Exam 3 Flashcards
(291 cards)
1
Q
Nicotine
A
the psychoactive ingredient in tobacco (natural source)
2
Q
dried tobacco leaves contain ___% nicotine?
A
5
3
Q
tobacco smoke is a very complex mixture that contains….
A
tar - carries nicotine to lungs
4
Q
cigarettes in the 20th century
A
became the dominant form of tobacco due to new curing methods and the invention of cigarette machine
5
Q
currently, about ___% of US population are smokers
A
15
6
Q
routes of nicotine administration
A
- smoking/vaporizing (“vaping”)
- by mouth (chew, dip, snus)
- by nose (snuff)
7
Q
pharmacokinetics: smoking/vaporizing (vaping)
A
- nicotine carried on tar or other particles
- absorbed via lungs
- provides highest blood nicotine
8
Q
pharmacokinetics: by mouth (chew, dip, snus)
A
- absorbed by membranes in mouth
- strong first pass metabolism
9
Q
pharmacokinetics: by nose (snuff)
A
absorbed by membranes in nose
10
Q
E-cigarettes
A
electronic devices that vaporize
11
Q
smoking/vaping causes nicotine to hit the brain how fast?
A
in 7 seconds
12
Q
how is nicotine metabolized?
A
metabolized into cotinine by a cytochrome P450 enzyme
13
Q
individual variation in the expression of cytochrome P450 enzyme (nicotine enzyme)
A
- the half-life of nicotine averages at 2 hours
- people with reduced nicotine metabolism are less likely to become smokers
14
Q
the pharmacodynamic action of nicotine
A
nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs), which are ionotropic receptors
15
Q
acetylcholine receptors (nAChRs), are ionotropic receptors found where?
A
- brain
- autonomic nervous system
- neuromuscular junction (NMJ)
16
Q
nicotine effects on cognition
A
- acetylcholine (ACh) is related to sustained attention and memory
- nicotine can enhance performance of attention-demanding tasks
- rat studies also show enhanced performance on cognitive tasks
17
Q
nicotine effects on mood
A
- relaxing, alleviates stress, helps concentration
- hypothesized to be partially associated with relief from withdrawal
18
Q
a high dose of nicotine
A
produces unpleasant symptoms
-largely due to autonomic actions of nicotine. But, strong tolerance to these actions
19
Q
lethal dose of nicotine (rare)
A
kills through depolarization block of muscles involved in respiration
20
Q
nicotine withdrawal symptoms
A
opposite to acute drug effects
-irritability, stress, difficulty concentrating when they don’ smoke
21
Q
nicotine: acute tolerance
A
develops over the course of the day due to desensitization of nicotinic receptors (nAChR)
22
Q
nicotine: chronic tolerance
A
over long time periods
-pharmacodynamic tolerance: nAChR upregulation
23
Q
nicotine: negative effects of chronic use
A
- increased risk for lung diseases, but also cardiovascular diseases and cognitive deficits
- smoking during pregnancy causes low birthweight
24
Q
the precursor for acetylcholine (ACh)
A
choline, a vitamin found in many foods
25
the enzyme that synthesizes ACh
Choline acetyl-transferase (ChAT)
26
what metabolizes ACh into choline and acetic acid?
acetylcholinesterase
27
vesicular acetylcholine transporter (VAChT)
packages ACh into vesicles
28
ACh (degradation and metabolism)
ACh undergoes rapid degradation/metabolism by AChE, converting it back to choline
29
Choline (reuptake)
choline is then taken up by the choline transporter and reused to make more ACh
30
Muscarinic ACh receptors (mAChRs)
metabotropic (GPCRs)
31
Nicotinic ACh receptors (nAChRs)
ionotropic (ion channels)
32
nicotinic ACh receptors (structure)
pentameric (5 subunits) ligand-gated cation channels
| -brain and muscle
33
Brain nAChRs (structure)
consist of 2 alpha subunits and 3 beta subunits or 5 alpha subunits
-higher affinity
34
Muscle nAChRs (structure)
consist of 2 alpha1 subunits, 1 beta1 subunit, 1 y subunit, and 1 d/e subunit
- ACh binding sites: both need to be bound for channel opening
* ****fancy letters that I couldn't type!*******
35
nicotinic ACh receptors
cation channel
36
nicotine postsynapse
rapid depolarization, which can increase neuronal firing or contract muscle
37
nicotine presynaptic (axon terminal):
enhance release of neurotransmitters
38
nAChRs desensitization
nAChRs desensitize with continuous exposure to agonist (the channel closes); this is reversible. Causes acute tolerance to nicotine.
