Neuropharmacology: Basic Principles and Applications

Introduction to Neuropharmacology

• The goals included translating basic neuroscience into new therapeutic agents

• The goals included elucidating mechanisms by which drugs act in disease

• The goals included the uses of chemical compounds as tools to investigate cells and synapse

• Fluoxetine binds and inhibits serontonin transporters, ultimately increasing serotonin

• Furosemide binds to and inhibits Cl- channels

Principles of Neuropharmacology I

• Pharmacology is concerned with drug-induced changed to the nervous system

• Psychopharmacology involves mood, thinking, and behavior

• Neuropsychopharmacology relates to the neurobiology of behavior

• Placebo is a pharmacologically inert compound that may have therapeutic effects and side effects

• Nocebo effect is increased anxiety or pain due to negative expectations

• Experiments that are double-blind means neither the patient nor observer knows what treatment the participant has received

• Bioavailability is the amount of drugs in the blood that is free to bind at specific target sites

• Pharmacokinetic components of drug action contribute to bioavailability

• Systemic routes means that the drug moves throughout the body through general circulation

• Oral administration (PO) means that the drug must pass through the stomach or intestine to reach blood capillaries

• Absorption defines movement of drug from the site of admin to the blood circulation

• First-pass metabolism suggests that ingested chemicals pass via the portal vein to the liver, where they are altered by enzymes before passing to the general circulation

Methods in Neuropharmacology

• Behavioral pharmacology measures are crucial

• Behavioral pharmacology measures help understand the neurochemical bases of behavior and drug-induced changes in that behavior

• Behavioral pharmacology can help in developing animal models of psychiatric disorders

• Behavioral pharmacology helps screen newly designed drugs in preclinical pharmaceutical settings

• Animal testing must be valid and reliable to produce useful information from it

• Studies using animals have several advantages, including rigorous control of living conditions, history, and ethics

• Studies using animals have advantages such as genetic history, ethics, and generalization

• Evaluating animal behavior means results can validate correlational relationships during drug development and evaluation

• Evaluating animal behavior follows strict animal care guidelines

• Experimental Validity: animal tests with high validity closely resemble those used on humans like blood pressure tests

• Predictive validity suggests that drug effects observed in laboratory tests closely parallel or predict the clinical effect

• Construct validity is the extent to which the animal measurement tool actually measures the characteristic being investigated

• Controls are when placebos are often injected as the solution the drug is dissolved in, or a negative control

• Positive control is a drug thats produces well-characterized effects on a behavioral test, and is tested in addition to the compound of interest

• Requirements of testing include predictive validity

• Requirements of testing should be specific for the class of drug being screened

• Requirements of testing should be sensitive to a normal therapeutic range of does and show a does-response relationship

• Requirements of testing should demonstrate the same rank order of potency in animal tests as the order of the therapeutic action of the drug

• Requirements of testing should have high reliability

• Evaluating behavior includes a wide variety of behaviors evaluated by psychopharmacologists

• Evaluating behavior includes simple observations such as tremors, salivation, catalepsy etc

• Evaluates of behaviors also include the measures of motor activity, which help identify drugs that produce sleep or sedan

• Operant conditioning is when an animal learns a response to obtain rewards

• Learning is a type of animal behavior

• Animal learns a response by pressing a lever to receive a food reinforcer

• Once the behavior is learned, requirements for reinforcement can be altered according to a schedule of reinforcement

• Fixed Ratio (FR) schedule involves a fixed # of responses

• Fixed-interval (FI) involves reinforcement after a fixed amount of time

• Measures of analgesia includes reduction of perceived pain without loss of consciousness

• A tail-flick test measures the response of the animal to heat applied to the tail

• Hot plate test is when an animal is placed in a cylinder on a hot plate, and the temperature is increased

• Operant analgesia testing uses negative reinforcement

• Anxiety involves anxiety-like behaviors that include light-dark crossing, open field and plus maze tests

