• Dosage
• Route of Administration
• Biochemistry (size, sex, etc.) of individual taking drug
• Experience of individual w/ taking drug
• Interactions w/ other drugs
• Environment (physical and social)
• Genetics
• Mood
• Specificity of Drug
• Potency of Drug
• “Set” – person’s expectations/beliefs about how a drug will affect them
• **How a person’s brain changes after repeated usage

1. Drugs of abuse may have sound medical uses
2. Every drug has multiple effects
3. The size and quality of a drug's effect is dependent on the amount taken
4. The effect of any psychoactive drug depends on the user's individual history and expectations

• initially banned recreational use of opium and all opiate analogs, but other drugs were lumped in later
• sparked by social issues created by opiate abuse

• modern foundation of the US drug enforcement policy
• regulates manufacturing, distribution, and dispensing of potentially dangerous drugs
• places drugs on 5 schedules based on potential for medical use and abuse
  • Schedule I:  High potential for abuse, no recognized legitimate medical use in the US.
    • Marijuana, heroin, LSD, etc.
  • Schedule II:  High potential for abuse, currently accepted for medical use
  • Schedule III:  potential for abuse less than I or II, current medical use.
  • Schedule IV:  low abuse potential, current medical use
    • Codeine
  • Schedule V:  lowest potential for abuse, current medical use 
  • Some states have added schedule VI for inhalants like toluene and nitrous oxide

• DEA - drug enforcement agency; branch of U.S. Treasury
• Research
  • all illicit substances must be approved for usage and supplied by NIH (National Institutes of Health)
    • NIMH - Mental Health
    • NIAAA - Alcohol Abuse and Alcoholism
    • NIDA - Drug Abuse

• made up of the metencephalon and myelencephalon
•  medulla
• pons
• reticular activating system (RAS)
• cerebellum

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• coordinates functions of basic life
• mediates respiratory and cardiac effects of some drugs
  • like opiates when they stop your breathing
• contains reticular activating system

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• together w/ medulla, contains reticular formation
• acts as relay station between cortex and cerebellum

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• involved in arousal and consciousness, sleep, wakefulness, and alertness
• important area for stimulant effects

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• maintenance of balance
• coordination of skeletal motor activities and learned motor skills
• sensitive to alcohol

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• mesencephalon
• controls important sensory and motor reflexes
• pain information
• non-spinal reflexes

• Telencephalon and Diencephalon
• contains limbic system, basal ganglia, and cerebral cortex

• Frontal
• • planning, inhibition of inappropriate behaviors, motor control 
• Parietal
  • somatosensory processing
• Occipital
  • visual processing
• Temporal
  • auditory processing
• Association Cortex
  • large portion (~80%) of cortex that integrates different types of information (like different senses or signals from different parts of brain)

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• A group of interconnected structures that are related to emotional behavior and emotional interpretation of the world.
• Sexual behavior
• Involved in the formation of memory, contains primary reward and punishment centers.
• Site of action of drugs which produce euphoria (direct and indirect)
• Structures
  • hippocampus
  • amygdala
  • hypothalamus
  • parts of cerebral cortex

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• important limbic system structure
• coordinates many motivated functions like eating and drinking
• controls activity of the pituitary gland and thereby controls much of endocrine and autonomic nervous system function (pituitary gland releases many hormones)

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• important limbic system structure
• involved in consolidation of declarative memories (sends to storage)

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• important limbic system structure
• Coordinates autonomic responses in with emotional states

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• important in inhibiting limbic system's ability to affect behavior
• interacts w/ subcortical structures to guide behavior
• drug abuse is often thought of as struggle between subcortical structures and cerebral cortex (especially prefrontal)

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• group of interconnected structures that control voluntary, smooth movement
• structures include
  • striatum (caudate and putamen)
  • globus pallidus
  • substantia nigra
• actions of stimulants in basal ganglia increase motor activity

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• VTA – NAc (DA synapse) is the primary reward synapse in the brain
• VTA dopamine neurons under GABAergic inhibition
• Amygdala, Ventral Pallidum and Hippocampus are part of reward circuitry
• Prefrontal cortex receives DA from the VTA and sends glutamate projection to the NAc

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• neurotransmitter - chemical messenger released from a presynaptic terminal that conveys information to a postsynaptic neuron
  • information can translate as IPSP, EPSP, or modulation that changes the excitability of postsynaptic neuron
• criteria
  • synthesized and stored by presynaptic neuron
  • released in response to action potential
  • presence of specific post-synaptic receptor(s)
  • mechanism for removal from synaptic cleft

• synthesis - how they are made; precursors and enzymes
• storage - how they get into vesicles
• degradation - incidental destruction
• release - exocytosis
• inhibitory feedback via autoreceptors
• activation of postsynaptic receptors
• deactivation

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• small molecule transmitters
  • ~1 aa in size
  • mediate fast synaptic actions
  • synthesized in cytoplasm of axon terminal
  • neurotransmitters like acetylcholine, serotonin, or glutamate
• neuropeptides
  • 3-36 aa in size
  • mediate slower, ongoing synaptic functions
  • synthesized in synaptic vesicles
  • all are neuromodulators
  • molecules like Met-Enkephalin

