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criteria for NTs
endogenous
synthesized in presynaptic axon terminal
released when AP reaches terminal
recognized by specific receptors on the postsynaptic membrane
blocking release of NT prevents presynaptic activity from affecting postsynaptic activity
types of amine NTs
ACh, DA, NE, E, 5-HT
types of amino acid NTs
glutamate, aspartate, GABA, glycine
types of peptide NTs
opioids (enkephalins, endorlphins), oxytocin, vasopressin
types of gas NTs
nitrous oxide - difuse freely and signal retrogradely
glutamate function
excitation, learning, memory
GABA function
inhibitory, anxiety modulation
ACh function
motor control, learning, memory (loss = Alzheimer’s)
DA function
motor control (mesostriatal pathway)
reward and reinforcment (mesolimbocortical, involved in schizophrenia)
5-HT function
mood, sleep, sexual behaviour, anxiety
NE function
arousal, mood, sexual behaviour, fight or flight
opioid function
analgesic and reward
NO function
vasodilation and synaptic plasticity
agonist
mimics NT and activates recpetor more
antagonist
blocks receptor without activating, preventing the NT from working
inverse agonist
produces the opposite effect of the NT
partial agonist
produces a medium effect regardless of dose
competitive ligand
bind at the same site as the NT, blocking its access
noncompetitive ligand
bind to a different site on the target (modulatory), can still affect the cell
ligand + receptor procedure
ligand binds, so receptor changes shape/activity
leads to ion flow, or second messenger cascade
signal ends when the ligand dissociates
binding affinity
strength of the ligand-receptor binding
binding efficacy
ability to activate a receptor once bound
dose-response curve
determines potency (how much dose to create an effect), efficacy (max response), and safety margin
routes of drug administration
oral, intravenous, intramuscular, inhalation, transdermal, sublingual, etc
must cross BBB - administering closer to brain = more effective
adaptations to drug presence in body
metabolic tolerance: faster breakdown
functional tolerance: receptor up/downregulation
cross-tolerance: developing tolerance to a full class of chemically similar drugs
sensitization
withdrawal
3 ways drugs alter presynaptic processes
production
release
clearance
production of drugs (presynaptic process)
inhibit enzymes that synthesize NT
this prevents NT storage in vesicles
eg: blocking DA synthesis enzymes results in less DA
release of drugs (presynaptic process)
blockage of Na+/Ca2+ channels prevents AP-triggered release
eg: Novocain, TTX
prevents vesicle fusion/release
eg: botox blocks ACh → cause paralysis
tetanus: blocks inhibitory ACh release → sustained muscle contraction
also alters autoreceptor activity
clearance of drugs (presynaptic process)
block reuptake transporters so the NT stays in the cleft longer (more effective)
eg: SSRIs
inhibits degrading enzyme for prolonged action
eg: acetylcholinesterase inhibitors stop the breakdown of ACh
direct receptor effects of PSP
antagonists block receptors
eg: curare blocks nicotinic ACh, leading to paralysis (no ACh)
agonists activate receptor
eg: LSD activates 5-HT receptors in visual cortex
cellular effects of PSP
alter number of receptors (eg: up/down regulation)
alter intracellular signalling (eg: gene expression, secondary messengers)
eg: lithium chloride is a mood stabilizer, via intracellular changes
DREADDs
Designer Receptors Exclusively Activated by Designer Drugs
selectively activate/inhibit specific neurons for research
autoreceptors
type of receptor located on a neuron thatbinds to the NT released by that neruon (basically activates itself)
triggers a feedback loop to inhibit further release of NT
function of autoreceptors
stimulation decreases NT release (bc autoreceptor senses NT in the cleft already)
inhibition increases NT release (bc no longer downregulating)
caffeine and autoreceptors
caffeine blocks adenosine autoreceptors
this increases catecholamine release (DA, NE, E) release to create alertness
NT reuptake
taking NT back into presynaptic terminal via transporters (eg: 5-HT reuptake using SER) to recycle the NT again
enzymatic degredation
NT is broken down in the synaptic cleft (often wasteful, cannot reuse NT)
diffusion
NT leaves synapse, gets swept off
first-gen antipsychotics
DA D2R antagonists
reduce positive symptoms of schizophrenia, but not very effective for negative symptoms
second-gen antipsychotics
affect both DA and 5-HT receptors
effective for both positive and negative symptoms of schizophrenia
show that both DA and 5-HT dysregulation results in schizophrenia
mechanism of antidepressants
prolong the activity of monoamines (DA, NE, 5-HT)
MAO inhibitor
monoamine oxidase
prevent enzymes from breaking down monoamines at the synapse
tricyclics
block reuptake of NE and 5-HT
SSRIs
block 5-HT reuptake so 5-HT stays in the synapse for longer
SNRIs
block reuptake of both 5-HT and NE, works similarly to SSRIs
antidepressants time frame
biological effects begin with hours at the synaspe, but clinical effects take 2-6 weeks
this delay is due to autoreceptors, which detect 5-HT in the cleft and reduce its release
weeks of using SSRIs lead to autoreceptor downregulation, so there’s less autoreceptors and sustains 5-HT release
anxiolytics
reduce nervous system activity
