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CNS 2 Spears
Substance abuse/ADHD
| Question | Answer |
|---|---|
| definition of Reward: | a stimulus that serves to reinforce a desired response |
| Misuse/Abuse is? | drug use in unapproved manner & causes negative consequences |
| Addiction is? | pattern of compulsive drug use despite negative consequences; Usually involves high rates of relapse (aka drug reinstatement) |
| Dependence is? | physiological adaptation characterized by physical withdrawl |
| Examples of stimulus is? | Natural rewards (food, sex, love, activity) DRUG rewards (similar effect, MORE POTENT activatiors of the reward circuitry |
| Kinetics influences drug abuse risk how? | faster onset= more abuse potential |
| Physiological Adaptations with Chronic Drug Use: Reinforcement is? | Natural or drug-induced; Strengthening, establishing a pattern of behavior; Driven by high levels of DA in certain brain areas |
| Physiological Adaptations with Chronic Drug Use: Overtime, chronic drug use leads to _________ ________ | Neurobiological adaptations |
| Neurobiological adaptations come as? | -Long-term plasticity (LTP, increase in synaptic response) -Tolerance -Sensitization (infrequent stimulation results in amplified response) -Dependence -Withdrawal (adverse effects accompanied by strong drug cravings) -Relapse/Reinstatement -Post-withdrawal/Extinguish |
| Relapse/Reinstatement of Drug Taking Behavior is? | Reestablishment of drug taking after a period of withdrawal (post physical withdrawal symptoms) |
| Triggers for relapse/reinstatement of drug taking behaviors are? | -Stress -Corticotrophin releasing factor (CRF) -Exposure to an associated cue -Important to change addiction environment -Belief of normal drug use “I can control it; just 1” |
| Remember that CRF (Cortocotropin releasing factor) is part of the ________ accesss | hypothalamus |
| Associated cue? | pared with the drug taking behavior can induce animals/humans to consime that abused substance |
| Theories of Motivation for Drug Use: Genes & environment (stress, family history, drug access/history) may increase? | the risk of some people to develop addiction after drug use |
| Transition from drug use to addiction occurs from? | Initially for positive effects Drug taking shifts from just reward to habit formation Drug taking thwarts withdrawal symptoms |
| We can also see key factors that will kind of give an indication if a drug has a high abuse potential and that's if its able to? | increase Locomotor stimulation causes animal to move around a lot more, usually an indication it will be an abuse drug *increased response, especially locomotor stimulation, from a drug may indicate greater risk for developing addiction |
| There are several circuits involved in reward/addiction. what are the receptors? | DA, Glutamate, GABA, Cannabinoid, Nicotinic, Opioid |
| Slide 7 (Spears) is a depictio of a rat brain: red circuits indicate 2 major dopamine pathways that have involvement in various brain regions. what regions? what function? | VTA (amygdala) important for fear response; Prefrontal cortex (important for cognition); Areas of the Stratum (important for regulating mood) |
| There are 4 types of Dopamine Neuronal Pathways, however we are only focusing on 2. What are they? | Ventral tegmental area to Nucleus accumbens (*Mesolimbic pathway); Ventral tegmental area to Prefrontal cortex (Mesocortical pathway) *important for drug addiction and drug abuse |
| The Mesolimbic pathway (Ventral tegmental area to Nucleus accumbens) is? | Where the VTA starts--> dopamine neurons originate in the VTA and they project into that area (striatum) |
| The Mesocortical pathway (Ventral tegmental area to Prefrontal cortex) is? | Dopamine neurons originate in the VTA and they project to the prefrontal cortex |
| Understand that these 2 regions in regards to drug addiction is that the drug (either opioids, cannabinoids, alcohol, whatever, will have their various mechanisms to increase Dopamine release into these areas so we will see more heigtened? | dopamine in the striatum and prefrontal cortex, and trying to maintain that rise in dopamine is essentially the neuro-circuitry change that is involved in sustaining DRUG ABUSE **All drugs of abuse increase Dopamine (VTA to NAc; VTA to PFC) |