39
Acetylcholine: autonomic nervous system
sympathetic: fight or flight
parasympathetic: rest and digest
40
acetylcholine: somatic nervous system
neuromuscular junction (NMJ)
41
acetylcholine: somatic nervous system
neuromuscular junction (NMJ)
42
animals and nicotine
nicotine is self-administered by animals
43
nicotine reinforcement
systemic nicotine increases activity of VTA dopamine cells --> more dopamine release at terminals in nucleus accumbens
44
what nAChR subtype is involved in the rewarding effects of nicotine?
alpha4beta2-containing receptors
45
what nAChR subtype is involved in cognitive effects (attention) of nicotine?
alpha7-containing receptors
46
smoking leads to occupancy of ______ nAChRs
alpha4beta2
47
Nicotine reinforcement in mice:
IV nicotine self-administration impaired in mutant mice with genetic knockout of either alpha4, alpha6, beta2, BUT NOT alpha7
48
alpha7-containing receptors are important for nicotine effects on __________?
attention
49
psychological (cue-induced craving) and pharmacological (dependence) nicotine treatment options
-Nicotine replacement therapy (NRT) helps with dependence /withdrawal
50
withdrawal and craving treatment options (nicotine):
Bupropion - weak nAChR antagonist
Varenicline - partial agonist at alpha4/beta2
-most effective treatment
51
opioids
analgesic and sedative-hypnotic
- at high doses can lead to coma and death
- best painkillers known
- produce a sense of euphoria
52
"opiates"
naturally occurring alkaloids found in the sap of the opium poppy
53
raw opium contains....
about 10% morphine, about 0.5% codein
54
opium routes of administration:
oral, smoking
55
since before recorded history, opium has been used in....
many medicinal preparations
56
history of opium medical use
primarily for pain; also diarrhea, coughing
| -laudanum: tinctures of opium
57
recreational use of opium
raw opium is usually smoked
58
principal active ingredients in opium:
morphine and codeine (natural source)
59
Morphine
medical use as analgesic
60
codeine
medical use: some analgesic effects, really good for cough
61
opiod form (semi-synthetic)
heroin (diacetylmorphine)
62
heroin
a semi-synthetic opioid formed from adding two acetyl groups to morphine
- first marketed by Bayer as a less addictive replacement for morphine
- quickly metabolized into morphine in the brain
- it is a pro-drug
63
street heroin purity
it varies
| -adulterants to enhance the effects (e.g. fentanyl, which is more potent
64
creating heroin by adding two acetyl groups to morphine
increases lipid solubility and speed to brain
65
potency of heroin
2-4x more potent than morphine when take intravenously
66
most "harmful" abused drug
heroin
67
desomorphine ("krokodil")
opioid form
- "flesh-eating" drug
- 8-10x more potent than morphine
68
opiates vs. opioids
opiates: natural opioids derived from opium poppy
opioides: all ligands for opioid receptors
69
prescription opioids
are used for severe pain (analgesic) and cough (antitussive)
70
chronic opioid use
seems to increase potential for abuse, addiction, and overdose
71
There has been a large increase in opioid overdose deaths (prescription, heroin, synthetic opioids) T/F
TRUE!!
72
what factor contributed to the prescription opioid and heroin epidemic?