• Fear and depression involve measures of fear, such as conditioned emotional response and fear potentiated startie

• Fear and depression involve measures of depressive-like behaviors, such as behavioral despair, forced swim and tail suspension tests

• Stress involves tests of chronic mild unpredictable and social defeat stress

• Stress involves tests of maternal separation

• Stress involves the sucrose preference test which measures anhedonia

• Rewarding involves the methods of assessing drug reward and reinforcement

• Rewarding can be assessed through the drug self-administration method

• Rewarding can be assessed through electrical self-stimulation

• Rewarding can be assessed through breakpoint and conditioned place preference

• New technologies include computer version

• New technologies include AI algorithms used to analyze video recordings of animals in habitat-based test environments

• Behavioral data is also collected from humans

• Techniques in neuropharmacology include stereotaxic surgery for accurate in vivo measure of brain function

• Devices can be implanted in the brain

• It involves brain site coordinates calculated using a brain atlas

• A similar apparatus is used for human brain surgery

• Lesioning is when an electrode is inserted to destroy brain tissue, and behavior is evaluates before and after

• Neurotoxins can be injected via a cannula to destroy cells

• Specific neurotoxins are for different neural pathways that use a particular Neurotransmitter

• Microdialysis is the measurement of NTs released in a specific brain region while the subject is actively engage in behavior

• In vivo voltammetry uses implanted microelectrodes to measure neurochemicals in extracellular fluid of freely moving animals

• Implanted macroelectrodes: electrical stimulation produces effects similar to NT injection

• Microelectrodes can be implanted into a single cell, enabling intracellular recording

• Patch lamp electrophysiology allows study of individual ion channels

• NTs and receptors, and other proteins can be quantified visually in the CNS

• The soup method separates and grinds tissue to form a homogenate used for analysis

• The slice method uses a slice of tissue for visualization

• Radioligand binding: the amount of bound ligand reflects the # of receptors in the tissue

  • This is found by determining the criteria if the ligand is binding to a receptor
  • You can calculate the Specificity, Saturability, Reversibility and affinity and Biological relevance

• Autoradiography: when a radioligand is added to a tissue slice, it shows distribution of receptors in the brain

• In vivo receptor binding: when an animal is injected with radioligand, it shows distribution of receptors while still alive

• We can determine assays of antibodies by using antibodies to bind to specific proteins

• Immunocytochemistry

• A western blot is a common labratory technique

• Radioimmunoassay help determine assays

• The enzyme-linked immunosorbent assay assists in measuring a targeted protein

• In Situ Hybridization: locates cells that are manufacturing a protein or much mRNA peptide

• DNA microarrays measure gene expression

• GWA studies uses gene chips consisting of SNPs to search for alleles associated with a disease

• New tools involve imaging techniques like SPECT/fMRI/EEG

• Genetic engineering is a new tool including KO mice, which lack gene for making particular proteins

• Genetic engineering involves knockin mice for inserted gene

• Genetic engineering involves transgenic mice where one gene has been substituted for another

• CRISPR is a faster way to genetically engineer mice

• Optogenetics uses light to exerted precise control in cells and the researchers can instantly excite or inhibit cells

• Chemogenetics or DREADD receptors can be genetically engineered and then ligand suppresses or activates it