| Variety of abused drugs: NIH-NIDA (commonly abused drugs) | Cannabis; Khat (plant cathinone. AMPH-like stimulants |
| Variety of abused drugs: (Synthetic Cathinones) such as? | “Bath Salts”, psychostimulant |
| Variety of abused drugs: Synthetic cathinones some are more potent reinforcers that cocaine, which ones? | Ketamine PCP & LSD Inhalants Barbiturates Benzodiazepines Pain medications |
| Variety of abused drugs: OTC medications? | antidiarrhea, antitussive agents |
| Variety of abused drugs: Kratom is an? | Opioid-like drug |
| Neuropharmacological classification of addictive drugs by cellular mechanism: 1. Disinhibtion: | Opioids; GHB; BZD; Cannabis |
| Neuropharmacological classification of addictive drugs by cellular mechanism: 2. DA activation: | Nictoine |
| Neuropharmacological classification of addictive drugs by cellular mechanism: 3. Block reuptake: | Cocaine, Amphetamines, Ecstasy |
| Neuropharmacological classification of addictive drugs by cellular mechanism: Disinhibition via Opioids, GHB, BZD, Cannabis--> they work on? | work on their receptor either on the cell body of the GABA interneuron or on the nerve terminal to overall decrease the release of GABA or its excitability of that GABA interneuron; *to decrease the release of GABA therefore DISINHIBTING and removing the break on the dopamine neuron |
| Neuropharmacological classification of addictive drugs by cellular mechanism: Dopamine Activation via Nicotine as well as Alcohol--> works by? | causing increased dopamine release by DIRECTLY ACTIVATING the dopamine neuron so we see that nicotine will bind to its receptor on the dopamine neurons in the VTA to activate their firing |
| Neuropharmacological classification of addictive drugs by cellular mechanism: Block reuptake via Cocaine, Amphetamine, Ecstasy as well as MDMA--> are located on the? | pre-synaptic terminal |
| Neuropharmacological classification of addictive drugs by cellular mechanism: general--> GABA interneurons are? | smaller neurons in between other neurons that will regulate and release GABA to REDUCE excitation of that neuron |
| OPIOIDS & HEROIN – Mechanism of Action of Heroin, Prescription analgesics, Synthetic Opioids (Morphine, Fentanyl, Carfentanil, etc.) is? | MOR agonists, DA neuron disinhibition **MOR>>DOR; excludes KAPPA so no dysphroia for reward circuitry |
| OPIOIDS & HEROIN – Mechanism--> On the pre-synaptic side when opioid binds to the opioid receptor, these Ca2+ channels close preventing? | Ca2+ influx and going to decrease release of GABA from that neuron ***subsequently, the DA neurons in the VTA are DISINHIBITED, so they have less GABA around to inhibit that DA neuron from firing, and the end result is increased DA release in the PFC and NAc |
| OPIATES & HEROIN – Behavioral/Adverse Effects include? | Analgesia, Euphoria, drowsiness, sedation, Incoordination, confusion, nausea, constipation, Respiratory depression |
| OPIATES & HEROIN – Behavioral/Adverse Effects: Short-term effects: (1) Analgesia; (2) Euphoria; (3) Sedation; (4) Constipation; (5) Respiratory depression. What about their withdrawal symptoms? | 1. increased pain sensitivity; 2. dysphoria/irritability; 3. restlessness/insomnia; 4. diarrhea; 5. Hyperventilation |
| MOA of Methadone is? Role in OUD? | MOR opioid agonist; SERT/DAT blocker; NMDA-R antagonist ↓ Withdrawal symptoms; ↓Opioid cravings |
| MOA of Buprenorphine? Role in OUD? | MOR partial agonist; KOR antagonist ↓ Withdrawal symptoms and cravings |
| MOA of Naltrexone? Role in OUD? | Neutral MOR antagonist OUD/AUD |
| MOA of Naloxone? Role in OUD? | MOR antagonist Reverses opioid overdose (higher doses for potent opioids) |
| MOA of Suboxone? Role in OUD? | Buprenorphine + Naloxone (orally inactive) *lower chance for misuse Lower the potential for misuse |
| Methadone therapy--> | wards off reduce exposure (doesn't produce euphoric effect but reduces cravings (long 1/2 life) |
