 1.5 hrs • “high” lasts ~30 minutes • Metabolites: • benzoylecgonine>>>detected in the urine for several days https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/benzoylecgonine Mechanisms of Action Mechanisms of Action blocks DASHT NEmembranetransporter • Monoamine reuptake inhibitor: bindsto 5h wnighest aflining blockingorDA transporter is what reinforces psychoactive § Blocks reuptake of dopamine (DA), norepinephrine (NE),erect addictive erects etc and serotonin (5-HT) Nature Reviews Neuroscience volume 4, pages 13–25 (2003) • Cocaine binds with highest affinity to the 5-HT transporter • Blocking DA reuptake appears to be most important for cocaine’s stimulating, reinforcing, and addictive properties Mechanisms of Action How do we know it is inhibition of DA reuptake that mediates the psychoactive effects? Str y Nt •SSRIs and SNRIs do not produce psychostimulant effects •DAT KO Mice display no further cocaine-induced increase in activity •SERT KO and NET KO show cocaine-induced increases in activity •destruction of NET nerve fibers has little effect on psychostimulant effects of cocaine Stillshoweffect •destruction of DAT nerve fibers does not produce psychostimulant effects following cocaine administrationTekken Mechanisms of Action • At high concentrations: also inhibits voltage-gated Na+ channels § acts as a local anesthetic I § Prevents transmission of signals along sensory nerves § Schedule II drug • Procaine (Novocain) and lidocaine (Xylocaine) • Also, a potent vasoconstrictor blows reuptake me excess ne Ne signalbloodvesselsconstrict http://www.frontiersin.org/files/Articles/100356/fnsyn-06-00019-HTML/image_m/fnsyn-06-00019-g010.jpg Acute Behavioral and Physiological Effects Acute Behavioral and Physiological Effects of Cocaine The cocaine “high”: § “consists of exhilaration and lasting euphoria, which does not differ in any way from the normal euphoria of a healthy person…one senses an increase of self-control and feels more vigorous and capable of work…long lasting, intensive mental or physical work can be performed without fatigue; it is as though the need for food and sleep, which otherwise makes itself felt peremptorily at certain times of the day, were completely banished…opinion is unanimous that the euphoria…is not followed by any feeling of lassitude or other state of depression. Freud, Uber Coca Acute Behavioral and Physiological Effects of Cocaine Short-Term Effects: • extreme happiness and energy • mental alertness • hypersensitivity to sight, sound, and touch • irritability • paranoia—extreme and unreasonable distrust of others • Helps some people perform simple physical and mental tasks more quickly>>> others experience the opposite effect • Large amounts of cocaine can lead to bizarre, unpredictable, and violent behavior Lawrence Taylor, “L.T.” Acute Behavioral and Physiological Effects of Cocaine Mesolimbic DA pathway Key role in the reinforcing effects: •Rats will self-admin cocaine do so directly into NAcc andwill repetitively •Re-instatement of cocaineseeking behavior in previously extinguished animals: stimulated by microinjection of DA receptor agonists directly into the NAcc •mutant mice expressing a cocaine-insensitive DAT show reduced cocaine selfadministration • a DAT protein that transports DA across the cell membrane but is not blocked by cocaine Acute Behavioral and Physiological Effects of Cocaine • All species readily learn to self-administer IV cocaine • Unlimited access in primates and rodents>>>>leads to continuous self-administration § Will not eat or drink! § powerful reinforcing properties and high abuse potential • In self-admin studies, there is often no alternative reinforcer available § Cocaine is available 24/7 Acute Behavioral and Physiological Effects of Cocaine What happens when two reinforcers available? • Animals were trained to press a lever for either .2% saccharin (very sweet!) or IV cocaine on FR1 schedule, separately • Both reinforcers were made available at the time of test • Cocaine has a higher breaking point than saccharine Saccharine Pref if givenchoice hitmore sacinarine eventhough sach hasnigher BP