Psychoactive Drugs and the Brain Midterm

Neuromodulation

NT release across brain to induce specific states, as opposed to information transmission

Mesolimbic Dopamine System

VTA > Nucleus accumbens; regulates reward and reinforcement learning

Nicotinic acetylcholine receptor

Ligand-gated, binds to both nicotine and actylcholine in the CNS as a neuromodulator- excitatory

Hebbian learning rule

“Neurons that fire together, wire together” = when two neurons repeatedly interface, they become more efficient

Long-term potentiation (LTP)

EPSP magnitude increases long term after repeated stimulation

NMDA receptor

Essential in LTP, detects glutmate release and depolarization coincidence > Ca influx to postsynaptic cell > additional AMPA receptor insertion

Dopamine in the Motor Cortex

SNc > D1 neurons in Striatum > Thalamus > excitation of MC >… Skeletal muscles

SNc > D2 neurons in Striatum > inhibition of subthalmic nucleus > globus pallidus > Thalamus > excitation of MC > … skeletal muscles

Increase in dopamine acting on D1 and D2 causes increased movement regardless of receptor type.

Outcome better than predicted

Increase in dopamine > D1 pathway excited, D2 inhibited > D1 direct pathway activated + LTP, D2 indirect inhibitory pathway not activated

Outcome worse than predicted

Lower dopamine level. D1 pathway is not activated > no LTP. D2 pathways not inhibited by DA, so LTP in indirect inhibitory pathway > action suppressed

Habit learning

Ties stimulus to response, ignoring outcome

Pavlovian learning

Ties stimulus to outcome, ignoring response

Instrumental learning

Ties response to outcome, ignoring stimulus

Nigrostriatal pathway

Dopaminergic pathway responsible for motor performance and learning

Mesolimbic pathway

Dopaminergic pathway responsible for motivation and reinforcement learning

Mesocortical pathway

Dopaminergic pathway responsible for cognitive functions

Psychomotor stimulant

A drug which stimulates the CNS to increase alertness, mode, and create a sense of well-being

Cocaine Chemistry

Alkaloid, weakly basic, free base, volatile

Cocaine Routes of Administration

Cocaine salts absorbed via mucous membranes (nasal), IV, or orally. Crack cocaine heated and smoked.

Cocaine Pharmacokinetics

Peak plasma concentration 5-10 minutes after IV, 60 mins after snorting. Half life of 60 minutes.

Cocaine Metabolism

Butyrylcholinesterase BChE) breaks down acetylcholine and cocaine

Consequences of Cocaine Use

Acute: euphoria, talkativeness, arousal → hypertension, stroke risk, cardiovascular risk

Chronic: Addiction, weight loss

Cocaine Mechanism of Action

Cocaine blocks DA transporters in the synaptic cleft, leaving excess dopamine to retrigger firing

Amphetamine Chemistry

Weakly basic, salts or free base, D-amphetamine more active than L-amphetamine

Amphetamine Pharmacokinetics

Peak levels 15 minutes after IV, 0.5-3 hours after oral. Dose lasts for 7-12 hours. Half life is 10 hours.

Amphetamine Metabolism

Methamphetamine becomes amphetamine in vivo, amphetamine is degraded by hepatic enzymes

Consequences of Amphetamine Use

Acute: Euphoria, cognitive performance, alertness. Increase heart rate, hypertension

Chronic: Addition, psychosis. Disruption of vesicular storage → reactive oxygen species accumulation → DAergic neuron death

Amphetamine Mechanism of Action

DAT reverse transport; amphetamines reuptook into neuron from extracellular fluid, break down vesicles → inverting DA concentration gradient → DA transporters pump DA into cleft

Positive and Negative Reinforcement

Theory of drug addiction; initial drug used caused by positive urges, addiction caused by avoiding negative

Reward-Related Learning and Memory

Theory of drug addiction; Drugs work by hijacking mesolimbic DA pathway which is responsible for reinforcement learning

Incentive Sensitization

Theory of drug addiciton; drug use causes long term sensitization to “wanting” feeling, causing compulsion

Alcohol Chemistry

Ethanol, volatile colorless flammable liquid

Blood Alcohol Concentration (BAC)

Measure of alcohol levels, percent of blood is alcohol. 0.08 is legally intoxicated, 0.4 are fatal.