| Opiate Use Disorder Therapies: Buprenorphine? | MOR partial agonist; KOR antagonist *Very high-affinity; Slow dissociation from MOR *need to make sure pt is detoxified |
| Key thing to know for Buprenorphine (Spears)? | mechanism to increasing dopamine is by DISINHIBITION of the GABA neurons and then we have our full agonist, partial agonist, and the role of our new opioid antagonist for treating opioid and heroin use disorder *remember that Buprenorphine is a partial agonist and can give partial activation but pts could experience a triggered withdrawal if not actively going through a withdrawal |
| Buprenorphine is not ideal for a pt while ________ from heroin/opiate addiction because it can precipitate withdrawal symptoms | detoxifying |
| Buprenorphine has a ______ _______ (a limit to effect due to partial agonist activity) | ceiling effect |
| Cannabis use disorder (Cannabis/Marijuana) plant-derived Δ-9-THC (tetrahydrocannabidiol) and other cannabinoids (> 60) MOA? Effects on? | CB1 (and CB2) receptor agonist Mimic effects of endogenous cannabinoids (Ca2+ channel inhibition on Glu neuron pain pathway Reward, appetite, memory/cognition, motor function, pain modulation |
| Cannabis/marijuana can have activity on CB1 which is primarily expressed in the _____ meaning higher density in the spinal cord and the brain | CNS |
| Endogenous cannabinoids known as Endocannabinoids. There are 2. What are they named? | Anandamide; 2-AG (2-arachidonoylglycerol) |
| Cells have the ability to make endocannabinoids on demand, usually done by the post-synaptic neuron (can generate those endocannabiniods in response to an increase in ___ ______) | calcium influx |
| These endocannabinoids can participate in whats called _______ ______ where they are released from the post-synaptic neuron and acts back onto the presynaptic neuron wher it can bind to hose cannabinoid receptors that are Gi coupled facilitating the closing of Ca2+ channels to limit the release of NT | RETROGRADE SIGNALING |
| So remember Cannabus Mechanism--> MOA? Effects? | CB1 receptor agonist; Addition, dependence & withdrawal *Ca2+ inhibition on GABA interneurons; *DISINHIBITION of VTA dopamine neurons |
| Short term effects of Cannabis and (their withdrawal symptoms) | Euphoria (Mild agitation); Increased appetite (irritability); Sedation or increased attention (restlessness/insomnia); Impaired memory & coordination (Sleep EEG disturbance); Antimetic (nause, cramping); Muscel relaxant/anticonvulsant; Amotivational syndrome *lethal overdose not observed |
| GHB: Mechanism--> Gamma hydroxybutyrate, oxybate--> MOA? effects? | weak GABA-B receptor agonist; -Addiction, dependence & withdrawal -Inhibition of GABA interneurons -DISINHIBITION of VTA dopamine neurons; ↑ DA release |
| GABA-B expressed on DA neurons and _____ ______ | GABA interneurons |
| Difference between GABA-A and GABA-B? | B--> G-protein coupled receptors that regulate 2nd messengers signals on the neuron that they're expressed; A--> ION channels (ionotropic) that are permeable to Cl- |
| GHB, oxybate MOA cont'd --> | decrease Ca2+ influx on pre-synaptic side in order to reduce GABA in pre-synaptic space lessening inhibition of DA neurons |
| NICOTINE: MOA? | Agonist at nACh receptor (CNS and periphery); In CNS--> primarily in the VTA (increase DA levels in the NAc/PFC) *agent that DIRECTLY STIMULATES the DA neuron in the VTA |
| Know that Nicotinic ACh receptors come in many subtypes and that their population can change based on? | where they are expressed |
| The NAc and PFC are permeable to (+) cations such as Na+ and Ca2+ and this allows for Dopamine neurons to be more? | excitable to release DA into the prefrontal cortex and striatum |
| Nicotine Short term effects and (their withdrawal symptoms) | Increased alertness (difficulty concentration); Mild euphoria (Dysphoria/irritability); Muscle relaxation (restlessness/anxiety); Nausea/reduced appetite (increased appetite); Increased psychomotor activity (Psychomotor impairment) |