takeawaysupports relapse abstinence can be dueto lack of omer reinone Cocaine Pref • • 0 = no preference 1.0 or -1.0 represents complete preference Acute Behavioral and Physiological Effects of Cocaine • “We speculate that the addictive potential of intense sweetness results from an inborn hypersensitivity to sweet tastants” •In most mammals, including rats and humans, sweet receptors evolved in ancestral environments poor in sugars and are thus not adapted to high concentrations of sweet tastants •Excess stimulation of these receptors by sugar-rich diets would generate a supranormal reward signal in the brain, with the potential to override self-control mechanisms and thus to lead to addiction. Acute Behavioral and Physiological Effects of Cocaine Thalamic Hemorrhage • Psychomotor stimulants: sympathomimetic § Activates sympathetic NS • Increased heart rate, vasoconstriction>>> body hypertension, increase down shut can organ hyperthermia temp • Low doses: usually not harmful to the Before Cocaine individual • High doses can be toxic or even fatal After Cocaine https://www.optica.org/about/newsroom/news_releases/2014/this_is_your_brain_s_blood_vessels_on_drugs/ • vessels are now darker, which signifies reduced blood constriction flow Acute Behavioral and Physiological Effects of Cocaine genetically • heterogenous Rats divided into two groups based on response to single dose of cocaine: 1. Low cocaine responder (LCR) atom 2. high cocaine responder (LCR) some Igraine In (Top): Baseline Dex • HCRhas lower cans ofbat LCRs have higher basal #’s of striatal DAT than the HCR rats • did not influence extracellular DA levels, DA signaling, or locomotor behavior under drug-free conditions Acute cocaine challenge (Bottom): • lower # of reuptake sites in HCR group resulted in more synaptic DA in HCR group (Bottom) • There is spare “free” DAT in LCR group Acute Behavioral and Physiological Effects of Cocaine • In humans, intensity of the “high” depends on amount of DAT occupancy ( to experience a “high”, DAT occupancy needs to be ~50%) but also on: • Rate at which DAT occupancy occurs>>>ROI-dependent • Baseline level of DA release in the mesolimbic pathway • Individual differences—may account for susceptibility to abuse You are performing a genomic analysis of genes in the DA system. In one cohort of 200 humans that are not drug users, you find that 100 have a polymorphism in the DAT gene that results in significantly increased levels of DAT (compared with the other 100 subjects). The (High DAT Group/ Low DAT group) will have a greater behavioral response to cocaine challenge. This is due to the finding that a(n) (increased/reduced) # of reuptake sites in low DAT group results in more synaptic DA following cocaine challenge. sites Int SIMI Effects of Chronic Cocaine Exposure Cocaine Abuse and the Effects of Chronic Cocaine Exposure • Capture ratio of cocaine: ~15% of initial intranasal users become abusers (“cocaine use disorder”)—most do not § reinforcers in the early stages: stimulating, euphoric, and confidenceenhancing effects • In humans, the euphoric effect of cocaine shows tolerance over time Contributes to increased drugtaking • Social responses may play a role in abuse—positive attention from friends § Cocaine Abuse and the Effects of Chronic Cocaine Exposure • Other factors contributing to abuse: • Comorbidity with other psychiatric disorders • “incubation” of cocaine craving • Craving increases over time following termination of use>>>relapse § Abnormal function of PFC in patients with Cocaine dependency—disinhibition, lack of self-monitoring • “Driving a car without brakes” • Seen in studies of primates repeatedly exposed to cocaine Cocaine Abuse and the Effects of Chronic Cocaine Exposure Neurochemistry of Tolerance and Sensitization in NAcc • adaptations in the NAcc underlying tolerance due to longaccess cocaine self-administration mi ima game anic potentialmean eine release reared in in • Reduced electrical stim evoked release and clearance in NAcc • In vivo microdialysis of DA in NAcc chronic SA = cocaine self-administration ityouinjectcocaine stimulateDa nucleusaccumbenst nsee release