Neuropharm Final Flashcards
what is pharmacology?
the scientific study of the actions of drugs and their effects on a living organism
define pharacokinetics
how substances are distributed through the body
define pharmacodynamics
interactions of the substance with a receptor
define neuropharmacology
drug-induced changes in nervous system functions
define psychopharmacology
drug-induced changes in mood, thinking, and behavior
define neuropsychopharmacology
drug-induced changes in the nervous system that influence behavior
what is a drug action?
a specific molecular change
drug binds to its target (receptor)
what is a drug effect?
a more widespread/systemic change
what are therapeutic effects?
desirable drug effects
what are side effects?
undesirable drug effects?
what are specific drug effects?
results from interactions btwn a drug and its target
what are nonspecific drug effects?
include mood, expectations, perceptions, attitudes
what is pharmacokinetics?
mechanisms involved in delivering a drug to its target, where it can have pharmacological effect
-administration
-absorption
-distribution
-elimination
—–metabolism and excretion
what is bioavailability?
the amount of drug in the blood that is free to act on a specific target
–depends on absorption, distribution, elimination
what are pharmacodynamics?
interactions btwn the drug and its target; mechanisms of drug action
describe lipid-receptor interaction
–dynamic and reversible
–in a constant state of binding and breaking away
–follows the law of mass action
how do you determine non-specific binding?
a very high concentration of unlabeled ligand is added, outcompeting the hot radioligand for specific binding sites
what is an agonist?
drug that mimics the effect of the endogenous transmitter
what is a partial agonist?
drug that cannot produce the full agonist response
what is an antagonist?
drug that block the effect of the endogenous transmitter
what is receptor affinity?
how tightly the receptor holds onto the drug
—lock and key mechanism
what is drug potency?
the amount of drug necessary to produce a desired level of effect
what is drug efficacy?
the maximum response produced by a drug
what is a competitive antagonist?
“compete” w the agonist for binding to the agonist binding site
***high affinity for the agonist binding site, but no efficacy
what is a non-competitive antagonist?
bind to a site different from the agonist binding site
***negative allosteric modulation
a competitive antagonist shifts the dose-response curve to the _____?
right
what is another name for the myelencephalon?
medulla
what is another name for the mesencephalon?
midbrain
what brain structures make up the metencephalon?
cerebellum and pons
what brain structures make up the diencephalon?
thalamus and hypothalamus
what brain structures make up the telencephalon?
neocortex, basal ganglia, limbic system
describe ligand-gated ion channels
–ionotropic
–fast transmission
–no intermediate chemical steps
–directly changes membrane permeability
describe G protein-coupled receptor
–metabotropic
–slow activation
–long-lasting effects
–alters intracellular biochemistry
terminal autoreceptors are _____-modulating
release
somatodendritic autoreceptors are _______-modulating
activity
the morris water maze is a test of ________
spatial learning
the open field test is a measure of _______
motor activity
the delayed-response tests is a measure of ______
working memory
the light-dark box measures ________
unconditioned anxiety
the elevated plus-maze measures ________
unconditioned anxiety
the forced swim test measures _______
behavioral dispair
the sucrose preference test is a measure of _______
anhedonia, the inability to derive pleasure from normally pleasurable events
drug self-administration measures _______
reinforcement value of substances
define breaking point
point at which effort required exceeds reinforcing value– the higher the breaking point, the higher the abuse potential
drug discrimination studies measure _____
how an animal experiences a drug
what are the ionotropic receptors for ACh?
nicotine
curare
what are the metabotropic receptors for ACh?
muscarine
atropine
what is the rate-limiting step of ACh synthesis?
choline uptake into nerve terminal
what does vesamicol do?
blocks VAChT
reduces amount of ACh released when the neurons fire
what does black widow spider venom do to ACh release?
massive release of ACh in the PNS
–muscle pain, tremors, nausea, vomiting, salivation, copious sweating
what does botulinum toxin do to ACh release?
inhibits ACh release
which drug is used to treat glaucoma?
physostigmine
which drug is used to treat myasthenia gravis?
neostigmine and pyridostigmine
does physostigmine cross the BBB?
yes!
do neostigmine and pyridostigmine cross the BBB?
nope!
what are the reversible AChE inhibitors?
donepezil and rivastigmine
what are organophosphates?