Purdue aggressively marketed Oxycontin (controlled release oxycodone)
73
what percent of people with opioid prescriptions for pain become addicted?
about 3%
74
Factors leading to opioid crisis:
- chronic use of Rx opioids
| - lacing of heroin with fentanyl
75
opioid recreational routes of administration
- IV injection
- SC injection
- smoking/inhalation
- snorting
76
IV heroin reaches the brain much ________ than morphine due to ______ ________.
faster, lipid solubility
77
opioid drugs differ in onset and duration, how?
half life:
- morphine and most oral Rx: 2-4 hours
- methadone (oral): 24 hours due to depot binding
78
Effects of opioids: Low to moderate doses
-analgesia
-suppression of cough reflex
-reduced gastrointestinal (GI) motility (constipation)
-euphoria
-some dysphoria
-nausea/vomiting
Also: slow respiration, pupil constriction, drowsiness, decreased concentration
79
effects of opioids: high doses
- unconsciousness
- pinpoint pupils
- reduced temperature and blood pressure (clammy)
- respiratory depression
80
respiratory depression (opioids)
main cause of death due to overdose
| -reversed rapidly by naloxone (antagonist)
81
withdrawal symptoms (opioids)
opposite to the acute effects
- rebound hyperactivity in GI tract, autonomic nervous system, brain, and spinal chord
- NOT LIFE THREATENING
- cross-dependence and cross-tolerance for all opioids
82
how does the duration of opioids effect withdrawal and intensity of withdrawal?
longer duration opioids cause longer withdrawal with lower intensity (methadone vs. heroin)
83
rapid tolerance to some effects of opioids but not others (examples)
rapid tolerance: analgesia
| NOT: GI effects (constipation), pupil constriction
84
factors driving opioid tolerance
- metabolic
- pharmacodynamics
- psychological (classical conditioning)
85
controlled, long-term use of opioids effects
- appears not to have serious health consequences
- low risk of long term effects to organs (unlike alcohol and tobacco)
- long term use of methadone is not harmful
- relapse rates remain high
86
multidimensional support (opioids)
-detoxification
-pharmacological support (opioid agonists and antagonists)
-group/individual counseling
reduce injury and crime (harm reduction) not cure
87
detoxification
- unassisted: going cold turkey
- short term replacement: long-acting opioid, methadone, for 5-7 days to reduce withdrawal
- clonidine: relieves some withdrawal symptoms
- ultra-rapid: opioid antagonists
88
opioid agonists (long-term replacement therapy)
- methadone maintanence
| - buprenorphine maintanence
89
methadone maintanence
- most common
- 80% abstinence rates
- long half-life --> stable blood levels across day
- oral once daily, supervised bc it can be abused if taken (methadone is reinforcing/rewarding)
90
buprenorphine maintenance
- partial agonist
| - longer duration
91
opioid antagonists
naloxone (Narcan) and naltrexone (Trexan)
- rapidly reverse opioid overdose
- prevent misuse of opioids
- addiction treatment
92
The pharmacodynamic action for ALL opioid drugs...
is to bind to opioid receptors in the central nervous system and periphery
93
first endogenous opioid discovery:
beta-endorphin ("endogenous morphine")
94
all endogenous opioids are....
peptide neurotransmitters
95
different endogenous opioids and what they act as
endorphins, enkephalins, and dynorphins
| -they act as neurotransmitters and hormones
96
all opioid peptides are products of 4 gene families:
- POMC
- PENK
- PDYN
- PNOC/OFQ
97
the short/long peptides are cleaved to give smaller/longer opioid peptides
long, smaller
98
synthesis, release, and inactivation of peptides (opioids)
- peptides are made in soma, cleaved and packaged into vesicles in Golgi, and then transported to terminals
- neuropeptides are not typically the only transmitter at a synapse. instead, they are co-released together with a classical neurotransmitter
- after release, peptides are degraded by peptidases (enzymes)
99
where are opioid receptors located?
CNS: brain, spinal cord
PNS: sensory neurons
Periphery: heart, lungs, liver, etc.