roundcontrolhasnigher levelsorDa releases c ocaine ionic in causes seeDalevelsconvogroup wiggin Foggy erase infona Cocaine Abuse and the Effects of Chronic Cocaine Exposure Modelling the transition from recreational to compulsive use: Iain m •ShA-1 hour access sessions •LgA- 6 hour access sessions ignition piggin fiscal both gig less stringPetangaine room shatDrugnaivenochange areagroup baselinethresholdt long rewireanear cocainebecome an rewardingafter §A: Intake across 1hr (ShA) or 6hr (LgA) §ShA: stable intake across sessions §LgA: escalating intake across sessions §B: Compare intake during 1st hour •LgA escalates across sessions §C: ICSS after each session §Thresholds increased in LgA group §Thresholds constant in ShA group Cocaine Abuse and the Effects of Chronic Cocaine Exposure PET imaging of cocaine-dependent individuals: • Baseline D2 receptor binding is reduced in the cocaine-dependent subjects (Comparison: Between aka off int Subjects) mail.imainigangmor • MP (Methylphenidate) has a greater effect in the control subjects (Comparison: Within Subjects) • DA system in dependent individuals is less responsive to DA reuptake blocking>>>contributes to behavioral tolerance • a "hypodopaminergic" state>>> lower levels of D2 receptors fairlevelRings excessis toreapn Striatum dit not'statistic Raclopride binding Iga softening re sameerect • Raclopride binds to Dget 2 receptors and is displaced by released DA Cocaine Abuse and the Effects of Chronic Cocaine Exposure • Systemic effects of chronic cocaine use: § Organ systems: heart, lungs, GI system, kidneys § perforation of the nasal septum (frequent snorting) § Cocaine use during pregnancy: • Not as bad as one would predicted § Some studies show attention deficits and behavioral or cognitive abnormalities in the child § High-dose use >>> panic attacks or temporary paranoid psychosis with delusions and hallucinations § Elevated body temperature >>>multiple organ failure is a major cause of OD death Treatment Options for Cocaine Abuse Treatment Options for Cocaine Abuse • Pharmacological approaches to treat cocaine abuse: § No FDA-approved medications • Ketamine? • A Diabetes Drug? • Gene therapy? Treatment Options for Cocaine Abuse • a significant decrease in cocaine use—by 67 percent relative to baseline (>24 hr post infusion) • A few patients remained abstinent for two weeks O…O…O…Ozempic (Semaglutide)! Iii if irina https://www.science.org/doi/epdf/10.1126/science.adk5720 Treatment Options for Cocaine Abuse GLP-1 (Glucagon-like peptide) • a satiety hormone—produced in intestine when food enters • a neuropeptide—produced in the nucleus tractus solitarius (NTS) of hindbrain • GLP-1 neurons in NTS send direct projections to VTA and nucleus accumbens • GLP-1 receptors in brain regulate intake of highly palatable food • Injection of GLP-1 agonists directly into the VTA reduces intake of palatable food • no effect on consumption of normal chow •Reed J., Kanamarlapudi V. (2018) GLP-1. In: Choi S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham neurons mepriest Iggy Ienigggionseeking Treatment Options for Cocaine Abuse • All completed clinical trials used older GLP-1 analogs bindinggagnot • Semaglutide binds more tightly to the GLP-1 receptor and induces greater weight loss than previous drugs. • almost all new trials use semaglutide: • Will it show greater capabilities against addiction • Will it help identify which patients are most likely to benefit • Will it clarify how the mechanisms • Insurance Issues--$12k/year • Probably not a cure-all--might be more like Prozac and other antidepressants, which only work for a fraction of patients. • But even that would be a boon, Ray says. “You can help a lot of people even if only one in five responds.” https://www.science.org/doi/epdf/10.1126/science.adk5720 https://www.science.org/content/article/hot-weight-loss-drugs-tested-addiction-treatments Treatment Options for Cocaine Abuse affinitiesagainstcocaine cocaineusedisorder forinclivwin immense c Previous work has shown that GLP-1 agonist drugs (reduce/increase) the intake of palatable food. In the brain, GLP-1 is produced by neurons