Neuropsychopharm: how do drug change behaviour

1. drug action: specific location: one target behaviour where the target is found (tissue/
cell target) (cell itself)
2. drug effect: widespread action (entire body) comes after drug action
a. can be distant from the drug action
b. traditional drug dev: compound that has desirable drug effect. (based on
the drug action)
3. reverse/target based pharmacology: have the 2ndary/ side efffects.

Example:
1. Atropine: dilate by eye drop 2. Morphine: need the drug to
a. Drug action: iris muscle - sie dilation
of action a. drug action:
b. drug effect: site of effect: b. drug effect: far away from
pupil (very close) drug action: pupil

*Can change the therapeutic based on the goal of the effect

*antidepressant: decrease depression + anxiety
a. theurapeutic effect: anti-anxiety
b. side effect: anti-depression

Name/ Terms:
1. Abbreviated chemical name: pharmacist recognize
2. Trade name: common name
3. IUPAC: full chemical name

Example: Target serotonin receptors:

1. non-specific effect : any binding beyond the serotonin occurs
a. side effect occurs
b. may result of uniq chars/ state ( mood/ gen,...): how polymorphism can effect
human drug effects.
c. expectancy of drug effect
2. specific effect:

Placebo effect: affected by expectancy and conditioning: change behaviour based on

expectancy
● particular confound in neuropsych
● 20-30% effective
● Prozac: have to endure 5 clinical trials to achieve 2 showing significantly better response
than just placebos (drug does better than placebos)
● Psychologist: effectiveness of psychological intervention.

Notes: Classic Levine 1973 on ulcer patient given placebo

● A: Efficacy of 70%: physician who assumed the medication would give relief
● B: efficacy of 25%: nurses who described it as experimental in nature
 Pharmacokinetics - A
Dynamics effects: bioavailability + efficacy of drugs in the human body

4 Principal components (ADME)

● A - Absorption
○ Administration: how the drug get into the body - control variable, the other
biological.
○ Absorption:
● D - distribution: how the drugs get from A into the other parts of the body
○ Binding
○ depot binding
● M - metabolism
● E - excretions

A - Routes of Administrations: - know the tables

● primarily used in the research method: IP, intracranial, intracerebroventricular,
intracisternal.

1. most convenient: oral

● first-pass effect (problem)
○ any drug is absorbed from the stomach/ intestine goes directly to the liver ( aim:
need to be broken down to be effective, can decrease the effectiveness)
○ larger doses of OA
● BBB affects usefulness for neuropharmacology: need to develop drug to pass
BBB or the concentration enough to go through first pass effect.

2. CSF: (experiment)
● Problem: highly invasive
● Advantage: by passes liver and BB to act very quickly.

A- Drug Absorption:
● movement of drug from the site of administration to the circulatory system
● administration affects absorption predominantly by the available surface area of absorb
for absorption, how many layers (passive diffusion) (go hand in hand)
● depend on drug polarity: non-polar, lipid soluble drug can freely diffuse accross cell
membrane.
○ drug can change from P to NP, i to NI since many orally administered drugs are
weak acides or bases - gaining or losing charges based on the pH on the
external environment (ASPIRIN can change)
○ ionized cannot cross brain barrier.
Alcohol
● Man: drink more: has to do with absorption: more muscle, more body fat: drug
absorption to drug act

Why intramuscular oil does not work well: non-polar: can cross BBB easily: easier to
cross the membrane
Polar: easier to travel blood

Surface area of body compartment:

● slow absorption: stomach
● fast absorption: intestines
● site of most absorption: oral

D - Distribution
● peripheral capillaries are highly porous allowing ready distribution of drug into tissues.
(absorption out of the blood)
● BBB permits passive diffusion of only lipophilic drugs: non-polar, fat-loving drugs
○ BBB creates by astrocyte so thing cannot just passively diffuse due to have a
highly impermeable barrier: only non-polar, fat loving, lipophillic
○ important (psychopharmacology) since we want the drug to get into the brain.
● specific transporters: passage of solutes: glucose and amino acid transporters: allows to
cross the blood brain barrier.
● actively removed from the ECF (external fluid) by efflux transporter (p-glycoprotein):
these drugs tried to cross the border.