• these are the primary neurotransmitters that convey EPSPs and IPSPs to postsynaptic neurons (not the only ones thought)
  • effects of a neurotransmitter are entirely dependent on the receptor and its proceeding mechanism of action
•  excitatory
  • Glutamate is the main excitatory transmitter
  • Aspartate is a bit more rare
• inhibitory
  • GABA - brain's main inhibitory transmitter
  • Glycine - spinal cord's main inhibitory transmitter

• key neurotransmitters: Glutamate and Aspartate (excitatory); GABA and Glycine (inhibitory)
• EPSP
  • released neurotransmitter binds to ionotropic receptor
  • ionotropic receptor then opens allowing passage of Na⁺ (or sometimes Ca⁺⁺) causing cell to depolarize
    • for glutamate and aspartate, the ionotropic receptors are sodium channels (so Na⁺ passes)
• IPSP
  • released neurotransmitter binds to ionotropic receptor
  • ionotropic receptor then opens allowing passage of Cl^- (or sometimes efflux of K⁺) causing cell to hyperpolarize

Glutamate

(Lifecycle of Glutamate)

• charged neurotransmitter incapable of crossing blood-brain barrier -> must be made in brain
• released by nearly all excitatory neurons
• Synthesis
  • glutaminase enzymes required for synthesis made in soma
  • glutaminase SLOWLY carried along microtubules to axon terminal
  • precursor glutamine molecules are converted to glutamate via glutaminase
• Storage
  • glutamate subsequently packaged into small, clear-core vesicles for release
• Neurotransmitter release
• Deactivation/ Reuptake
  • glutamate is reabsorbed by synaptic glial cells through VGlut channel
  • glutamate in glial cells is converted back to glutamine via glutamine synthase
  • glutamine leaves glial cell via glutamine transporter and re-enters presynaptic cell via glutamine transporter
• Why this route?
  • circuitous, excessive route is likely way of pulling glutamate out of synaptic cleft as quickly possible
    • glutamate can be toxic to neurons w/ excessive exposure

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GABA

(Lifecycle of GABA)

• charged neurotransmitter that must be produced in brain
• gamma-aminobutyric-acid
• nearly all inhibitory neurons in brain release GABA
• synthesis
  • enzymes required for synthesis are made in soma 
  • enzymes SLOWLY carried to axon terminal via microtubules
  • glutamate precursor is converted to GABA in axon terminal via Glutamic Acid Decarboxylase (GAD)
    
    • glutamate is derived from processing of glucose through glycolysis and Kreb's Cycle
• Storage
  • GABA is packaged into small, clear-core vesicles for release
• Neurotransmitter release
• Deactivation/Reuptake
  • GABA is reabsorbed directly by the presynaptic neuron via the GABA transporter where it can be repackaged

• this would not be possible due to the way neurotransmitters are released
  • during release, the neuron indiscriminately releases docked small, clear-core vesicles
  • if a neuron was designed to release both GABA and glutamate, these would get in the way of one another 
• it also creates an impossibility in the synthesis of GABA
  • release of glutamate as a neurotransmitter would constantly compete with the production of GABA

• GABA receptors are an important site of drug action
• many anti-anxiety medications stimulate GABA receptors
• many epileptic seizures can be tied to GABA deficiencies
• alcohol also stimulates GABA receptors creating the lack of inhibition that is a hallmark of the drug

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• systems in which neurons diffusely project to many parts of the brain regulating overall brain states like mood, arousal, and sleep
• monoamine transmitters (serotonin, catecholamines, etc.) and acetylcholine work through these systems
• common targets of drugs

Acetylcholine

(Lifecycle of Acetylcholine)

• first neurotransmitter discovered
• synthesis
  • acetyl-CoA(from glucose metabolism) and choline(from dietary lipids or liver) precursors are made into acetylcholine via Choline Transferase (ChAT)
• storage
  • loaded into small, clear-core vesicles for release
• neurotransmitter release
• deactivation
  • broken down to choline by acetylcholinesterase (AChE)
  • choline can then be reabsorbed w/ Na⁺

• functions:
  • excitatory at NMJ and ANS synapses
  • in the brain, it is an important neuromodulator
    • Ach neurons found in mesopontine tegmentum(brainstem) as well as basal nucleus of meynert and medial septal nucleus (basal forebrain)
• functions in sleep, attention and memory
  • deficiencies associated w/ Alzheimer's and Parkinson's
• nicotine acts as an agonist
• Acetylcholinesterase (AChE) is target for
  • drugs used to treat neuromuscular diseases and Alzheimer's
  • animal venoms
  • insecticides and chemical weapons

• 5 main biogenic amine neurotransmitters
  • serotonin
  • histamine
  • dopamine
  • norepinephrine
  • epinephrine
• very important in psychopharmacology

• dopamine, norepinephrine, and epinephrine
  • dopamine acts on substantia nigra and VTA
  • norepinephrine acts on locus coeruleus
  • epinephrine is used by key neurons stemming from the medulla