in the (NTS/Amygdala/hippocampus) which sends projections to structures in the (mesolimbic DA circuit/mesocortical DA circuit/nigrostriatal DA circuit). Amphetamines • Background • Basic Pharmacology • Mechanisms of Action • Behavioral and Neural Effects • Stimulant Withdrawal Background The Amphetamines: Background and History Amphetamine • Synthetic derivative of phenylethylamine § parent compound of a family of synthetic psychostimulants that are structurally related to DA CH3 Natural The Amphetamines: Background and History Natural amphetamines Cathinone get ginwear Ephedrine pseudoephedrine CMEA https://www.deadiversion.usdoj.gov/pubs/brochures/pseudo/cmeatrifold_060508.pdf https://www.nytimes.com/2023/01/04/us/boulder-colorado-meth-library.html?smid=nytcore-ios-share&referringSource=articleShare The Amphetamines: Background and History Alexander Shulgin AKA: Dr. Ecstasy "Phenethylamines I Have Known And Loved" Basic Pharmacology Basic Pharmacology of the Amphetamines • Amphetamine: PO or IV § “uppers,” “bennies,” “dexies,” “black beauties,” “diet pills” L raging • Methamphetamine: more potent on CNS than Amphetamine • “meth,” “speed,” “crank,” “zip,” “go” • taken orally, snorted, injected IV, or smoked § Methamphetamine hydrochloride (HCL) in a crystalline form >>>smoking (“ice” or “crystal”) § Peter does Crystal Meth A New Meth Epidemic? methis coming back became won after amethcreative pseudoephedrine more as zoosrear at https://www.nytimes.com/2018/02/13/us/meth-crystal-drug.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=second-column-region&region=top-news&WT.nav=top-news Basic Pharmacology of the Amphetamines • IV amphetamine or methamphetamine + heroin = “speedball” • Amphetamine and methamphetamine are metabolized by the liver at a slow rate • long half-lives § Amphetamine: ~6 hours § Methamphetamine: ~12 hours Mechanisms of Amphetamine and Methamphetamine Action • Amphetamine and methamphetamine § indirect agonists of the catecholaminergic (NET and DAT) systems • Two modes of action: 1. enter DA (NE) nerve terminals via uptake by DAT (NET) and cause vesicles to release DA (NE) into cytoplasm 2. Reversal of DAT (NET) • very high levels of DA (NE) in the synaptic cleft deficient DA uptake Behavioral and Neural Effects Behavioral and Neural Effects of Amphetamines http://www.slate.com/articles/arts/culturebox/features/2013/daily_rituals/auden_sartre_graham_greene_ayn_rand_they_loved_amphetamines.html Behavioral and Neural Effects of Amphetamines • Therapeutic uses: § Nasal and bronchial decongestants (OTC: late 30’s) § narcolepsy (Modafinil) § Appetite suppression and weight loss—Desoxyn • Induces CART § Psychostimulants (methylphenidate) in low doses produce a calming effect in more than half of children with ADHD • How does treating a child with ADHD with an amphetamine analogue result in calming? https://www.theatlantic.com/health/archive/2012/04/the-lost-world-of-benzedrine/255904/ Behavioral and Neural Effects of Amphetamines affectDA that Annepsychomotor p • Stimulant Meds for ADHD § Dexedrine (D-amphetamine) § Adderall (amphetamine salts) Amphetamines § Vyanse (lisdexamfetamine) § Ritalin (Methylphenidate)—DAT and NET blocker d • Non-stimulant Meds (No effect on DA) NE • Strattera (atomoxetine): NET inhibitor • Intuniv (guanfacine): a2 agonist (post-synaptic) predom Hypothesis: DA and NE activity in the PFC is deficient in patients with ADHD it enhance signaling s improvementbehavior Behavioral and Neural Effects of Amphetamines • Over the 20-year period, the estimated prevalence of diagnosed ADHD in US children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016 (P for trend <.001). • All subgroups by age, sex, race/ethnicity, family income, and geographic regions showed a significant increase in the prevalence from 1997-1998 to 2015-2016. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2698633 Behavioral and Neural Effects of Amphetamines • PFC functioning is an inverted U-shaped function mediated by the activity of catecholaminergic systems • ADHD meds enhance catecholaminergic activity in the PFC to restore balance § ADHD is fatigued state Behavioral and Neural Effects of Amphetamines • Amphetamine-induced psychosis: Provided initial impetus and support for the DA hypothesis of Schizophrenia • Chronic, high-dose abuse >>>psychotic reactions most § visual, olfactory, and/or auditory hallucinations § development of a paranoid state with delusions of persecution>>>some insight remains § Formication i faithIn 809 go § Extreme anxiety and fear common § None of these are actually all that relevant to schizophrenia Behavioral and Neural Effects of Amphetamines Neurotoxicity • Methamphetamine use causes damage to DA axons and terminals igggitaittiineaamii.im § Remember Ricuarte? § doses used are often much higher than those used in human users • also damages serotonergic fibers in several brain areas (neocortex, hippocampus, and striatum) • Many potential mechanisms for neurotoxicity: oxidative stress, excitotoxicity, neuroinflammation (microglial activation), and mitochondrial dysfunction dilating 199 1 Then • Methamphetamine-induced loss of tyrosine hydroxylase immunoreactivity in the nigrostriatal compared with the mesolimbic DA pathways in mice Behavioral and Neural Effects of Amphetamines • Brain imaging: reduction in striatal DAT binding with chronic methamphetamine and methcathinone use • Damage is similar in a Parkinson’s disease patient, where the DA innervation of the striatum is known to be severely compromised § However, loss of cell bodies in SN is not seen-–a neurochemical response, not physical damage? y measure DAtransporter level in striatum one AYEEE innituse Gygmeguer mining aparkinson Behavioral and Neural Effects of Amphetamines • Heavy methamphetamine use: cardiovascular problems including elevated heart and blood pressure, atherosclerosis, heart attack, increased risk of stroke, and increased mortality rate • anecdotal evidence of premature aging Behavioral and Neural Effects of Amphetamines Meth Mouth Photo of a meth user's mouth. Copyright Dr. Chris Heringlake, DDS, St. Cloud Correctional Facility. YMouttparalymp Patna • • • broken, discolored and rotting teeth salivary glands dry out>>>allows the mouth's acids to eat away at the tooth enamel, causing cavities Teeth are further damaged when users obsessively grind their teeth, binge on sugary food and drinks, and neglect to brush or floss for long periods of time Behavioral and Neural Effects of Amphetamines Synthetic cathinones (“Bath Salts”, ”Zombie drugs”, Flakka ) Iatiable omg anger on • contain one or more human-made chemicals related to cathinone • chemically similar to amphetamines, cocaine, and MDMA • marketed as cheap substitutes for these drugs • PO, snorted, smoked, or IV • cause: • paranoia • increased sociability • increased sex drive • hallucinations • panic attacks euphoriaproducing a dminister animals verynignere https://nida.nih.gov/publications/drugfacts/synthetic-cathinones-bath-salts • Animals will self-administer http://www.nature.com/news/2010/100330/images/news.2010.159.chemical_structure.jpg You are a physician examining a patient and notice that she has very bad teeth. The patient tells you that she is a methamphetamine addict. You explain to her that methamphetamine is a (parasympathomimetic/sympathomimetic/sympatholy tic) drug that causes a(n) (increase/decrease/no change) in synaptic (NE/ACh/DA) levels in peripheral nerve terminals. This leads to a(n) (increase/decrease/no change) in secretions from salivary glands and contributes to poor oral hygiene. Withdrawal from Psychostimulants nophysiologicalcomponent butratherpsychological norebound toenhance peripheralactivity Psychomotor Stimulants and Withdrawal Cocaine/Psychostimulant Withdrawal • For many years, cocaine and amphetamine were not thought to be addictive substances noreboundhyper excitability ofnervoussystem • Psychostimulant withdrawal often has no visible physical symptoms • Withdrawal from cocaine occurs rapidly after last dose § Due to the relatively short half-life of cocaine gritof inshorthairtile veryavg.hn Psychomotor Stimulants and Withdrawal • Gawin and Kleber's Phasal Model of Cocaine Withdrawal (1986) Ingoglia that n Yological py pby natune migraine