| NICOTINE – Addiction--> Strong behavior component? | Time of day/activities, addiction becomes strongly associated with behaviors linked to smoking; incerased BP (CV disease and stroke); Increased cancer risk; Fetal impairment during pregnancy; High prevalence for addiction |
| 3 therapies for Smoking cessation) what are they? | NRT; Bupropion; Varenicline |
| NRT MOA? Role in Therapy? Effect? | nACh receptor agonist (come in gum, patch, spray, gel); *(e-cigarettes/vaping ≠ NRT) Smoking Cessation; ↓ Cigarette/tobacco products ↓ Nicotine cravings, withdrawal symptoms |
| Bupropion MOA? Role in Therapy? Effect? | Norepinephrine Dopamine Reuptake Inhibitor; KOR antagonist Smoking cessation; Antidepressant ↓ Nicotine cravings, withdrawal symptoms |
| Varenicline MOA? Role in Therapy? Effect? | Partial nACh receptor Agonist Smoking cessation ↓ Nicotine cravings, withdrawal symptoms |
| Alcohol MOA? Other sites of action? | Stimulant at low doses (DISINHIBITS DA neurons) Sedative at high doses (Enhances GABA activity) Other SOA? Decreases Glu excitation; Endogenous opioid release/receptor activity (genetic/family history); NON-DAT/reuptake transporter inhibition |
| Alcohol-Behavior/AE include? | -Decreased motor coordination -Increased risk taking - impulsivity -Memory impairment -Sexual dysfunction -Respiratory depression -Seizures -Fetal alcohol spectrum (developmental damage from EtOH use during pregnancy) |
| Alcohol Short term effects and (their withdrawal symptoms) | Loss of inhibition (irritability/tremor); Anxiolysis (Anxiety); Sedation (Sleep disturbance); Decreased motor coordination (Seizures) |
| ALCOHOL (comorbid diseases) include? | Gastritis, cirrhosis, malnutrition, depression |
| ALCOHOL dependence and withdrawal? | -Kindling effect and seizures -Delirium tremens (shaking and hallucinations during withdrawal) -Severe return to alcohol or drug use -Wernicke-Korsakoff syndrome (encephalopathy with memory loss) -Brain vitamin B1 deficiency -Alcohol impairs thiamine absorption, transport, and utilization by cells |
| ALCOHOL Therapy options include? | Disulfiram; Naltrexone; Acamprosate DETOXIFICATION/ABSTINENCE FROM ALCOHOL PREFERRED (disulfiram > acamprosate > naltrexone) |
| Disulfiram MOA? Role in AUD? | Acetaldehyde Dehydrogenase Inhibitor Aversion therapy *Causes immediate hangover effects after alcohol consumption *Hepatic build-up of acetaldehyde (flushing, malaise, ALDH2 deficiency) |
| Naltrexone MOA? Role in AUD? | Neutral Opioid Receptor Antagonist -Taken before alcohol consumption to block EtOH opioid receptor agonism and reward feeling |
| Acamprosate MOA? Role in AUD? | NMDA receptor Antagonist -Balances Glu and GABA systems, reduces alcohol intake -NOT an anxiolytic, antidepressant, or anticonvulsant activity *Spears notes--> reduces Glu and enances GABA effects that come from alcohol like constipation and reduces overall alcohol intake |
| BZD: Mechanism? | Positive allosteric modulators of GABAA receptors Ionotropic, chloride channel *GABA site--> Beta-alpha subunits *BZD site--> Alpha-gamma subunits *DISINHIBITION (bind to GABA-A receptor on the GABA interneuron decreasing hyper-excitability of GABAergic neurons and reduces GABA release so that you have more activation of VTA dopamine neurons |
| BZD Effects? | Increase GABA binding; No effect on Cl- passage alone; Increases in Cl- flux is GABA-dependent |
| BZD's to remember consist of? | Alprazolam (Xanax); Clonazepam (Klonopin); Diazepam (Valium) |
| BZD Adverse effects consist of Behavioral effects and (their withdrawal effects) | Confusion, Light-headedness, Amnesia; CNS depression (Anxiety/irritability); Sedation/relaxation (Sleep disturbances, insomnia); Muscle weakness (Muscle pain, stiffness, tremor); *Addictive depressant effects with alcohol, opioids *Tolerance to sedative/hypnotic, anticonvulsant and anxiolytic effects |
| Flumazenil--> Therapy for BZD toxicity--> MOA? | Neutral, Competitive antagonist at BZD binding site; *Specific BZD antidote; (not other GABA A modulators (Ethanol, barbituates); *reverses symptoms associated with toxic BZD levels (Respiratory depression, Severe mental impairment, Ataxia) BOXED WARNING--> SEIZURES and lowers seizure threshold |