Alcohol Pharmacokinetics

Absorbed in small intestine, slowed by food. Decreases linearly, HL = 4-5 hours

Alcohol Metabolism

95% of alcohol is metabolized in the liver by alcohol dehydrogenase. Rest is excreted through breath and sweat.

Consequences of Alcohol

Acute: Euphoria, sociability, sedation, impaired judgement and motor precision.

Chronic: Tolerance, addiction, withdrawal. FAS. Liver damage.

Liver Damage Progression

Healthy → alcoholic hepatitis/liver steatosis → fibrosis liver → cirrhosis liver

Alcohol Mechanism of Action

Stimulates GABA receptors (ergo disinhibiting DA neurons). Inhibits glutamate receptors and neurotransmission. Increases VTA DA neuron firing. Induces opioid peptide synthesis, especially beta-endorphins.

Alcohol Use Disorder (AUD)

Addiction to alcohol. 25% of 18+ people have binge drank in the past month. 15 million 12+ people have AUD.

AUD Treatment

Disulfram: disrupts alcohol metabolization, causing nausea

Naltrexone: blocks opioid receptors

Acamprosate: restores baseline in NMDA-mediated glutamate and GABA neurotransmission

Chemistry of Nicotine

Alkaloid, weak base, volatile

Nicotine Pharmacokinetics

Consumed by smoking, chewing, snuff, or vaping. 7-20 seconds after inhalation to crossing BBB. 1 cig = 2mg nicotine in blood. Nicotine half-life is 1-2 hours, excreted through urine.

Nicotine Metabolism

80% metabolized by hepatic enzyme CYP2A6, becoming cotinine. Cotinine stays in blood for 20 hrs, used as an indicator.

Consequences of Nicotine Use

Acute: mood boost, alertness, memory, decreases stress and appetite

Chronic: Highly reinforcing, sensitization, dependence, withdrawal

Nicotinic Acetylcholine Receptors (nAchRs)

Ligand gated ion channels activated by acetylcholine and nicotine. Comprised of many subunits. Nicotine is an agonist for these receptors, and repeated exposure causes up-regulation.

Homomeric nAchRs

nAchR made of only one kind of subunit; e.g. 5 alpha7s or 5 alpha9s

Heteromeric nAchRs

nAchR made of multiple kinds of subunits; e.g. alpha4beta2, alpha4alpha6beta2beta3, etc.

Nicotine Mechanism of Action

Nicotine is an nAchR agonist, causing increased firing of VTA DA neurons w/ alpha4,6 and beta2 subunits. Activates glutaminergic VTA neurons w/ alpha7 subunits. Desensitizes GABAergic terminals in VTA, disinhibiting VTA DA neurons.

Habenulo-Interpeduncular Pathway

Neuronal pathway which has nAchRs. After exposure to nicotine, causes nicotine withdrawal.

Tobacco Use Disorder (TUD)

Most common drug use disorder in the US- 40 million smokers.

TUD Treatments

CBT = therapy

Nicotine Replacement Therapy (NRT) = small, continuous release of nicotine to reduce withdrawal and cravings.

Buproprion = antidepressant which also alleviates some withdrawal symptoms

Varenicline = nAchR agonist which can stop withdrawal cravings

Opioid

Synthetic narcotics similar to opiates, which are derived from the poppy plant

Opioid Routes of Administration

Can be taken IV, IM, orally.

Heroin Pharmacokinetics

HL 30 mins, duration of action 4-5 hours

Morphine Pharmacokinetics

Peak concentration 15 minutes post intake. HL 2-4 hours. Duration of action 4-5 hours.

Fentanyl Pharmacokinetics

DOA 5 hours, 50 times more potent than heroin

Morphine Metabolism

Morphine is converted to morphine-3-glucuronide (M3G) and (M6G) in the liver, brain, and kidney

Heroin Metabolism

Heroin → Morphine → M3G & M6G

Fentanyl Metabolism

Fentanyl → norfentanyl in liver

Endogenous Opioids

Over 20 endogenous opioid peptides, including endorphins, enkephalins, dynorphins, nociceptin, endomorphins

mu Opioid receptor

Prioritizes endorphins. Regulates sedation, analgesia, gastrointestional transit, hormone and NT release

delta Opioid receptor

Prioritizes Enkephalins. Regulates analgesia, hormone and NT release

kappa Opioid receptors

Prioritizes dynorphins. Regulates analgesia, gastrointestinal transit, and has psychotomimetic effects

Opioid Mechanism of Action

Exogenous opioids mimic endogenous opioid peptides, binding to ORs. Opioidergic cells block pain signals from PNS. Opioids inhibit GABA interneurons w/ muOR → disinhibiting VTA DA neurons → DA excess

A-delta nerve fibers

Myelinated afferent nerves which carry information about sharp and localized pain.