Permeable sites to the brain: some gaps ( main door)

1. CTZ: medulla oblongata: vomit center
a. allow direct detentions of toxins into the blood
b. alcohol poisoning: CTZ detects too much poisoning and trigger excretion
2. Hypothalamus:
a. allow direct access to capillaries for secretion of neuro-hormone and
hormone-release factor.

Placental barrier: similar to BBB

● drug can enter the placenta since placenta does not have strong barrier as BBB: acute
toxicity/ teratogenic/ severe deformation (fetus)

Depot binding: inactive drug binding sites - rest area, if a drug binds here, nothing will
happen (adipose tissue, muscle, plasma protein)
● decreases circulating drug concentration ( extra drugs - bind to something, less drugs
hanging out in your system)
● prolongs drug actions - keeping it for later
● can explain individual differences in drug efficacy.
M - Metabolism:
● biotransformation and elimination affects bioavailibility
● primarily in the liver (under control microsomal enzymes)

1. cytochrome P450: breakdown for the most of drugs: oxidize the majority of
psychoactive drugs (liver)
a. Smoke: activate CYP1A2
b. drink grapefruit juice: inhibit breakdown of CYP3A4 - “do not eat
grapefruit”

2. non-specific detoxification process: 2 phases:

● type 1: non-synthetic modification (ORH)
○ first pass: active metabolites of the pharmaceutical preparation of drug
● type 2: synthetic modification
.
3. Metabolic products (active and inactive) are returned to circulation from the liver and
reach target sites of action/ excretion (Kidneys, biliary, fecal excretion) (some drugs are
design to be broken down first, if it is not active, usually sent to site of excretion)

Example: symvastatine: hydrophobic:

● type 1: broken down: hydrolyzed (liver) into an bioactive acid form ⇒ acidic and
doing it own thing. ( in an active form)

Factor influence metabolism:

1. enzyme induction: tolerance and cross tolerance: the more drug u take, the more
enzyme the body make to get familiar to get metabolize. - lờn thuốc: SSRI will be break
down in the same mechanism/ structure.
2. enzyme inhibition: drugs not going to be broken down: MAOI

E - Excretion: anyway to get the drug out of your body: ( in half -life, why some drugs are
take longer to get in since different half life)
● primarily means is filtration by kidney and excretion through urine
● most drugs are excreted by first-order kinetics (exponential)
● Alcohol: removed by zero-order kinetics (constant rate)
● half-life correlatates with addictability: leaves very quick and get high really quick ⇒
nghiện (corcaine, morphine)
 Pharmacodynamics
Receptors:
1. Specificity: high binding affinity to elicit a biological response
2. Reversibility:
a. binding to receptors should be reversible: dissocialble and recoverable
b. distinguish receptor-ligand interactors from enzyme-substrate interaction: binds
the substrate and just it, not unbind.
Extra - more water soluable - solibility of ligands
● common target for psychoactive drugs
Intracellular receptors: located in cytoplasm
different hormone receptors ⇒ different genes binding

Agonist - Antagonist: ligand bind to the receptor on the cell surface (always lock and the
key)
1. Agonist: turn on
a. Agonist function: dose-response (S curve): ED50: elicit half-maximal effect,
increasing the does, the response increase to maximum response and then back
to the receptor saturability. (not use ED100 since you are death)
b. different drugs with different ED50 (different opiods): show different
potency, but have the same efficacy (efficacy: the maximum drug effect
possible when given a drug).
c. Aspirin differs in both potency and efficacy ~ work different mechanism
d. Partial agonist: elicit part of the response, can decrease efficacy of the
endogenous agonist
e. Inverse Agonist: bind with constitututive activity (negative response)