| PSYCHOSTIMULANTS - Cocaine, Amphetamine, Methamphetamine, Ecstacy-MDMA, Methylphenidate; MOA? | increase extracellular monoamine levels via blocking or reversing reuptake transporters |
| Psychostimulants-->substrates for the transporter--> get taken into the presynaptic cell, where it can cause vesicular release of NT and b/c the concentration gradient has shifted--> it causes? | the amount of monoamine transporter w/in the cell to be elevated which then drives more NT out of the cell (efflux)--> increasing release of DA/NE from vesicle which drives hte transport mediated efflix of NT |
| This vesicle release of DA/NE which drives the transport mediated efflux of the NT has 2 different names for the same process, Spears called it? | Amphetamine-dopamine induced release OR Amphetamine induced dopamine efflux *achieved by amphetamine compounds but not by cocaine |
| Stimulants Behavior/Adverse effects include? | CV (tachycardia, increased BP); increased Body temp, energy, alertness, tremors, reduced appetite, anxiety, panic, insomnia, paranoia, seizures |
| ADHD symptoms first described in 1902 as a __________ disorder and affects children and adults | hyperkinetic |
| ADHD symptoms include? | Restlessness, Hyperactivity, Inattention, Impulsiveness |
| ADHD risk factors include? | Genetics (familial link, likelihood boys > girls); Cigarette smoking, alcohol use, or drug use during pregnancy; Exposure to environmental toxins during pregnancy or young age (Lead, polycholorinated biphenyls (PCBs)); Low birth weight; Brain injuries |
| ADHD: Dopamine & NE Hypotheses: Reward deficiency syndrome--> | Dysfunction of brain reward system drives engagement in activities to increase DA **decreased extracellular levels of DA/NE are thought to contribute to developing ADHD |
| ADHD: Dopamine & NE Hypotheses: Dopamine and NE deficit | -DAT, D2/D4 receptors, COMT, D5 receptors -NET, α2 receptors -Hyperactive DAT/NET function or expression -Sub-sensitive postsynaptic receptor |
| Remember the main neuronal projections--> | VTA---> NAc (ML) VTA---> PFC (MC) |
| Psychostimulants (Amphetamines) drug names? | Mixed amphetamines salts; Dextroamphetamine(d-AMPH) (adderall) short-acting and intermediate-acting); Lisdexamphetamine (prodrug--> conversion to d-AMPH) *low doses able to increase attention; ER formulations help reduce abuse liability |
| Psychostimulants (Methylphenidates) drug names? | Methylphenidate (Ritalin) Dexmethylphenidate- racemic methylphenidate (Focalin) Serdexmethylphenidate and dexmethylphenidate (Azstarys) (IR/ER/Sustained release) *AE: abuse potential (CV box warning), hypertension, Tachycardia, SS w/ other serotonergic agents), insomnia, HA, reduced appetite, weight loss) |
| MOA: Amphetamine & Methylphenidate: MOA? | Blockade or reversal of DAT and NET reuptake transporters; incerases extracellular DA and NE levels |
| What drugs are our non-stimulants? | Atomoxetine, Viloxazine, Clonidine, Guanfacine |
| Atomoxetine MOA? AE? | selective NET inhibitor (Ki ~5 nM); *suicidal ideation, cardiovascular, psychosis, aggression, N/V, abdominal pain, hepatotoxicity, priapism |
| Viloxazine MOA? AE? | MOA: NET inhibitor (Ki ~155 nM) SNMA: 5HT/NE modulating agent, ↑NT in PFC 5HT2C agonist (EC50 32 µM) 5HT2B antagonist (IC50 27 µM) *suicidal ideation, cardiovascular, headache, N/V, abdominal pain |
| Atomoxetine and Viloxazine are more focused on the targeting of? | the transport protein to elevate NT levels in the region |
| Clonidine (ER) MOA? AE? | ADHD mechanism unknown; Non-selective agonist at post-synaptic a1/a2a/b/c-adrenergic receptors in PFT Drowsiness, headache, dizziness, rash, dry mouth, upper abdominal pain |
| Guanfacine (ER) MOA? AE? | Selective agonist at postsynaptic a2a-adrenergic receptors *a2A subtype concentrated in PFC Drowsiness, headache, fatigue, insomnia decreased appetite, abdominal pain |
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Xander635
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