100
Bioassay for opioids (guinea pigs):
ability of opioids to influence contractions of guinea pig intestine (ileum) strongly predicts human analgesic properties
101
four major types of opioid receptors
- mu (MOR)
- delta (DOR)
- kappa (KOR)
- nociceptin/orphanin FQ (NOPR)
102
abused opioids all bind to what receptor?
mu-opioid receptor
103
opioid receptors are all:
- metabotropic receptors coupled to Gi proteins
- opioid binding causes inhibition of AC and actions at G-protein-gated ion channels (opening K+ and closing Ca++ channels)
- they can be presynaptic or postsynaptic
104
endogenous opioids are found in multiple brain regions, especially those involved in....
pain and emotion (affect) signaling
105
Opioid agonists and antagonists
agonist: many Rx and abused opioid drugs
competitive antagonists: naloxone, naltrexone
partial agonists: buprenorphine
106
although they bind to other receptors, all abused opioids are agonists at the _________ receptor
mu-opioid receptor
107
analgesic effects of opioids:
1. spinal cord: opioids inhibit incoming pain signal
2. periaqueductal gray
3. forebrain: sensory and emotional response to pain
108
what causes the release of endogenous opioids?
painful stimuli
109
mu receptors
- strongly implicated in reward and euphoria
| - strong self-administration and conditioned place preference for mu receptor agonists
110
evidence that dopamine does mediate opioid reward: mu agonist
mu agonist
- increase DA cell firing in VTA, and DA release in striatum (NAc)
- self-administration
- increase locomotion
111
evidence that dopamine does mediate opioid reward: dopamine antagonist
DA antagonists:
- block opioid CPP
- reduce opioid self-administration
- block increased locomotion
112
Evidence that DA does not mediate opioid reward:
- DA receptor blockade and 6-OHDA lesions do not affect heroin self-administration
- DA-deficient mice still show morphine CPP
113
GI effects of opioids due to.....
mu and kappa binding in stomach and small/large intestine, which decreases GI motility (and causes constipation)
114
Loperamide
is a modified opioid that acts peripherally
| -used to slow GI motility and reduce diarrhea
115
opioids interact on all levels of respiratory control:
1. fundamental drive generated by brainstem
2. conscious modulations from cortex
3. subconscious modulations from blood chemoreceptors
116
codeine
is often considered the "gold standard" in antitussive therapy (cough sepression)
117
opioids probably reduce cough via:
- central actions in the brainstem (cough reflex)
| - peripheral actions on sensory nerve endings
118
dextromethorphan
was developed as a non-addictive substitute for codeine; it is an opioid derivative but does not act at opioid receptors
119
opioid-induced nausea acts via several mechanisms:
1. area postrema
2. increased vestibular sensitivity
3. delayed gastric emptying
120
pupil constriction
due to opioid disinhibition of brainstem nuclei
121
Where do opioid drugs act to produce analgesia?
spinal cord, periaqueductal gray, forebrain
122
Where do opioid drugs act to produce reward?
brain-dopamine neurons (evidence for and against)
123
Where do opioid drugs act to produce gastrointestinal effects?
stomach, small/large intestine
124
Where do opioid drugs act to produce respiratory depression?
brainstem, cortex, blood chemoreceptors
125
Where do opioid drugs act to produce cough suppression?
brainstem, sensory nerves
126
Where do opioid drugs act to produce nausea and vomiting?
area postrema, vestibular system, and GI
127
Where do opioid drugs act to produce pupil constriction?
brainstem
128
Cannabis contains many ________ (natural)
cannabinoids
129
where are cannabinoids concentrated and secreted?
they are especially concentrated in the sticky, yellow resin secreted at the flowering top of the female plant
130
cannabis contains...