Example: GABA:
a. Agonist: indice sedative effect
b. IA: cause anxiety

2. Anta: turn it off, does not unlock the key, prevent drug action, prevent agonist from
binding.
a. reversible/ irreversible
b. Reversible: endogenous agonist (most common)
i. competitive antagonism: just to block some of them, just decrese some
endogenous bind but does not change the efficacy.
ii. Non-competitive: reduced BOTH - the receptors never be available
anymore.
c. Irreversible: bind the same as endogenous ligand irreversibly. (CR ⇒ PI)
d. Allosteric modulators: bind different to endogenous ligand, function
through other comformational effects on the protein. (do not via direct
binding)
 3. Theurapeutic index (TI): dose response can be measure for adverse effects of
drugs
a. TD50: toxic effect
b. LD50: lethal effect
⇒ TI = TD50/ ED50: safety margin, the larger TI, the better it is since
avoiding TD and maximize ED50, get to 100% then TD1 (always prescribe in this
margin) - start with the lower end.

Long term effect of drugs (some drugs could show both)

● Tolerance: diminished effect of a given dose of drug over time
○ cross-tolerance can cause drug interactions.
● Sensitization: enhancement of a particular drug's effect on repeated exposure.
○ Cross-sensitization between drugs acting on the same receptors (one drug effect
can increase the exposure)

Tolerance
Forms of Tolerances:
1. Metabolic: how the drug gets out of the system
a. increased: enzyme induction
b. decreased bioavailability of drugs
2. Pharmacodynamic: changes in nerve cell function in response to drug
a. Receptor down-regulation: saturation and diminished effect.
3. Behavioural: Context-specific tolerance (habituation and conditioning

Drug Dependence: you can have both or you can have 1

● persistence of tolerance influenced heavily by metabolic and pharmacodynamics
● Dependence is the requirement for drug use in order to maintain “normal function" after
the development of drug tolerance.
● Acute administration disrupts homeostasis

Desmontration of dependence: Morphine

● Acute morphine treatment decreased CAMP
● after long level: CAMP get up
● withdrawal of morphine resulted in a dramatic rebound well above normal.

Addictions:
● Dsm: substance abuse disorder
● compulsive drug seeking behaviour: impulse control disorder (OCD)
● or result from voluntary norm-violating behaviour.
 Acetylcholine
Criteria for neurotransmitter (NT6)
1. Presynaptic cell should contain the substance as well as a mechanism to
synthesize it
2. substance should be release when depolarizing stimulus is applied to the neuron
3. receptor should be present on the post synaptic cell.
4. known antagonist should block the effects
5. a system to inactive the substance must exist
6. exogenous application of the substance to the post-synaptic cell should produce
the same response.

ACh: important for memory consolidation ( episodic - hyppocampus)

Neuromodulator: can be hormone like (act as distance) (crine)

● does not elicit direct effect, but alters the action of a classical neurotransmitter
● Enhaces, reduces, prolong nT action
● may be released from glial cell

Feedback loop: ACh synthesis is tightly regulated

● high level of ACh: too much not making it anymore
● precursor availability: dietary: increase what you eat (AD: ate high in Choline, not see
any significant increase in symtomps or syn of ACh)
● neuron activity: increased during high activity:
○ activity dependent synthesis ensure sufficient ACh is available during high
periods of high activity.

ACh storage and realease

● transport is inhibit by the drug vesamicol.
● stored in the vesicle by vesicular ACh transporter (VAT), right nT right vessels
● released by classical vesicular exocytosis (voltage-dependent Ca2+ influx)
○ triggered by latrotoxin: neuromuscular junction, extra ACh ⇒ muscle pain, sweat.