1. L-Tyrosine(aa) is converted to L-Dopa via tyrosine hydroxylase (TH) - cytoplasm
2. L-Dopa is converted to dopamine via Dopa-Decarboxylase/ Aromatic L-Amino Acid Decarboxylase (AAAD) - cytoplasm
3. dopamine enters vesicle via VMAT
4. dopamine is converted to norepinephrine via dopamine β-hydroxylase - vesicle
5. norepinephrine leaves vesicle via VMAT
6. norepinephrine is converted to epinephrine via PNMT - cytoplasm
7. epinephrine enters vesicle via VMAT

• converts tyrosine to L-Dopa
  
  • rate-limiting step
  • first unique enzyme of pathway
  • requires 3 cofactors: BH₄, Fe²⁺, and O₂
    • these cofactors act as key factors in regulation of catecholamine synthesis
• found in cytoplasm

• otherwise known as Dopa-decarboxylase in this pathway
• converts L-Dopa to Dopamine
• ubiquitous enzyme that is located in cytoplasm (so not unique like TH)
• end of pathway for dopaminergic neurons
  
  • vesicular monoamine transporter (VMAT) just has to load the dopamine into vesicles

• converts dopamine to norepinephrine
  • unique to pathways of noradrenergic and adrenergic neurons 
  • requires 2 co-factors: ascorbic acid and O₂
    
    • again, potential site of regulation
• in vesicles
• process ends here for noradrenergic neurons (VMAT not required at this step as it is already in vesicle)

• PNMT for short
• converts norepinephrine to epinephrine
  • unique to adrenergic neurons
• in cytoplasm
• requires VMAT to bring norepinephrine into cytoplasm and VMAT to put epinephrine into vesicle

• Roles
  • coordination of movement - basal ganglia
    • deficiencies associated w/ Parkinson's
  • reward, motivation, and reinforcement learning - mesolimbic reward pathway
    • problems lead to addiction
• Synthesis
  • tyrosine → L-Dopa → Dopamine
  • requires TH and AAAD as well as VMAT for loading
• Degradation/removal
  • dopamine active transporter (DAT)
  • monoamine oxidase (MAO)
    • target of inhibition for depression and parkinson's drugs
  • catechol O-methyltransferase (COMT)
    • target of inhibition for parkinson's drugs

• Roles
  • main role as neurotransmitter of sympathetic nervous system
  • sleep/wakefulness
  • arousal/attention
  • feeding
• Synthesis
  • tyrosine → L-dopa → dopamine → norepinephrine
  • requires TH, AAAD, dopamine β-hydroxylase, and VMAT for movement of dopamine into vesicle
  • unique synthesis occurs in vesicle
• Degradation
  • norepinephrine transporter (NET)
  • monoamine oxidase (MAO)
    • target of inhibition by depression and Parkinson's drugs
  • catechol O-methyltransferase (COMT)
    • target of inhibition for parkinson's drugs

• Role
  • acts at cardiovascular and respiratory tissues
  • fight/flight response
  • less common ANS transmitter
• Synthesis
  • tyrosine → L-dopa → dopamine → norepinephrine → epinephrine
  • requires TH, AAAD, dopamine β-hydroxylase, PNMT, and VMAT for transport of intermediates/product into and out of vesicle
  • unique synthesis in cytoplasm

• abbreviated 5-HT
• Roles
  • sleep/wakefulness
  • depression/anxiety
• Synthesis
  • tryptophan is converted to serotonin via tryptophan-5-hydroxylase 
• Removal/Degradation
  • serotonin transporter (SERT)
    • common drug target for depression and anxiety (prozac)
  • monoamine oxidase (MAO)
    • common target for depression and parkinson's drugs

• many double as hormones
• roles in modulating emotion, pain, stress, and homeostasis
• co-localized w/ small molecule neurotransmitters
• examples
  • somatostatin, CCK, Substance P, and VIIP
  • opioids
• synthesis
  • pre-propeptides synthesized in rough ER of soma from mRNA
  • pre-propeptides moved to golgi apparatus, have their signal sequence removed to become propeptides, and are packaged into transport vesicles
  • propeptides enter large, dense-core synaptic vesicles and are broken down by enzymes w/in those vesicles into neuropeptides 
• deactivation/removal
  • no mechanism for reuptake like other transmitters
  • neuropeptides broken down by peptidases

• class of neuropeptides
• endogenous opioid peptides 
  • endorphins
  • enkephalins 
  • dynorphins
• co-localized w/ GABA and serotonin
• tend to be depressants (lead to reduced neurotransmitter release)
• act as analgesics - control pain
• very addictive agents of abuse

• all amino acid transmitters, acetylcholine, and serotonin have both metabotropic and ionotropic
• all other transmitter have only metabotropic receptors

• metabotropic neurotransmitter receptors located on presynaptic membrane 
• activation of autoreceptors leads to inhibition of subsequent neurotransmitter release
  • commonly through inhibition of voltage-gated calcium channel
  • or inhibition of key synthetic enzymes like TH for catecholamines