>110 cannabinoids (many of which are psychotic)
131
what seems to be the most important psychoactive drug??
delta9-tetrahydrocannabinol (delta9-THC or "THC")
132
other cannabinoids besides THC....
delta8-THC, cannabinol, cannabidiol (CBD)
133
marijuana
refers to dried cannabis and contains a mixture of leaves, small stems, and flowering tops
134
THC content varies with...
strain (breeding) and growing conditions
| -Ex: if prevent pollination and seeding in female plants, THC contents increase (sinsemilla = "without seeds")
135
How has content in seized marijuana changed?
it has increased over the decades
| - 2010: 8-12% typical
136
concentrated forms of THC (3)
- hashish
- hash oil
- dab
137
hashish
is a dried resin concentration consisting of trichomes (small outgrowths from top of female plant; the plant part with the highest THC content)
-20-60% THC
138
hash oil
is an alcoholic extraction from hashish
139
dab
includes other extractions from cannabis
| -can be >90% THC
140
routes of administration (marijuana)
```
smoking
-20-30% of the THC can be absorbed
vaporizing (including "dabbing")
eating
-low absorption of THC due to first-pass metabolism in stomach and liver (but metabolic products are even stronger)
```
141
cannabis sativa (hemp)
is one of the earliest cultivated non-food plant and among the strongest natural fibers
142
history of cannabis use
- recreational use and intoxication only became common in the US in 1900s
- anti-marijuana propaganda called it a social menace
- anti-marijuana propaganda included movies ("Refer Madness") and books
- cannabis use became very popular in 1960s-70s among counterculture
143
current cannabis used
- the most popular US illicit drug
| - typically first used in adolescence
144
potential medical uses of marijuana
- treatment of glaucoma: to decrease intraocular pressure
- antiemetic: to reduce nausea and vomiting (cancer patients)
- appetite stimulant (AIDS patients)
- anticonvulsant: to reduce seizures
- analgesic: to reduce pain
145
legalization status of marijuana
many US states have legalized medical marijuana, and some have legalized recreational marijuana. BUT, still. illegal at the federal level (Schedule I)
146
cannabidiol (CBD)
thought to have similar benefits as THC without strong psychoactive effects
147
medical cannabinoids
- dronabinol: synthetic THC in pill form
- Schedule III: treatment of nausea and anorexia
- cannabis extract mouth spray
- Nabilone: synthetic agonist
148
pharmacokinetics of marijuana: absorption and distribution
- cannabinoids are highly lipid soluble
- THC reaches the brain quickly after inhalation
- distributes to fat stores (depot binding), causing rapid decrease in peak blood concentration
149
half life of marijuana
LONG, 20-30 hours
150
drug tests detection of marijuana
drug tests can detect single-use >2 weeks later (even if longer with repeated use)
151
pharmacokinetics of marijuana: metabolism and elimination
- metabolism is mostly in liver
- 11-hydroxy-THC: Active metabolic product after oral consumption of delta9-THC (first-pass metabolism), more potent than delta9-THC itself
- 11-nor-9-carboxy-THC: inactive metabolite used in drug test
152
THC effects: low to moderate doses on behavior and mood
- disinhibition, relaxation, drowsiness, floating sensation
- enhanced feeling of well being, euphoria
- impaired short-term memory
- impaired time estimation and reaction time
(effects vary with dose, setting, past exposure, expectations)
153
THC effect: low to moderate doses on physiology
- increased hunger ("munchies") - very reliable effect
- decreased muscle strength, small temor
- increased heart rate (pounding)
- increased blood flow (causes red eyes, good for glaucoma)
(effects vary with dose, setting, past exposure, expectations)
154
THC effects: High doses behavior and mood
- increasingly disorganized thoughts, confusion
- paranoia, agitation
- anxiety (dependent on setting)
- synesthesias and pseudohallucination
155
THC effects: high doses physiological
pronounced motor impairment
NOT lethal even at very high doses
156
effects of repeated cannabis: dependence and addiction
withdrawal symptoms peak for 1-2 weeks after chronic use in humans (and are opposite to acute effects of ccannabis)
- irritability
- anxiety
- depressed mood
- sleep disturbances
- heightened aggression
- decreased appetite
157
factors that contribute to increased risk of addiction (marijuana)
- early onset of use (young age)
| - daily use
158
effects of repeated cannabis use: tolerance
- behavioral tolerance
| - pharmacodynamics tolerance: after repeated use, desensitization and downregulation of CB1 receptors in the brain
159
synthetic cannabinoids
spice and K2: synthetic cannabinoids sold under a number of names
- marketed as "safe" legal alternatives to marijuana. But not safe or legal
- intoxication, withdrawal, psychosis, and overdose death
160
what receptors does marijuana act at?