Catecholamines

• Catecholamines are monoamines, meaning they have a catechol and amine group
• Dopamine (DA) falls under catecholamines
• Norepinephrine (NE) falls under catecholamines
• Epinephrine (EPI) falls under catecholamines
• They are dopaminergic, noradrenergic, and adrenergic
• Catecholamines synthesize because of tyrosine
• Tyrosine hydroxylase (TH) is the RATE LIMITING ENZYME
  • This is affected by the DA and NE levels
  • The DA and NE levels provide negative feedback
  • Cell firing activates TH
  • Catecholamine increase due to precursers
  • Drugs that reduce enzyme can only block TH
  • Alpha-methyl-para-tyrosine (AMPT) blocks TH
• Can increase formation with presecsors that have tyrosine and L-DOPA
• Catecholamine Storage and Release regulates vesicular uptake, cell firing and autoreceptor activity
• It’s loaded into synaptic vesicles by vesicular monoamine transporters or VMAT
  • Can be blocked by reserpine, an irreparable inhibitor
  • Psychostimulants lead to release by amphetamine and methamphetamine
• DA release is inhibited by autoreceptors also known as neuron firing activity with single spike
• Burst mode with 2 to 20 spikes leading to trauma that can’t be clear as well as some axons en passant that have swelling
• DA tranpsortes causes the transporters will return back
• Methyphinade and amphetamine
• Reuptake inactivate which is a process to be released after Catecholinamines are used which the DA will take transporters to repack it
• Uptake is cells by post synaptic for selective
• Increase or NE through receptors which increases available new receptors
• The Monoamine can cause levels due to involves Mono and COMt and the MAO can be dangerous because the non selective MAO can damage
• Selective MAO inhibitors: moclobemide (MAO-A) for depression and Selegiline (Eldepryl) and rasagiline (Azilect) for Parkinson's disease
• COMT acts on compounds containing the catechol structure
• Action of MAO and COMT produce metabolites: the
  • DA metabolite is homovanillic acid HVA
• Organization of Dopaminergic System are in the midbrain and the A9 ascends to the dorsal striatum
  • A10 in the ventral tegmental area to the limbic
  • Parksinson is losss in the DA in substantia and mutated genes for tetrahydrobiopterin
• Modelling loss neurotoxis include administration and tetrahydro
  • This is injected to the brain
• The gene for TH will be knocked causing severe feeding behavior and L-DOPA can restore it
• The five subtypes is D1 and D2:like these are the metatropic
  • The D1 receptors cause stimulation to increasing the rate of synthesis and the D2 receptors inhibit syntheses

More Catecholamines

• The D1 receptors stimulate adenylyl cyclase and increase the rate of cAMP synthesis

• The D2 receptors inhibit adenylyl cyclase and decreases the rate of cAMP synthesis

• Apomorphine is the agonist that stimulates receptors

• SKF 38393 is for animal reserach only because it will cause side affects

• DETO is for D1 receptors that does not have tolerance development

• Quinprome D2/D3 agonists reduce symptoms

• NE and DA have shares

• DOPA-DA-NE

• NE has receptors and transporters

• The load is the VMAT

• The transporters get NE

• Ritalin blocks norepinephrine – The PFC is for control NOT a triger

• Inactivate by the MAO degraded NE and the COMT degrade on the celf

• In areas close to locus cerulus are the NE neurons

• Release receptors on the target

• NE can function as a hormone

• The andrenogic receptors are Beta and alpha

• The Beta receptos timilate cAMP

• Receptors prevent Camp systheses

• Projetc to Facilitate

• LC also projects to the PFC

• The A agonist enhances

• The a1 deceases funtion

• Stress from the learning from Epi

• NE from the medications can stimulate but there are medication can block adrenergic receptors

• Stimulate of adrenaline

• SEROTONIN

• Caused vasoconstiction

• Reguated by activity and synthesis which cause synthesis for tryptophan

• It also is catalyzes by trypopam

Serotonin info

• Synthesis is enzymatic and precursor availability

• Serotonin is synthesized by tryptophan

  • Catalyzed by tryptophan

• Catalyzed by decarboxylase

• Neuro endorcrine elevated and elevates

• Elevates nonselctive inhibitor

• stimulated triptophan

  • The transport determines in brain if its stimulated
  • Para blcoksht5
  • availability to help memorize/soothen sleep