• Synthesis:
• • Increase or decrease the rate of synthesis by actions on synthetic enzymes
• Storage: 
• • enhance or prevent neurotransmitter storage
• Release: 
• • increase or decrease the amount of neurotransmitter release
• Metabolic breakdown: 
• • increase or decrease the rate of neurotransmitter metabolism
• Bind to receptors: 
• • agonist or antagonist depending on whether the drug activates the receptor
  • Also, can bind to autoreceptors (presynaptic) and regulate release of neurotransmitter
• Reuptake: 
• • reduce or enhance reuptake of neurotransmitter back into the presynaptic terminal

• effect of drug is based on how much of drug gets to brain and how fast it gets there based on its ability to travel through body and reach brain intact
• important factors
  • molecular structure of drug
  • concentration of drug at site of action depends on:
    • dose administered
    • rate of accumulation/removal from site of action
• not just dependent on dose of drug but also its pharmacokinetics

• refers to processes involved in the movement of drugs w/in biological systems w/ respect to absorption, distribution, metabolism, and excretion

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[image] 

• refers to getting drug from where it is administered to site of action - brain in terms of psychoactive substances
  • looks at the many barriers between getting from admin. site to site of action
  • these barriers are generally posed through passing various biological membranes (particularly BBB)
• absorption of drugs is dependent on
  • lipid/water solubility (ability to cross membrane) - most important
  • concentration of drug - drugs will move from high to low if they can pass through membrane
  • dosage form (route of admin + additives)
  • other more minor factors
    • area of absorptive surface
    • body pH
    • gastric motility
    • presence of other substances

• drug must be able to cross membranes
• this requires them to be lipid soluble, but must also have way to travel through aqueous environments of body (water soluble)
• principles of lipid/water solubility
  • like dissolves like -
    • hydrophilic (polar/charged) molecules dissolve in water
    • hydrophobic (nonpolar) do not, but are better dissolved in lipids
• most drugs, by necessity, have both hydrophobic and hydrophilic tendencies so they can dissolve in both the aqueous environment of blood as well lipid bilayer
• important measurement of lipid/water solubility is oil -water partition coefficient

• partition coefficient is relative solubility of molecule between two media
  • in case of oil-water, it is the relative solubility of molecule in oil vs. water
• higher oil-water partition coefficient = greater solubility in lipid membrane (more easily passes)
  • also indicates lower solubility in water

[image]

• route of administration is an extremely important aspect of how much of drug can be absorbed
  • it determines number of barriers drug must pass to reach site of action
  • more membranes drug has to pass = slower absorption
• common routes of administration
  • oral (p.o.)
  • injection
    • intravenous (i.v.) - into vein
    • subcutaneous (s.c.) - underneath skin
    • intramuscular (i.m.) - into muscle
  • inhalation
    • smoking
    • vaporous inhalation
  • topical/absorption through skin and membranes
    • intranasal - applied to mucous membranes of nose
    • sublingual - applied under tongue
    • transdermal - applied to skin
• speed of onset
  • least to most
  • oral < s.c. < i.m. < sublingual or intranasal < inhalation ≈ i.v.
    • inhalation has very fast onset, sometimes even faster than i.v.

• standard form of administration we use daily - pills
• many drawbacks - very slow absorption and much of drug can be lost along the way
  • in stomach, drug must withstand stomach enzymes and acid
  • drug must then pass through epithelial cells lining GI tract and then pass into bloodstream
  • a large portion of GI blood circulation is run through liver where it faces more potentially degradative enzymes (hepatic portal system)
• first pass effect - only applies to oral administration
  • blood supply to GI tract goes directly to liver
• other factors affecting absorption
  
  • slow admin causes reduction of concentration in blood such that drug may not reach levels capable of inducing effect
  • it is dependent on rate of movement of contents through GI tract
    • rapid movement of GI tract decreases absorption due to shorter duration of contact
  • also dependent on contents of GI tract
    • empty stomach is more acidic environment that will favor weakly acidic drugs (aspirin) while decreasing absorption of other drugs

• drug passes directly into bloodstream bypassing all barriers faced by oral admin aside from BBB
• this can make many drugs that are entirely ineffective when taken orally very effective or drugs that were safe orally toxic
• results in fastest onset and highest concentration reaching bloodstream
• disadvantages to i.v. administration
  • drug has to be in solution
  • weakens veins over time (can lead to collapse of walls of veins)
  • can lead to blood clot formation
  • raise more potential hazards in terms of blood-born illnesses 
  • much harder to stop overdose w/ this form of admin as its onset is so fast

• regulates passage of substances from bloodstream to brain
• maintains integrity of the brain’s environment so that it is not subject to transient fluctuations in the blood.
• to pass through BBB, a drug must be:
• • very small
  • compatible w/ active transport system
  • most importantly, lipid soluble

• the faster that the drug is absorbed, the more intense the euphoria; more intense euphoria = greater likelihood of addiction
  • route of administration can be really important to this
    • route of administration can affect intensity of effect of drug
    • it also affects time-course
    • this is particularly true w/ cocaine
• chosen routes of administration is based on the plasma concentration of drug in blood at any given time, the speed of onset, and the subjective feeling of high