irreversible AChE inhibitors
**insecticides
**nerve agents
describe the nAChR
5 subunits are arranged around a central pore
-each subunit has 4 TMDs
homomeric nACh receptor is permeable to which ion?
calcium!
what is an agonist for nAChR?
nicotine
what is an antagonist for nAChR?
curare
describe the mAChR
M1-M5
what is an agonist for mAChR?
muscarine
what is an antagonist for mAChR?
atropine
scopolamine
what does ACh do in cognition?
memory consolidation
sensory attention
behavioral arousal
deficits in ACh signaling are involved in _______
dementia
mACh receptor antagonists are ______ and impair performance on ______
amnestic
learning tasks
ACh synthesis
choline + acetyl CoA
—-choline acetyltransferase
acetylcholine
—-acetylcholinesterase
choline + acetic acid
what is the most abundant excitatory neurotransmitter in the brain?
glutamate!
glutamate synthesis
glutamine
—-glutaminase
glutamate
—-glutamine synthetase
glutamine
what is the most abundant inhibitory neurotransmitter in the brain?
GABA
ionotropic glutamate receptors
NMDA
AMPA
KA
metabotropic glutamate receptors
group 1 (1 and 5)
group 2 (2 and 3)
group 3 (4, 6, and 7)
which iGlu receptors are permeable to ca2+?
NMDA
AMPA lacking GlueA2
properties of NMDA receptors
ligand-gated ion channels, requiring co-agonists glu and gly
voltage gated
–removal of Mg2+ block
GABA a ionotropic receptors
permeable to Cl- leading to hyperpolarization
two alpha, two beta, and one gamma subunit
what is a GABA binding site agonist
muscimol
what is a GABA binding site competitive antagonist
bicucculine
GABA b receptors are ______
metabotropic
what do postsynaptic GABAb receptors do
open k+ ion channels
inhibition of AC/ decrease cAMP
what do presynaptic GABAb receptors do
autoreceptors, heteroceptors
inhibition of Ca2+ channels
inhibition of AC/ decrease cAMP
what are positive allosteric modulators for GABA a
benzodiazepines
barbiturates
neurosteroids, EtOH, Anesthetics
what are negative allosteric modulators of GABAa
pictrotoxin
behavioral effects due to a-1
sedation (Ambien)
behavioral effects due to a-2/3
anxiolytic (Xanax)
behavioral effects of a-5
amnestic
how do you obtain tyrosine?
In diet
catecholamines synthesis
tyrosine –(TH/Fe2+, O2, BH4)—> L-DOPA –(AADC/vitamin b6)–> dopamine –(DBH/cu2+, o2, ascorbic acid)–> norepinephrine –(SAM)–> epinephrine
what is the rate-limiting step in catecholamine synthesis?
TH
AMPT
TH inhibitor
Reserpine
irreversible VMAT inhibitor
tetrabenazine, deutetrabenazine, valbenazine
reversible VMAT inhibitor
6-OHDA and MPTP
DA neurotoxins
amphetamine
catecholamine releaser and reuptake blocker
cocaine
catecholamine reuptake blocker
what is a noradrenergic alpha2 autoreceptor agonist
clonidine
what is a noradrenergic alpha 2 autoreceptor antagonist
yohimbine
where is the nigro-striatal pathway located and what is it in control of?
substantia nigra
activation, motivation, cognition
where is the mesolimbic system located and what is it in charge of?
VTA
behavioral arousal, reward learning
where is the mesocortical system located and what is it in charge of?
VTA
attention, working memory
where is the tuberohypophyseal system located and what is it in charge of?
hypothalamus
prolactin release
what do the D1 and D5 receptors do?
increase cAMP
Gs coupled
stimulate adenylyl cyclase activity
what do D2, D3, D4 receptors do?
decreases cAMP
Gi coupled
inhibit adenylyl cyclase activity
increase gk, hyperpolarize
methylphenidate
catecholamine reuptake blocker
apomorphine
nonselective D1 and D2 receptor agonist
SKF 383393
D1 receptor agonist
DETQ
D1 receptor positive allosteric modulator
Quinpirole
D2/D3 receptor agonist
bromocroptine, pramipexole, ropinirole, rotigotine
D2/D3 receptor agonist
SCH 23390
D1 receptor antagonist
Haloperidol
D2 receptor antagonist
DA regulates _______ along a continuum
behavioral activation
reducing da synthesis ______ behavioral activation?