• Try loading pure

• brain is lost with memory consiladtion and

• Release:similar processes regulates storage releases -ht5 and respernine

• heightened arousal -MDMA is toxic by sindrom

  • high=less 5 depletion

Serotonin and GABA

• 5ht transporter that

• The drugs are inhibors

• Breakdown the metabolite

• instem and projects area

• found in along raplhe nucleus/median orsal

• The large family is metabolic

• .HT1 concentrated and helps slow/decrease synthesiz

• hT2 cortex ares that LSD stimilartion/scizo meds block

• Seretonin have high toxicity

• Knock 5ht is increased

• 5Ht is critical and SSRI target

• Awake is more regauls and sleepy is less

• deficiency assoated with hyperagegrssuibe

• Gabah Inhabition is impotant and it does inhibit also movements require activation

• The PSP is hyper

• presynaptic blocks it

• action blocks all

• The glutamate does one steps 1.thiosenicarbizone

• transporters move glyince

• transportes is GAT and tliagbine will Elevate and epilepsy

• Gaba and metabolize is trns

• In astroyce is synthes -can remake from Neurons interion

• The sterllara rare/death of purkinie cells.

GABA Receptors, Glycine, and Glutamate

• GABA receptors Actions are media gated-A receptors and B receptors

• The Cl allows to polarize/inhibit channel

• The A drug is from mushroom agonist/ biucicine competitve the bloqueadas

• Benzodiazepines, barbiturates, and ethanol increase it but bzs and ethnanol only alter, but barbit and neuroaterioids can open it

• Both receptors are from the K channel and auto inhibit

• Baco is relax and sac is antagonist

• Gaba is excitatory but 2 things

  • The potential alters we mature and Nkkk increases

• ACETYLCHOHOMONE is in most synthesis like muscles and neurons and is catalyzed choline

• Ach is synthesized form choline and is made from nurons this is control by cells

• Many alteration with ACH

• Transports Vacht

• The amount will fire neurons – the storing and releases the black withe spider and this toxins Ach.

• Deadlt poison cause toxizns

• Choline breaks down Ach and the muscle relaxers it the nueromusuclat

• transports can cause Ach decline/toxins is deficient if the receptors

• Receptors and age related dementia/

• the BBB can give glaucona/tozic by gusses

• the Myastehniu grvais leads to mucle weakness and fatigue, synethic with NEE

• The org causes key role cns and PNS

• The symphatic ganglion is NE

• stimuluation regulation/ low DA can be treat,ment

• nuerons in brain area and BFCS structure -Ach receptors

• nicotine response aganist tabacco/scarioe

• recepots are fast excititory

• open channels depolaize

• lonorpropic desensization that enhance

• depolation is agonist

• antagoinist at ganglia/muscule agaisnts

• -The receptor can also have agnosit

• METATRPIC IS 2 MESSENGER

• the Camp stimulation inhibits the termainal

• The cortex can the function

• Sypthseis caused by acetyl and coline

• Coline can be rebased/reabsorbed by cells

• the tranpoters that blocks will redce rate

• ko with death

• importantAA synthesis for brain synsaptes

• the 8O prcs is glu

• the ions and asphatrs are gluta

• the role is cellular and is pool from transion and used

Glutamate and GABA

• Gultuamte and transports move into vesicles –TheVGLUT is cortex expresssied

• VGLUT1 express cortex and KO DIE

• VGLUT3 DEAF- inner hair

• The AA transporters OCUR in different

• Astrotyes is EAAT irl

• 2 has transport in the 13and5 cells that dramic

• The cells do Synthe

• Glutante is pathway and protein cells

• Both are ionized and deprolazing membrance AMPA recpots fast response

• kaine selective agonist Nmda

• nmda allow 2 ions

• Amnpa Is 4 SUBUNIT/ THE NBX WONT WORK AS 3 RESOIPOTS ABNORMAL and the nmda is flow

• 2 binds gylcin

• memtinte treats ALZYMEMER because they have a non competi

• other abuse DUGS

• there are 8 metabotrppic -they have 11-222 that possitve and negative and a antagonist to human patinces