C-nerve fibers

Unmyelinated afferents, carrying dull and delayed pain sensations to the brain.

Consequences of Opioid Use

Acute: Euphoria, pain relief

Chronic: Dependence, addiction

Opioid Use Disorder

Overprescription of opioid painkillers. 50,000 die/year due to opioid overdose

Treatment of OUD

Medical detox = facility monitored sobriety & mangement of withdrawal

Drug tapering = decreasing dose of drug over time

Methadone = slow acting muOR agonist, treats withdrawal without producing euphoria

Buprenorphine = partial muOR agonist → replaces cravings w/o euphoria, less chance of abuse

Naltrexone = OR antagonist, reduces effects

Soboxone = buprenorphine + naltrexone

Naloxone (narcan) = rapid opioid antagonist, treats overdose

Controlled Substances Act

1970. Classifies drugs into difference schedules based on addictiveness, danger, and medical potential. Schedule 1 drugs do not get federal funding.

Phytocannabinoid

Compounds found in cannabis plant: THC and CBD

Endocannabinoid

Cannabinoids produced by the body: anandamide, 2-AG. Involved in learning, memory, mood, and pain response.

Phytocannabinoid Chemistry

THC has a cyclic ring, CBD has a hydroxyl group. Different strains have different THC:CBD ratios. Sativa = 5:3, Indica = 1:1

Phytocannabinoid Pharmacokinetics

Inhalation leads to faster onset. Bioavailability is greater for inhalation. DOA is longer orally.

Phytocannabinoid Metabolism

Metabolized in liver, excreted through waste. THC and CBD distribute to adipose tissue, fat rich areas.

Consequences of Cannabis Use

Acute: Relaxation, euphoria, time perception

Chronic: Can slow brain development, decrease tonic dopamine levels, liver damage, male reproductive toxicity

CB1R

Cannabinoid GPCR expressed mainly in CNS. Binds to THC.

CB2R

Cannabinoid GPCR expressed mainly in PNS. Activated by CBD.

Anandamide

Endogenous cannabinoid, agonist for CB1R and CB2R. Degraded by Fatty Acid Amide Hydolase (FAAH) in Glial cell. Synthesized on-demand when Ca influx occurs.

2-AG

Endogenous cannabinoid agonist for CB1R and CB2R. Degraded by monoacylglycerol lipase (MAGL) in Glial cell. Synthesized on-demand when Ca influx occurs.

Retrograde Signalling

Endocannabinoids are synthesized on demand and released from postsynaptic cell. Bind to presynaptic cell and regulate future presynaptic NT release.

Cannabinoid Mechanism of Action

Acutely increases DA output in nucleus accumbens. Disinhibition of VTA DA neurons. Leads to chronic decrease in DA activity, DA tonic levels decrease.

Cannabis Use Disorder (CUD)

Rising in recent years, likely due to increase in THC concentration of weed products. Inability to stop using, increasing dosage, social impact, withdrawal. Among teenage users, increases chance of psychosis 1% → 4%

Treatment for CUD

CBT = therapy

Motivational Enhancement Theory (MET) = tries to get users to want to stop

Contingency management = paying for sobriety

CB1R agonists = treats withdrawal w/o high

CB1R antagonists = blocks effects of THC, but serious side effects

muOR agonists = Reduce the high effect of cannabis-released endorphins

Butyrylcholinesterase (BChE)

Enzyme in blood which breaks down Acetylcholine and Cocaine

Alcohol Dehydrogenase

Hepatic enzyme which degrades alcohol into acetaldehyde

Acetaldehyde

Toxic intermediary of alcohol, broken down by aldehyde dehydrogenase

Disulfram

Disrupts aldehyde dehydrogenase, making alcohol use more unpleasant

Naltrexone

muOR antagonist, blocks opioid effects

CYP2A6

Hepatic enzyme which breaks down nicotine into cotinine

Bupropion

nAchR antagonist

Varenicline

nAchR agonist, allieviates cravings/withdrawal

Methadone

slow acting muOR agonist, treats withdrawal

Naloxone

Narcan, rapid opioid antagonist, treats overdose