• distribution of drugs throughout body is key to determining drug effect
  • more drug accumulating in areas other than site of action means less drug at site of action
  • lipid solubility of drugs allows most to deposit in many locations around body (not just brain)
• same factors involved in absorption also determine whether and how drug is accumulated or stored in body
• sites of accumulation are often where drug causes toxicity
• adipose tissue acts as a storage depot for many drugs
  • psychoactive drugs are particularly susceptible to this
  • high lipid solubility required to cross BBB

Metabolism

(Biotransformation)

• metabolism refers to any process that results in chemical change in a drug in the body
• it can make drugs less active, have no effect, or sometimes more active
  • eventually, metabolism pretty much always reduces effect of drug, but initially metabolism may be required to feel effect of drug
• liver is key site of drug metabolism
  • first pass metabolism for oral administration

• liver is key site of drug metabolism
  • especially for orally administered drugs
• liver contains many different enzymes which metabolize different drugs
• hepatic microsomal enzyme system
  • enzyme system evolved to deal w/ toxic substances
  • developed to deal w/ wide variety of chemicals making the system non-specific and capable of acting on many different types of substrates
  • Cytochrome P450 enzymes are a key portion of this system
    • ex. CYP 2D6 involved in catabolism of more than 20% of all drugs
• for certain drugs, metabolism requires specific enzymes designed to act on only that drug
  • processing of alcohol, for example, requires alcohol dehydrogenase 

• drugs are metabolized in liver into more water-soluble metabolites that can be passed through urine
• the excretion/elimination of these drugs/metabolites can be seen as an exponential decay function (like nuclear decay)
  • this means time-course of elimination can be explained w/ plasma half-lives
• most drugs are removed from body via kidneys 
  • kidneys remove most efficiently when drug concentrations are high (conc. grad)
  • higher drug concentration = faster removal (for most drugs) - why drugs like cocaine dissipate so quickly when inhaled vs. taken orally
• for psychoactive drugs
  • high lipid solubility makes excretion slow 

• lipid/water solubility of drug
• acidity of urine and acidity of drug
  • acidic drugs like aspirin more effectively excreted in more basic urine
    • drink bicarbonate in soda
  • basic drugs like morphine more effectively excreted in more acidic urine
    • consume vitamin C

1. Dosage
2. Frequency
3. Drug Interactions
4. Environment - both social and physical
5. Route of Administration
6. Metabolism
7. How drug is eliminated/exterminated
8. Set - psychology and expectations of user

• amount of drug taken at one time
  
  • drug's action dependent on amount of drug available which is dependent on dose, so very important factor
• drug effects typically discussed in terms of dose-response function
  • relationship between dose given and response observed
  • this relationship is tested by giving groups of individuals different levels of drug
    • almost always involves placebo group - or group receiving no drug w/out knowing as control
    • may also use double-blind procedure to ensure that researcher's bias does not effect results

• concentration 
  • amount of molecule of interest in its vehicle (i.e. pill or other form of admin)
  • example: concentration of fluoride in city water is may be 1 mg/L
• dose
  • amount of drug administered to person
  • example: if person drinks 5 L of city water, their dose of fluoride would be 5 mg
  • response is more related to dose, as concentration does not tell you anything about the exact amount of drug consumed 

• two key relationships underlie the dose response relationship
  1. dose-plasma concentration relationship
     • amount of drug that actually makes it to blood is key in determining drug effect
  2. plasma concentration-response relationship
     • concentration in plasma is not only factor affecting drug effect, so concentration-response relationship is a constant
• it is important to also note the difference between log-dose and linear dose response curves
  • log scale advantages
    • full range of doses can be observed
    • much easier to illustrate effects/interactions of agonists and antagonists
• shape of dose-response curves is because drug-receptor interaction obeys law of mass action
  • # of receptors occupied by drug is based on drug concentration and Kd
    • Kd = ratio of receptor dissociation to association rate constants (basically measure of affinity for receptor)

[image]

• Think about michaelis-menten enzyme kinetics in biochem
• E = (E_max * [D]) / (Kd + [D])
  • E = Observed effect of dose of drug
  • Emax = maximal response
  • Kd = dissociation constant of drug receptor complex
    • High Kd “ weak interaction – low affinity
    • Low Kd: strong interaction = high affinity
  • As concentration of free drug increases, ratio of concentrations of bound receptors to total receptors approaches unity 
    • unity = every receptor bound by drug (why slope falls off as drug concentration increases)

[image]

• graded
  • measured in single biological unit
  • continuous scale
  • relates dose to intensity of effect
  • example: measuring blood pressure change in individual on continuous scale
• quantal
  • population studies
  • looks at all-or-none pharmacological effect as opposed to effect intensity
  • relates dose to frequency of effect in population
  • example: instead of measuring exact blood pressure, measure whether there was any effect on blood pressure among members of population

[image]