cannabinoid receptors
161
where are CB1 receptors located and for what?
presynaptic terminals, for retrograde signaling
162
What are the endogenous ligands for CB receptors (CB1 and CB2)??
endocannabinoids
163
endocannabinoids
high lipid solubility
164
two endocannabinoids
Anandamide
-partial agonist for CB1 receptors
2-AG
-full agonist for CB1 and CB2
165
endocannabinoids: signaling
endocannibinoids are lipid neurotransmitters and retrograde messengers
166
why are their no vesicles with endocannabinoids signaling?
- too lipid soluble to be stored in vesicles
| - synthesized on demand in the post synaptic side of the synapse
167
endocannabinoids signals travel retrogradely to the...
pre-synaptic terminal and bind to the CB1 receptor
168
endocannabinoid signaling deactivation
degradation by intracellular enzymes
169
two known cannabinoid receptors
CB1 receptor
CB2 receptor
-both metabotropic, coupled Gi proteins
170
CB1 receptor expression
mostly in brain and spinal chord
171
CB2 receptor expression
mostly in immune system
172
CB1 receptor
- basal ganglia, hippocampus, cerebellum, cortex
- rewarding effects and "high" from cannabis
- the most abundant GPCR in mammalian brain
173
Endocannabinoids: function
- Gi protein from CB1 acts to reduce activity of voltage-gated Ca++ channels, thus inhibiting calcium-mediated neurotransmitter release
- regulator of synaptic transmission for both excitatory and inhibitory synapses
- short-term and long-term synaptic plasticity (LTP/LTD, a component of learning)
174
endocannabinoids are the principal components of _________ ___________ _________.
retrograde synaptic signaling
175
endocannabinoid signaling plays an important role in....
long-lasting synaptic plasticity, including long-term depression (LTD)
176
animal studies of cannabinoid effects on:
- reward
- feeding
- learning/memory
177
cannabinoid effects: reward (low doses and high doses of THC)
low doses of THC:
-conditioned place preference (CPP), self-administration
high doses of THC:
- conditioned place aversion (CPA), no self-administration
178
what mediates the rewarding effects of cannabinoids?
dopamine
179
evidence dopamine mediates the rewarding effects of cannabinoids:
1. CB1 agonists increase DA firing in VTA and DA release in NAc (via inhibition of GABA, or "disinhibition" of DA)
2. animals will self-administer THC, 2-AG, or CB1 agonists directly into VTA or NAc
180
cannabinoid effects: feeding
cannabinoids injected i.v. or into NAc cause pleasurable reactions to tastes
181
cannabinoid effects: memory
- the hippocampus, causes deficits in working memory
| - blocked by CB antagonist rimonabant into hippocampus
182
CB1 antagonists or CB1 gene knockout: (endocannabinoid roles: reward)
- block self-administration of THC
- also decrease self-administration of other drugs
- decrease sensitivity to all rewards (food or drugs) and decrease NAc dopamine release
183
how does CB1 antagonist AM6545 affect food consumption?
decrease
| - reduced motivation and reward
184
CB1 antagonist Rimonabant
was used medically in Europe as obesity treatment... but stopped
185
endocannabinoid roles: memory
- CB1 knockout mice show impaired extinction learning (they keep freezing)
- indicates that endocannabinoids are important for extinction learning (probably due to role in LTD at synapses)
- CB1 knockout mice also show enhanced retention of other types of memory
- CB1 knockout (KO) mice retain recognition memory for longer
186
THC effects in mice:
- rewarding
- increased feeding
- impairs learning/memory
- hypoalgesic (reduced pain)
- ALL blocked by CB1 antagonist
187
CB1 antagonist or knockout effects:
- reduces reward
- decreases feeding
- impairs extinction learning
- hyperalgesic (enhanced pain)
188
can cannabis use lead to addiction?