Reuptake in synapse (broken down) - AChE

● transported back by the choline transporter
● re-uptake inhibited by hemicholinium-3 ⇒ more choline in synapse ⇒ run down of
activity ( alot of traffic and hard to get into)

Botox: type of toxins

● cause paralysis effect
● create BoNT A/B: prevent vesicle to binding in presynap mem to relaease ACh ⇒
muscle contract (ACh the muscle contract)
● local injection.
plant akyloids: 2nd metabolities: affecting ACh and affect animals
● structure of BBB since insect form different, can cross BBB and get into CNS, but in
human cannot go in.

Drugs affecting ACh break down

● AChE inhibition prolongs ACh signalling
● physostigmine is a BBB permeable inhibitor of AChE (Calabar beaks)
● synthetic BBB - impermeable analogues neostigmine (Prostigmin) and
pyridostigmine (Mestinon) treat autoimmune system: Myasthenia gravis
● reversible inhibitor of AChE: (cannot remove them)
○ physostigmine
○ pyridostigmine
○ neostigmine
irreversible AChE inhibitor: Sarin and VX (nerve gas) - very dangerous
● preventative agent: pyridos-tigmine: competes for the same site as VX/ sarin

Guld War syndrome:

● confusin-ataxia syndrome
● cognitive impairment, dizzinss, balance, coordination problems.

Acetylcholine system and receptors

Cholinergic neurotransmission: system ACh works in
● Autonomic nervous system (ANS): preganglionic neurons of both branch
○ ganglionic neurons of the parasympathetic branch

Agonist: parasympathomimetic: mimic effects of activation of the parasympathetic

nervous system - calm and digest

Antagonists - prevent that calm and digest: parasympatholytic ~ sympathetic

CNS
1. BFCS: large system involve in cholinergic: learning, memory, and attention
2. Striatum: motor function
a. Interneuron: affected in parkinson
b. balance activity of cholinergic system that degrade with the desease, early
stage, balance bt ACh and DA (not just DA in parkinson's) - caudate
putamen
3. dorsolateral pons: arosal (reticular activaitng system) + addictions
BFCS - medial septum, diagonand band, nucleus basalic, substantia innomiante
● Project to big area: cortex, hippocampus, amygdala (target)
● loss of cholinergic: cognitive decline in AD

Atropine
● plant akyloid found in nightshade
● antagonist of muscarinic ACh - prevent the parasympathetic ⇒ dilate the pupil,
prevent the constriction of pupil
● BBB permeable ⇒ deathly
● oral administration inhibits cognition in animals (acquisition and mentanance of learning
tasks)
● Administration is amnesiac in human: produce amnesia \

Research studies: role of BFCS in cognition

1. Microdialisis: increased during sustained attention
2. operant control task: reward task (level press for food reward)
3. F19-s schedule of reinforcement: with a predictable delay

Saporin: toxin
● water soluble toxin - easy to get into the body
● RIP
● investigated as anti-cancer agent

NAChr
Arousal system: is one componet or reticular activating system, involve in pons
(addiction)
● cholinergic prjection: pons (pedunculopontine and laterodorsal tegmental): active
while awake and trigger transition to REM sleep
● increasing attention: trigger arousal ⇒ more attential (exciting, want more of it)

Addictions**:
● cholinergic neurons originating: DLT pons invervate the Ventral - tegmental area
● ACh stimulate dopaminergic neurons ⇒ nucleus accumbens: reward pathway
● Nicotine: activate Nicotinic ACh receptors ⇒ direcly activate dopaminergic neurons
in the ventral tegmental area (VTA) - acts on both GABA and DA

why nicotine so highly addicted ? activate DA without activate ACh due to has the
receptor (NAChR and MAChR)
ACh Receptors
1. Nicotinic receptors (NAChR) - agonist, iontropic receptors pass Na+ and Ca 2+
a. ligand gated channel
b. selective agonist of NAChR
c. neuromuscular junsction (par and symp) and CNS
d. most throughly studies channel, widely available around body
e. depolarization block: NaChR desensitize
i. Succinnylcholine: muscle relaxant that causes prolonged activation fo
NAChR and subsequet muscle paralysis
f. Class of transmission:
i. antagonist include curare poison (D-tubocurarine)
2. Muscarinic receptors (MAChR) -G protein receptors
a. 5 types: M1 - M5
b. specific agonist muscarine isolated from the fly aa