• increasing doses has a maximal effect for (pretty much) all drugs
• for some drugs, increasing dosage past a certain point is actually associated w/ declining effects
• this is an extremely common observation when looking at the therapeutic index of a drug
  • after a certain dosage, the amount of drug can cause other things to happen w/ tolerance that take away from general effect of drug
  • side effects may take away from overall health benefits
  • too high of a dose discourages subjects from administering drug
• [image]

• threshold dose
• maximal response
• ED₅₀ - amount of drug required to elicit drug effect in half of subjects (effective dose)
• LD₅₀ - amount of drug required to kill half of subjects (lethal dose)
• side effects - unintended effects that accompany therapeutic effects (death would typically be considered side effect) 

• the therapeutic benefits of a drug typically follow a biphasic function
• the peak of this function would be our therapeutic window where the maximal response is elicited
• measure of a drug's relative safety can be determined w/ therapeutic index
  • calculated as ratio of LD₅₀ to ED₅₀
  • higher ratio = safer drug
  • ratio of 100 or greater is generally considered safe 
  • ratio of less than 10 is considered extremely unsafe
  • there is quite a bit of subjectiveness to scale as drug like lithium has therapeutic index of between 4 and 5, but is still considered safe enough to prescribe

• efficacy - how well a drug can produce a desired effect
  • not all drugs in given class equally good at producing same maximal response
  • when determining, we look at which drug has a higher maximal response
• potency - how much of drug is needed to produce a given effect
  • not all drugs produce the maximal effect at same dose
  • when determining, we look at which drug requires the lowest dose to reach its maximal response (regardless of how high maximal response may be)

• potencies and efficacies of drugs can be affected by presence of other drugs
• antagonistic interactions between drugs cause potency and/or efficacy of drug to decrease when taken w/ other drug
• synergistic interactions between drugs cause potency and/or efficacy of drug to increase when taken w/ other drug

• Synergistic drug interaction in which taking drug A and B together increases efficacy in comparison to either drug alone
  • does not consider potency

• synergistic drug interaction in which taking drug A and drug B together causes an increase in potency in comparison to taking either drug alone
  • does not consider efficacy

• form of antagonism in which antagonist binds to same binding site on receptor as drug
  • not necessarily true, but good simplified way of thinking of it
    • actually is when antagonist cannot bind when drug and receptor are bound
• this form of antagonism can be combated by increasing drug concentration
  • this increases likelihood of drug binding instead of antagonist
• potency is affected in this interaction while maximal response/efficacy is not

[image]

• form of antagonism in which the antagonist binds to receptor in a site other than the drug binding site
  • again, simplified
    • specifically, when drug is able to bind to receptor when drug is bound
• this type of interaction can be due to 
  • antagonist binding may cause steric hindrance making it difficult for drug to reach binding site
  • antagonist binding may change shape of receptor, so drug binding does not affect receptor in same way
  • in ion channels, antagonist binding may block the conductance of the ion channel
• noncompetitive antagonism cannot be overcome by increasing drug concentration
• this type of antagonism reduces drug efficacy but not potency

[image]

• full agonists are molecules that bind to enzyme eliciting maximal response
  • induce large stimulus to cellular signaling machinery
• partial agonists are molecules that bind to enzyme eliciting a smaller response
  • induce small stimulus to cellular signaling machinery
  • will never reach maximal effect even when all receptors are bound
• example: heroin vs. buprenorphine

[image]

• produce response that is below baseline responses when drug is absent
  • essentially create opposite effect 
• works by abrogating intrinsic activity of free receptor
• similarities between competitive antagonists and inverse agonists
  • reduce activity of receptor
  • in presence of full agonist, act to reduce agonist potency
• differences between competitive antagonists and inverse agonists
  • inverse agonist deactivates receptors that are constitutively active in absence of agonist
  • competitive antagonist has no effect in absence of agonist

[image]

• behavioral pattern of drug use characterized by: 
  • preoccupation w/ attainment of drug
  • compulsive use
  • high tendency to relapse after withdrawal
• can be thought of as an extreme on a continuum of drug use
  1. occasional use 
  2. frequent use 
  3. physiological dependence (habituation) 
  4. compulsive drug use (preoccupation) 
  5. overwhelming involvement
• in this model, relapse is not just failure of treatment but an actual symptom of addiction

• Use: used for psychoactive effects, without any immediate problems
• Abuse: persistent use that often leads to negative consequences (“problem” use)
• Dependence: defined by presence of physiological dependence – having tolerance & withdrawal
• Addiction: defined by the presence of behavioral compulsion – inability to stop taking the drug despite significant negative consequences; impairment of “normal” functioning

• all addiction is labeled as substance use disorder (SUD) and qualified on mild, moderate, severe spectrum
• example:
  • early stage alcoholism might be referred to as mild substance use disorder for alcohol

[image]

• set forth by the DSM-5
• criteria
• 1. The substance is often taken in larger amounts or over a longer period than was intended.
  2. There is a persistent desire or unsuccessful effort to cut down or control use of the substance.
  3. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.
  4. Craving, or a strong desire or urge to use the substance.
  5. Recurrent use of the substance resulting in a failure to fulfill major role obligations at work, school, or home.
  6. Continued use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of its use.
  7. Important social, occupational, or recreational activities are given up or reduced because of use of the substance.
  8. Recurrent use of the substance in situations in which it is physically hazardous.
  9. Use of the substance is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
  10. Tolerance
  11. Withdrawal