impairs
what happens when reserpine blocks VMAT
sedation in animals
depression in humans
what happens when AMPT blocks TH activity
associated with relapse into depression following positive response to antidepressant medication
what happens following a bilateral central lesion?
sensory neglect
motivational deficits
parkinsonian motor deficits
what happens after a unilateral 6-OHDA lesion to the SNpc
loss of DA input to lesion side, however DA continues to release behavior on intact side
adrenergic agonists in the LH promote ______
wakefulness
adrenergic input to the PFC can improve or impair _______
working memory
how do a2-AR agonists like guanfacine and clonidine affect performance of delayed task resonse?
improve
does a1-AR have a high or low affinity for NE?
low
serotonin synthesis
tryptophan –(TPH2/fe2+, 02, BH4)–> 5-HTP –(AADC/ vitamin B6)–> 5-HT
what is the rate limiting step in serotonin synthessi
TPH
what happens with TRP depletion
induces symptoms in people with major depression
what does PCPA do?
blocks 5-HT synthesis by irreversibly inhibiting TPH
5-HT is loaded into vesicles by ______
VMAT2
what kind of receptors at 5-HT 1B/1D
terminal autoreceptors
what kind of receptors are 5-HT1A receptors
somatodendritic
what do 5-HT 1b/1d terminal autoreceptors do
inhibit 5-HT release
decrease Ca2+ influx
decrease cAMP
what do 5-HT 1a somatodendritic autoreceptors do
opens K+ channels, hyperpolarizing Vm
decrease neural activity
important in psychopharmacology of SSRIs
SERT
5-HT transporter
target of SSRI, cocaine, and MDMA
MAO-A
enzymatic degradation
5-HIAA is major metabolite
para-chloroamphetamine and fenfluramine
5-HT releaser
MDMA
5-HT releaser
buspirone
5-HT1a partial agonist
what other condition is MDMA used for?
PSTD
where are majority of 5-HT neurons found in the CNS?
raphé nuclei
8-OH-DPAT
5-HT1a full agonist
WAY-100635
5-HT1a antagonist
DOI
5-HT2a agonist
LSD
5-HT2a agonist
katanserin and ritanserin
5-HT2a antagonist
triptans
5-HT1b/1d agonists
lasmiditan
5-HT1f agonist
how is territorial aggression tested on animals
resident-intruder tests
impaired 5-HTergic signaling ______ behavioral aggression
increases
what is the 5-HT Deficiency Hypothesis
impaired 5-HTergic signalling increases behavioral aggression
5-HT1a _______ are anxiolytic
partial agonists
5-HT1b and 5-HT2c agonists do what to behavior?
reduce feeding
what is addiction?
a chronic, relapsing behavioral disorder
describe the impulsive stage of addiction cycle
binge intoxication
pleasurable effects
abstinence neutral affect
reward craving
describe the compulsive stage of drug addiction
prolonged intoxication
relief
protracted abstinence negative affect
relief craving
what are the rewarding properties of drug abuse
the positive experience associated with the drug
the “high”
what are the positively reinforcing properties of drug abuse
consuming the drug strengthens whatever preceding behavior was performed
how hard an animal will work for a drug
rewarding properties of drugs are commonly evaluated using which two animal tests?
place conditioning
electrical self-stimulation
withdrawal from ethanol _____ threshold for electrical self-stimulation of reward pathway
increases
how is relapse to drug use modeled
reinstatement
how is reinstatement performed in animals?
CS’s, stress, or drug exposure
describe the impulsive stage
driven by positive reinforcement, drug reward properties
activation of the reward circuit
describe compulsive stage
driven by negative reinforcement; removal of negative stimuli
recruitment of anti-reward circuitry
what brain regions are in reward pathway
VTA
Nuc. Acc
what brain regions are involved in antireward pathway
CaA, BNST
LC
PFC dysfunction in addiction is characterized by
intrusive thoughts
craving
poor impulse control
cocaine-HCl
oral, intranasal, IV
vulnerable to heat
free base cocaine
dissolve in H2O, NaHCO3
heat & dry = “crack”
lipophillic cocaine
easily crosses BBB
metabolites for cocaine
benzoylecgonine
coc+EtOH –> cocaethylene
what are the drug actions for cocaine
inhibit NT transporters
–high affinity for NET and SERT
increased DA release independent of DAT
–inhibition of NET in PFC drives excitation of VTA
m/AMPH drug actions
enters DA nerve terminals by DAT uptake, provoking release from synaptic vesicles into cytoplasm
DAT functions in reverse, releasing DA into extracellular fluid
what are the behavioral effects of cocaine?