Monoamine - Epinephrine - Dopamine

Monoamine: common single functional drugs

VMAT: VMA-transporter: transporter that load dopamine into synaptic vesicle

Reserpine inhibit VM,AT and depletes DA and NE as cytosolic, catecholamines are

rapidly degrades
● Sedation: animal
● Depression: human

Dopamine transporter:
● cocaine and amphetamine affect DAT function by preventing dopaminereuptake
○ increasing dopamine in the synapse
○ prolongs dopamine signalling
○ hyperactivity of dopaminergic circuits

Dopaminergic synapse:
● presynaptic cell rich in anabolic enzyme: TH, DOPA decarboxylase
● VMAT: expressed on vesicles for loading dopamine
● autoreceptors in presynaptic membrance for feedback inhibitor
● DAT responsible for reuptake

Receptors:
● Excitatory: D1 family: 1,5 - signalling through Gsa
● Inhibitory: increasing cAMP: D2 family: 2,3,4: signalling through Gia
Dopaminergic pathway: 90% of catecholamine neurotransmission in the CNS
1. Nigrostatial: substantial nigra and VTA ⇒ striatum (caudate and putamen)
2. Tuberoinfunfibular: hypothalamus ⇒ medial eminence: stimulus pituitary prolactin
secrection
3. mesolimbic/ mesocortical system: VTA ⇒ limbic system, nucleus accumben

Dopaminergic lesions: 6-OHDA: selective neurotoxin

● Bilateral nigrostatial lesion: sensory neglect motivation, motivational deficit motor
impairment
● Unilateral lesion: postural asymetry and turning

Nigrostratial system: A9: substantial nigra

● project to the striatum
● involved in motor control
● D1,2 family receptor
● Degradation in Parkinson’s ⇒ motor symptoms (L-dopa treatment, precursor to
dopamine)
● MPTP: neurotoxin: degrade dopaminergic neuron in Substantial nigra ⇒ parkinson
disease (Resistant to L-DOPA treatment)

DAT knockout cause hyperactivity ⇒ decreased re-uptake prolongs DA signalling at the

synapse (Cocaine)
● D1 receptor knowckout ablates cocaine’s hyperlocomotion

Salience:
● Motivational: addiction: nucleus accumbens: target in D1, D2
● sensory salience: psychosis
 Schizophrenia
Hyperactivity in mesolimbic system leads to positive symptoms in Sz
● motivational salience - addiction
● sensory salience - sensory gating

● excess dopamine ⇒ hallucination

Antipsychotic: inhibit D1 and D2 family dopamine

● efficacy is correlated with D2 binding potential
● stimulant (amphetamine) can induce psychosis at sufficient dose
● Adverse side effect:
○ extrapyramidal side effect (nigrostratial) (4)
1. akinesia - inability to initiate movement
2. Akathisia: inability to remain motionless
3. acute dystonic reaction - sustained muscle contraction, twisting and
repetitive movement
4. pseudo-parkinsonism - fixed (non-progressive) parkinsonism without
degeneration of dopaminergic neuron

● Tubero-fundibular: hyper-prolactinaemia can result from antipsychotic treatment

Dopamine activity: level in post morten ScZ brains are elevated in the striatum
1. PET and SPECT: increased basal levels of dopamine
a. Dopamine receptor D2/3 antagonist: high impulsive rats have reduced binding
potential in ventral striatum
2. typical antispychotics targeting dopamine only address positive symptoms

Dopamine and addiction:

● impulsive control is a manifestation of inhibitory control (component of excessive
function)
● In rats:
○ impulsive rats:
1. increased premature responses
2. increased self-administration of cocaine
 Norepinephrine