• typical time-course
• potential causes
• epidemiology

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• treatment efficacy
• precise neuronal mechanisms
  • we have some general ideas but are missing specific, complete process
• environmental factors
• vulnerable groups

• subjects are those w/ pre-existing SUD or those w/ "casual" use (as well as inexperienced controls)
• assessments used
  • self-report - subject reflects on their own opinion of how they felt during study (subjective high self-reports)
  • longitudinal - study groups of subjects over time
  • genome-wide association - compare genomes of users w/ those of unafflicted individuals
  • cue/stress reactivity - more of a psychological approach w/ presentation of cues or stressors and recording of response and time it takes to respond
• imaging
  • anatomical - static images of brain structures
    • looking at things like degradation of certain structures or things like this
  • functional - intuitive images of brain structures that capture level of activity

• Types of animals used
  • rodents
    • various lines, strains, genetic modifications
    • most common as they are much cheaper than nonhuman primates, but still fairly generalizable to humans
  • nonhuman primates
  • zebrafish
  • drosophila
  • C. elegans (roundworm)
• importance
  • experimental studies can only be ethically achieved w/ animals
    • every facet of animal's life can be controlled in lab to minimize confounding variables
  • can determine direct brain-behavior relationships
  • studies are still generalizable as mouse-human homology is greater than 90%

• compulsion or desire to experience effects of drug because it produces pleasure (early use) or reduces discomfort (later use)
• heavily influenced by context user is in - result of learning and memory
• cause:
  • all abuse-prone drugs enhance or lower threshold for brain reward
  • drug-taking behavior regularly followed by rewarding effects of drug encouraging further use
  • drug-taking behavior also influenced by fear of entering withdrawal
    • in some cases physical dependence can be formed independent of psychological dependence
    • still results in reinforcement of drug-taking behavior due to fear of withdrawal (coffee)
• most psychotherapeutic drugs are designed to minimize the risks of psychological (not physical) dependence
  • antidepressants and antipsychotics have long history of patients not wanting to take them

• reward 
  • something brain processes as having positive value
  • behaviorally: elicits approach
• reinforcement 
  • stimulus that increases likelihood of behavior that is paired w/ it
  • not perceived as good or liking it like reward
  • reward ≠ reinforcement
• drugs of abuse can be rewarding and reinforcing
  • upon initial consumption, they produce a rewarding state of mind
  • some drugs are more reinforcing than others which results in different potentials for addiction

• natural reinforcers
  • resources that are necessary for survival/homeostasis
  • food, water, sex, etc.
  • these reinforcers stimulate reward pathway via sensory and other internal pathways
• drug reinforcers
  • tap into same reward circuitry by directly manipulating its chemistry
  • allows for production of extreme euphoric states unachievable through natural sources
  • also causes extreme reinforcement and can lead to compulsive behavior

• mouse study
• design
  • mouse presses lever to earn sugar pellet
  • we already know that sugar pellet is reinforcing and rewarding, but this can provide frame of reference for other substances
  • results show linear increase in lever presses over time despite unchanging rate of sugar pellet release
• Conclusion: if mouse continues to increasingly press the lever over time regardless of how many responses it gets, substance is both rewarding and reinforcing

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• difficulties in proving existence of addiction in animals
  • oral administration made reinforcement extremely difficult for rodents due to long time-course
  • animals were made physically dependent, but would not consume drugs independently (sign of psychological dependence/addiction)
    • people thought animals were unable to learn association between drug and relief of withdrawal
• emergence of technology allowing i.v. admin of drug solved previous issues as animals showed that they could learn association as they freely consumed morphine
• drug as positive reinforcer?
  • Schuster showed that animals that were not physically addicted would self-administer drugs
  • animals also self-administer drugs that are known to not cause physical dependence
  • conclusion: drug is acting as positive reinforcer
• Pickens and Thompson
  • showed that cocaine would act as positive reinforcer in rodent studies w/ lever and cocaine admin
    • decrease in lever pressing when no longer followed by drug
• Olds and Milner showed that lever pressing behavior was also reinforced via shocking certain brain areas

• Why would a drug continue to act as a positive reinforcer even when it produces unpleasant /negative consequences?
  • the more immediate the effect, the more influence it will have on behavior

• Genetics
  • Genetic factors may contribute more to drug abuse than use (addiction not just likelihood of general use
  • Possible in-born differences in neurotransmitter systems may contribute to drug seeking behavior
  • example: children of alcoholics more likely to become alcoholics whether raised by biological or adoptive parents
• Sociology
  • family - weak family involvement correlated w/ drug use
  • religion - religious involvement correlated w/ non-abuse
  • prior exposure to licit substances like alcohol
    • can encourage use of illicit substances which can increase likelihood of other illicit substance use
• Psychology
  • many hypotheses emphasize personality traits
    • antisocial and thrill-seeking personalities