- euphoric high
- behavioral activation (repetitive stereotyped behaviors, locomotion, rearing, sniffing)
- sympathetic arousal (tachycardia, vasoconstriction, hypertension, hyperthermia)
psychostimulant microinjection into the Nuc. Acc. induces what behavioral effect?
increase locomotor behavior
psychostimulant microinjection into dorsal striatum induces what behavioral effect?
increase stereotyped behaviors
6-OHDA lesion in Nuc. Acc induces which behavioral effect?
decreased locomotor
6-OHDA lesion in dorsal striatum induces which behavioral effect?
decreased stereotyped behaviors
true or false: COC-insensitive DAT-ki mice do not self-administer cocaine
true
Do D1 KO mice self-administer cocaine?
no
do D2 or D3 KO mice self-administer cocaine?
yes
once-daily, intermittent administration of cocaine results in _______
sensitization
continuous cocaine administration results in _______
tolerance
what does chronic cocaine use do to the brain?
decreased gray matter volume
hypofunction of PFC
what are the names of natural opiates?
morphine, codeine, thebaine
postsynaptic inhibition of endogenous opioids
opens k+ channels
axoaxonic inhibition of endogenous opioids
close Ca2+ channels
presynaptic inhibition of endogenous opioids
reduce transmitter release
what are the PNS effects of opioids?
pinpoint pupils
vomiting
cough suppression
constipation
how does death by opioids occur?
respiratory depression
cardiac depression
what are the three symptoms of “opioid overdose triad”
pinpoint pupils, unconsciousness, respiratory depression
what do 6-OHDA lesions do to self-administration for opioids?
reduce, but not stop completely
injection of naloxone into which brain structure produces the physiological symptoms of WD?
LC/ PAG
injection of naloxone into which brain structure produces the aversive properties of WD?
N.Acc
ethanol synthesis
alcohol –(alcohol dehydrogenase/NAD)–> acetaldehyde –(aldehyde dehydrogenase/NAD)–> acetic acid –(oxidation reaction)–> carbon dioxide
in acute tolerance, effects of alcohol are _____ during the elimination phase
reduced
how does EtOH interact w GABA receptors?
increases Cl- flux through GABAa receptors
how does EtOH interact w glutamate receptors?
EtOH inhibits iGlu receptors, decreasing release.
how do blackouts occur?
acute EtOH inhibits NMDA receptors and decreases LTP
what is wet brain
EtOH induced excitotoxic damage
chronic EtOH associated with _____ of alpha1 and ______ of alpha 4 and 6
down-regulation
up-regulation
what are the two THC metabolites?
11-OH-THC
THC-COOH
what is the half life of THC
20-30 hours
what are the two endocannabinoids
anandamide
2-AG
anandamide
CB1 partial agonist
degraded by FAAH
2-AG
full, nonselective CB1 and 2 agonist
degraded by MAGL
what converts DAG to 2-AG
DAG Lipase
retrograde signaling by endocannabinoids is involved in ______
synaptic plasticity
what are CP-55,940 and WIN 55,212-2
full CB1 and 2 agonists
what is SR 141716A
selective CB1 antagonist
what is Epidiolex
first FDA-approved drug that contains a purified drug substance derived from cannabis
–lennox-gastaut syndrome
–dravet syndrome
CB1-R in VTA
hyperpolarize IN
decrease GABA release
increase VTA firing
increase dopamine release
prazosin
alpha1-AR antagonist
increases peripheral vasodilation
reduces nightmares in PTSD
propranolol
beta-AR antagonist
negative chronotropic and negative ionotropic effects on heart
reduces performance anxiety in social anxiety disorder
5-HT1a autoreceptors
dorsal and median raphé
inhibit neuronal firing and 5-HT release
agonists are anxiolytic
5-HT postsynaptic receptors
hippocampus and amygdala
emotional and cognitive aspects
agonists are anxiogenic
short allele
smaller amygdala and sgACC volume
increased amygdala activity
greater symptom severity in anxiety disorders
early elevated 5-HT
short allele is low-expressing
SERT KO are more anxious
what are benzodiazepines
positive allosteric modulators of GABA a receptors
long-acting BZD
metabolites are psychoactive
librium
valium
short(er)-acting BZD
metabolized in one step
xanax
ativan
klonopin
short-acting BZD
rohypnol
versed
neurontin and Lyrica
anticonvulsants
block active calcium channels
reduces excitatory neurotransmission
off-label use
how to view anhedonia in animal models
sucrose preference
how to view anxiety in animal models
novelty-suppressed feeding
what is the specific action of TCAs
inhibit NET and SERT
what are the HAM side effects and how are they caused?