NA synapse:
1. NE is synthesized (vescicles) from dopamine via DBH
2. After release, NE is recycled into the cell by the NE transporter (NET)
3. NE is breakdown by MAO AND COMT or is recycle into vesicles through the VMAT
Adrenergic receptors:
1. alpha - arenergic receptors:
a. a1 coupled to Gqa
b. a2 coupled to Gia
i. can lower blood pressure
ii. Brainstaim: autoreceptors
iii. Clonidine: treathypertension
iv. ADHD: increasing NE tone in the PFC at postsynaptic a2A
c. phenylephrine is a selective agonist - a1/2
● vascoconstriction

2. Beta:
a. 1,2,3 coupled to Gsa
b. isoprenaline is selective agonist (B1/2/3)
● vasolisation
● treat asthma: albuterol: agonist: direct effect
● treat arrhythmia and angia pectoris: B-Blocker: metoprolol

NA projection emanate to locus coeruleums

● medial septum: arousal, attential, vigilance
● NE: affecting eating behaviour (paraventricular nucleus - hyppothalamus)
○ microinjection stimulate eating behaviour even in food-satiated rats
● limbic cortex, amygdala, hippocampus: depression

Depression (NE):
● Antidepressants: often norepinephrine reuptake or breakdown (a1)
○ MA: common target reduce the breakdown of all MANTs
 Monoamine hypothesis
First antidepressants: iproniazed: anti-turboculosis drug

MAOI: elevation of MA by inhibiting their catabolism

Phenylzine: cheese effect: most common MAOI

TCA
● Imipramine (Tofranil) is an inhibitor of both NET and 5-HT transporter (SERT)
● impaired reuptake ⇒ elevated NE/5-HT
● side effects on muscarinic receptors (anti-cholinergic)
○ parasympatholytic - dry mouth, constipation, urinary retention
● poor safety margin - induces mania at higher doses

2009 meta analysis questioned the efficacy of reboxetine

Attention disordera:
- Clonidine: a2A agonist increas NE tone in PFC
- reboxetine - NET inhibitor
- thought to act to increase/ prolong NE signalling to cortex, affecting attention

a2 receptors are target to treat symptoms of opiod withdrawal

● clodine is an a2 agonist
● activation decreases the release of NE
● Yohimbine is an a2 antagonist: increase/ provoke withdrawal symptoms
○ IV administration: increase anxiety in patient
 Serotonin (Chapter 6)
● only MA that is not catecholamines
● 90 of the 5HT is in the gut
● major NT in the enteric NS and is released by enterochromaffin cells
● stimulates peristalsis and secrete into the intestines
● act as area postrema: non contain in the blood brain area CTZ ( vomit centre) - anti
nausia will block 5- HT

Synthesis Metabolism
● Synthesis: L-Tryptophan (diet) ⇒ tryptophan hydrolase (TPH) ⇒ 5-HTP ⇒ dài dài ra
5HT
● 5HT broken down = only by MAO but NOT COMT ⇒ 5-HIAA

Trytophan can cross BBB by special transposter that Trytophan has to pass to use, and
has the one for large aa
● has to compete (wait for turn)
● turkey effect: eating food rich in Tryptophan will increase the amount of
Tryptophan here, but the same amount of large aa ⇒ taken into the brain and
blocking the large aaa going in, and some aa có trách nhiệm keeps your gut
awake , but you sleepy because aa blocked away from the awake center.
● production of melatonin: increasing sleep and you happy about it. (5-HT with circadian
rhythm)

Tryptophan depletion
● PCPA is used in animals to rapidly deplete 5HT
○ irreversible inhibitor of tryptophan hydrozylase: will never work again
○ 1-2 doses of 5HT by up to 90% for up to 2 weeks ( 2 weeks of depletion of
serotonin)
● reserpine depletes 5HT by inhibiting VMAT (also use VMAT to transfer to vesicle)
● lack of trytophan: make people more sad but not depress ⇒ serotonin depletion could
also play a rule in depression