eg: tranquilizers, depressants
barbiturates
reduce anxiety, promote sleep, prevent seizures
narrow safety margin and high risk of overdose (respiratory depression)
benzodiazepines
GABA-A receptor agonist, which enhance the inhibitory effects of GABA
safer and more specific than barbiturates
eg: Xanax, Ativan (Lorazepam)
bind to orphan receptor sites on GABA-A
no known endogenous ligand
neurosteroids
modulate different GABA-A sites, which are elevated during stress to calm down the brain
eg: allopregnanolone
source of opiates
opium, from poppy seeds
examples of opiates
morphine, heroin, oxycodone, fentanyl
opiates effect on body
potent analgesic and highly addictive
brain mechanism of opiates
bind to metabotropic opioid receptors in:
PAG
locus coeruleus
amygdala
produces euphoria and analgesia, reducing arousal
opiate effect on periaqueductal grey
pain reduction
opiate effect on locus coeruleus
reduces NE system, regulating arousal
opiate effect on amygdala
emotional processing, eg: reduced anxiety/fear response
opiate dependence
chronic use leads to decreased emotional system activity, lowered cortisol, decreased arousal
so, body compensates and increases receptor sensitvity
withdrawal leads to massive NE release, high pain sensitvity, insomnia, jitteriness
orphan receptor discovery
opioid receptors were first called orphan receptors because they didn’t know any natural ligands that bound to them
led to discovery of endogenous opioids (natural analgesics):
enkephalins
endorphins
dynorphins
shows that the brain has a natural system for pain relief and reward
opiate antagonists
naloxone and naltrexone block opioid receptors
rapidly reverse opioid overdose
blockign therewarding effects help treat addiction
function of naltrexone
used for alcohol use disorder by blocking alcohol-induced euphoria via endogenous opioid release
suggests that alcohol plays a role in releasing endogenous opioids to bring pleasure
source of cannabis
cannabis sativa
THC
active part of cannabis, gives psychoactive “high”
CBD
provides medicinal, anxiolytic, non-intoxicating effects
CB1 receptor location
CNS:
substantia nigra, hippocampus, cerebellar cortex, cerebral cortex
CB1 receptor function
mediates rewarding properties of cannabinoids
CB2 receptor location
immune system and periphery, eg: microglia
CB2 receptor function
regulates nociception, reduce cytokine release, decrease immune activation, lower eye pressure in glaucoma
endogenous ligand in cannabis
anandamide
nicotine effects on body
increase heart rate/blood pressure, intestinal activity, skeletal muscle contraction, cortical activity
mechanism of nicotine
agonist at nicotininc ACh receptors
receptors on VTA → NaCC, pleasure/reward pathway
chronic use of nicotine
leads to downregulation of nicotininc ACh receptor, leading to tolerance
extremely addictive, 1 cigarette binds 88% of brain’s total incotininc receptors
mechanism of cocaine
block monoamine transporters and prevents DA, NE, 5-HT reuptake
strong VTA → NaCC activation for pleasure pathway
early cocaine effects
tolerance via DA receptor downregulation
chronic cocaine use effects
sensitization of D1/facilitating pathways, and downregulation of D2/inhibitory pathways in PFC and dorsal striatum
leads to decreased executive control and increased habit bias
risks of cocaine usage
addiction due to habit-formation via glu/LTP, increased impulsivity
(meth)amphetamine structure
resembles catecholamines, but induce NT release without needing APs
amphetamine mechanism
block reuptake, competing with breakdown enzymes
potentiate AP-triggered release to help trigger other NT action
short-term effects of amphetamines
induced euphoria, stamina
long-term effects of amphetamines
insomnia, weight loss, psychosis, brain damage (from toxic monoamine levels)
alcohol effects in low doses
stimulates mesolimbic DA pathway via VTA disinhibition
alcohol effects on high doses
widespread inhibition, especially in PFC (decreased executive function) and cerebellum (decreased motor coordination)
mechanism of alcohol
activation of GABA-A receptors = inhibitory effects
inhibition of NMDA receptors = blocks LTP, impairing memory and learning
chronic heavy use of alcohol
cortical atrophy, white matter lose
PFC dysfunction
cerebellar degeneration, ataxia (lack of movement)
recovery from heavy use of alcohol
some brain volume and function can improved with prolonged abstinence, but some deficits may still persist
psychedelics
alter sensory perception to produce unusual experiences
serotonergic hallucinogens
LSD, psilocybin, mescaline
mescaline
serotonergic and noradrenergic hallucinogen
dissociative drug
ketamine
muscarine
a cholinergic hallucinogen
salvia
a hallucinogen acting on kappa-opioid receptor
ketamine mechanism
blocks NMDAR in PFC, leading to depersonalization
MDMA
a type of hallucinogenic amphetamine
chronic use of MDMA
leads to serotonergic neuron damage
MDMA mechanism
increases 5-HT, DA, oxytocin, empathy, euphoria
mild severity of substance abuse
2-3 symptoms
moderate severity of substance abuse
4-5 symptoms
severe severity of substance abuse
6+ ssymptoms
moral model of substance abuse
addiction is due to a lack of willower/morals, but this theory is not supported by evidence
disease model of substance abuse
addiction is an illness, however there is no clear pre-existing pathology