***caused by off-target sites antagonism
H1- sedation/fatigue, weight gain
a-AR - hypotension, arrhythmia
mACh - dry mouth, constipation, dizzy
fluoxatine
“activating”
5-HT2c antagonist
sertraline
“activating”
DAT blockade
paroxetine
anxiolytic
NET blocker
anti-cholinergic
lexapro
the purest SSRI
trazodone and nefazodone
multi-action AD, used for sedative properties
serotonin antagonist and reuptake inhibitor
sedating (H1) effective in insomnia
antagonism reduces SSRI side effects, though priapism is possible
effexor
SNRI
selectively boosts DA in PFC
duloxetine
SNRI
AD in absence of pain
fetzima
SNRI
which two dual-action ADs have the lowest incidence of sexual dysfunction?
wellbutrin and mirtazapine
viibryd
5-HT1a partial agonist
trintellix
5-HT1a antagonist
zulresso
PPD
positive modulator for GABAa receptors
continuous IV infusion over 60 hours
spravato
nasal spray used in conjunction w AD
acute AD administration _____ release of 5-HT
reduces
ketamine
non-competitive NMDA receptor antagonist
what is necessary for ketamine to be an effective AD?
dendritic spines
what is the name of the phenothiazine
chlorpromazine
what is the name of a butyrophenone
haloperidol
describe neuroleptics
D2 receptor antagonists
effective antipsychotics
significant side effects
**EFFECTIVE IN TREATING POSITIVE SYMPTOMS
nigrostriatal pathway function w neuroleptics
EPS side effects
meso-limbic pathway function w neuroleptics
antipsychotic efficacy
tubero-hypophyseal pathway function w neuroleptics
endocrine side effects
clozapine
effective atypical antipsychotic for 1/3 people non-responsive to neuroleptics
EPS side effects are less severe
reduces risk of suicide
side effects of clinical use of clozapine
loss of WBCs
substantial weight gain
reduced seizure threshold
what do atypical antipsychotics have high affinity for
5-HT2a antagonists
2 pips and a rip
D2 partial agonist
5-HT1a partial agonist
adjunct in MDD
abilify
rexulti
peens and dones
depressive episodes in BD
quetiapine
lurasidone
T/F: CRF acts as both a hormone and a neurotransmitter
true
T/F: inhibitions of the LC can elicit alerting and fear responses in animals
false
T/F: the role of serotonin is not entirely clear bc some serotonin receptor subtypes can have opposite effects on anxiety
true
T/F: barbiturates are not commonly used for the treatment of insomnia bc they can induce dependence and can be lethal in overdose
true
T/F: some BZD, such as valium and librium, are long-acting anxiolytics bc they have active metabolite
true
In general, the addiction potential of a drug is positively correlated with its
a. duration of action
b. speed of onset
c. ability to cause relapse
d. all of the above
b. speed of onset
T/F: drug self administration studies typically produce a dose-response curve that is sigmoid shape
false
an increased threshold for electrical self-stimulation during withdrawal from alcohol is generally interpreted to indicate a(n)
a. state of intoxication
b. increase sensitivity of the reward circuit
c. state of craving
d. decrease in sensitivity of the reward circuit
d. decrease in sensitivity of the reward circuit
Koob and Le Moal propose that after repeated bouts of intoxication and withdrawal, drug use is driven by
a. rewarding properties of the drug
b. negative reinforcement
c. prefrontal cortex deficits
d. the reward circuitry
b. negative reinforcement
which of the following structures are part of the proposed circuitry involved in the rewarding and reinforcing effects of abused drugs?
a. amygdala
b. PFC
c. nuc. acc.
d. ventral pallidum
e. all of the above
e. all of the above