At the synap:
● serotonin (presin) ⇒ VMAT (cell) ⇒ presyn autosynap ⇒ taken back by serotonin
transporter and within the cell it will be broken down. (SSRI will block 5HT transporter)

5HT Releasers: 5HT in weight loss and weight control

1. Fenfluramine: weight loss in obese patients
2. substituted amphetamines:
a. Para-chloro…
b. MDMA: Psychoactive recreational drug: sweat out and dehydrated and go out all
water weight
Dopamine and 5HT are directly opposed in regulating appetite
● 5ht inhibit dopamine, when having 5ht stop eating
● Fenfluramine is a 5HT release, active the release of extra 5HTP: alone ⇒ drowsiness.
● Phentarmine: suppress appetite through catecholamines: by targeting dopaming (type
of amphetamine) : make you not tired
⇒ co-treatment avoid mood effect, took them together not tired.

5-HT transporter (SERT)

● responsible for inactivation of 5HT signalling by repuptake
● Similar to DAT nad nET (cocane, amphetamines, antidepressants)
● can found in lungs, plancenta, platelets
○ pumps 5HT in to platelets
○ function in clotting cascade as a vasoconstrictor: increasing clotting too much ⇒
block.
● popular drug target. (quizlet)

serotonin systems and receptors

● start in the midbrain and go to the forebrain

Raphe Nuclei:
1. caudal raphe nuclei (down): projection to cerebellum ⇒ spinal cord
a. mediate sensory, motor and autonomic function of 5HT
2. Rostral raphe nuclei: ventral send information send cerebellum ⇒ spinal cord, to basal
ganglia,...
a. Dorsal: go to midbrain
i. activity during reoetitive movement
b. medial

Lesion these area

⇒ Seratonergic neurotoxins: MDMA: very high doses will lesion 5HT and cells (only)
● 5,7-DHT in experimental thing, micro - injection due to impermearble
● deficit in food intake, reproductive behaviour decrease, pain sensitivity, anxiety, learning,
memory, motor function
● has been shown to improve the clinical response in patient undergoing treatment for
● MDMA was originally synthesized by the Merck pharmaceutical company as part of a
project to find new substances that would : reduce appetite
Behaviour - dependent activity:
● Measure: microelectrodes implanted into the dorsal raphe nuclei in free moving cats
● Awake: steady firing pattern (same as quiet waking)
● repetitive movement: walking, grooming: increase the pattern than non-repetitive
movement.
● rem sleep: paralyze: no activity
● sudden sensory stimulus causes an abrupt cessation ⇒ hold the activity and will cause
a certain brain in activity (novel stimulus: no longer 5HT responsible) (in dorsal
raphe nuclei)

Note: 5HT binding capacity with more of a receptor will be more spiritual
● only one ligand-gated: 5HT3
● family 1: inhibitory: 1A,B,D
● family 2: Gq/I: 2A,B,C

5-HT1A: spirituality
● Agonist: buspirone - partial agonist: anxiolytic, antidepression
○ cannabidol (CBD) - partial agonist: why people increase spiritual event
○ hyperphagia ⇒ decrease 5HT release, prevents attenuation of appetite (do
not get full)
○ concentrated in hippocampus, amygdala, septum
○ target GIRK instead of cAMP
● functions as an autoreceptors

1B and 1D
● inhibit both cAMP and GIRK
● 1B not express in human, instead we have 1DA and 1DB
● intracranial blood vessels
● target of anti-migrane medicatio n
○ sumatripan (imitrex) agonized in 1B and 1D receptor

Migraine pathogenesis:
● lots of activity followed by the low activity
● reception aura: visual/ auditory
● constriction in blood flow in meninges: your self brain cannot feel brain
● reactive vasolidation causes pain ⇒ sensory fibers release vasodilating peptide ⇒ get
biiger and squishy and get hurt ⇒ inflamation cause sensitization to cause pain: less
stimulus to cause the same pain.

5HT1D receptors are inhibitory

● vasconstriction rather than vasolidation
● less in the pain but what cause in the pain too.