• repeated exposure to the same dose of a drug results in a lesser effect
  • increasingly large doses of drug become required to achieve same effect
  • in some cases, original effect can never be achieved again
• tolerance can work on both potency and efficacy
  • potency - more drug required for same effect
  • efficacy - same level of effect cannot be achieved w/ any level of drug

• development of tolerance to one drug results in decreased sensitivity to another type of drug in same category
  • barbiturates and alcohol
  • cocaine and amphetamine

• drug distribution/pharmacokinetic tolerance involves adaptations in pharmacokinetics of drug
  • how your body deals w/ drug
• most common form of this type of tolerance is metabolic tolerance
  • involves liver synthesizing more drug-metabolizing enzymes than normal when exposed to drug for some length of time
  • all of drug's effects will develop tolerance in this model because it is due to overall decrease in drug concentration
    • example: phenobarbital increases microsomal P450 enzymes; in later uses phenobarbital concentration has to decrease as increased P450 breaks down more drug 

• involves adaptations in way that individual neurons respond to drug
  • a drug may induce changes in homeostasis
  • these would include changes in receptor sensitivity
  • can be viewed as brain's attempt at maintaining its level of functioning w/in normal limits
• agonists of nt action - tolerance to drugs that tend to mimic or amplify effects of a neurotransmitter tend to decrease receptor activity to combat homeostatic change
  • down-regulation
    • important mechanism of tolerance by which number of functional receptors is decreased
  • de-sensitization
    • decrease in receptor's ability to elicit changes (does not change receptor #)
  • *regardless of specific mechanism, downregulation and desensitization of receptors will occur at postsynaptic neuron
•  antagonists of nt action - tolerance to drugs that dampen the effects of neurotransmitter tend to increase receptor activity
  • upregulation
    • increase in # of functional receptors
  • sensitization
    • increase in receptor's ability to elicit changes (does not change receptor #)
  • *again, specific mechanism is unimportant to tolerance changes occuring at postsynaptic membrane

• tolerance caused by learned adaptation to drug
  • individuals may learn to adapt to altered state of nervous system and attempt to compensate for impairment
  • when drug is taken in one environment and displays tolerance in that environment, but loses tolerance when taken in different environment
• examples:
  • animal study
    • rats administered opiates in one cage every time and their dose was increased w/ rising tolerance; when rats were moved to another cage, same dose used in original cage caused 68% of sample population to die
  • heroin addict returning from jail 
  • Erhman et al. (1992) paper

• one of the leading theories for context-specific tolerance is that classical conditioning is likely involved
  • acquisition - drug is paired w/ particular environment of usage
  • when in this environment, even w/out drug, body's adaptive mechanism can be triggered
    • withdrawal and cravings may be experienced
    • however, body is also preparing itself for drug administration
  • when in different environment, conditioned stimulus is absent, and body does not prepare for drug administration

• Although psychoactive drugs used in our culture may not be terribly harmful when taken in reasonable doses , development of tolerance causes many issues
• • users begin to require larger and more frequent doses
  • these larger doses can amplify the toxic effects of these drugs despite providing the same high
  • tolerance to effects of drugs does not develop uniformly w/ some effects may experience little to no tolerance
  • people can even become more sensitive to side effects while tolerance is occuring to only the desired effect
• example: alcohol and sedative/hypnotics: the beneficial/recreational effects of the drug may show tolerance, but there is little tolerance to the lethal effects
  • in other words, increasing doses required to experience desired effect gradually become closer to lethal doses which are unaffected by tolerance

• tolerance does not develop uniformly affecting some effects of drug more than others
• alcohol/barbiturates
  • tolerance to desired effects of drug, but no tolerance to lethal side effects
• amphetamines
  • tolerance to euphoria, but user can become more sensitive to psychotic-producing effect

• defined by the occurrence of a withdrawal syndrome
• withdrawal syndrome
  • set of defined symptoms associated with a decrease in the blood levels of a particular drug
  • usually effects of withdrawal are opposite from effects of drug
  • withdrawal syndrome varies from drug-to-drug

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• set of defined symptoms associated with a decrease in the blood levels of a particular drug
• Withdrawal is due to changes in the nervous system that are in place in response to the chronic presence of the drug
• When the drug is removed, the compensatory mechanisms are exposed and an imbalance results
• Heroin example – constipation
  • body’s attempt to address heroin effect is to increase GI motility (in vain)
  • when user stops taking drug, they don’t need compensatory mechanism and shit themselves
• Withdrawal syndrome varies from drug to drug
• **The duration and intensity of withdrawal syndrome is highly correlated with the duration and intensity of a drug's direct effects

• PAWS
• longer lasting symptoms that are heavily associated w/ relapse
• how does it work?
  • chronic drug use alters reward pathways in brain
  • natural rewards no longer produce the same levels of dopamine than before drug taking
  • Patients report feeling depressed, having flat affect and that “nothing feels good”
  • The specific mechanisms vary depending on the drug used
• common symptoms
  • Inability to think clearly
  • Memory problems
  • Emotional overreactions or numbness
  • Sleep disturbances
  • Physical coordination problems
  • Stress sensitivity