yes
189
individuals with cannabis addiction often report:
- social problems
- financial difficulties
- poor general life satisfaction
190
treatment options for cannabis addiction:
mostly centered around psychotherapy
- cognitive behavioral therapy
- relapse prevention (high relapse rates)
191
what are the long lasting effects of repeated cannabis use?
remain long after abstinence/withdrawal period
- lung damage? NO
- reduced cognitive function? maybe (adolescent use)
- increased risk for psychosis
192
lung damage from long term cannabis use?
no clear evidence of long-term lung problems with heavy marijuana use
193
cannabis use effects on cognitive function (negative)
evidence of reduced cognitive function (IQ) following weekly adolescent use
194
cognitive function (marijuana affect on brain makeup)
reduced gray matter in areas of orbitofrontal cortex (even with smaller IQ)
195
rats were exposed to synthetic CB agonist (CP) only during adolescence. In adulthood they showed (as well as the conclusion):
- reduced cognitive (memory) function
- reduced dendritic complexity in prefrontal cortex
Conclusion: CB1 receptors are important in neurodevelopmental changes during adolescence
196
adverse affects of cannabis use: increased risk for psychosis
- increased incidence of psychosis among cannabis users
| - establishing a causal link is very difficult
197
comprehensive report on cannabis
comprehensive review of recent research on health effects of recreational and therapeutic use
- cannabis users in US (age >12) increased
198
comprehensive report on cannabis: therapeutic effects (conclusive evidence)
- reduced pain
| - reduced nausea/vomiting
199
comprehensive report on cannabis: risks (conclusive evidence)
immediate effects
- increased risk of motor vehicle accidents
- impaired learning, memory, and attention
repeated use
- NO increased risk of cancer
- increased risk of developing schizophrenia, psychoses, and social anxiety disorder
200
drug categories of hallucinogens:
1. psychedelics
- classical psychedelics (serotonergic agonists): LSD, psilocybin, DMT, mescaline
2. dissociatives
- NMDA antagonists: PCP, ketamine, dextromethorphan
- Kappa opioid receptor agonists: salvinorin A
3. deliriants
201
psychedelics
produce hallucinations and an altered state of consciousness
- only weak rewarding properties, not considered addictive
- psychedelic = alters perception and cognition
- hallucinogen = hallucinations
202
dissociatives
distort perceptions and produce feelings of detachment (dissociation) from the environment and self
- depressant properties
203
deliriant
produce a state of delirium, including stupor, confusion, and distorted memory
204
two main classes of psychedelics
1. indolamine psychedelics (tryptamines)
- structural similarity to seretonin (5-HT), which is indolamine
- natural source: psilocybin, DMT and 5-MeO DMT
- synthetic source: LSD (semisynthetic)
2. phenethylamine psychedelics
- structural similarity to catecholamines (Da, Ne, Epi) which are phenethylamines
- natural source: mescaline
205
psilocybin/psilocin
- numerous mushrooms produce alkaloids with hallucinogenic properties (magic mushrooms, shrooms)
- dried mushrooms are eaten
- major ingredient is psilocybin and the related compound psilocin
206
psilocybin/psilocin after ingestion
psilocybin is converted (dephosphorylated) to psilocin (aka 4-HO-DMT). Psilocin is the active psychoactive agent
207
DMT and 5-MeO DMT
- naturally occurring substance found in a number of plants in South America and in the Sonora Desert toad
- native tribes make snuffs from plants, also can be smoked
- Ayahuasca is a drink that comes from at least two plants to provide DMT and beta-carboline
208
LSD
semi-synthetic compound derived from fungal alkaloids
- taken orally
- VERY POTENT
209
Mescaline
- found in several species including peyote cactus, native to the southwestern US and northern Mexico
- mescal button or peyote button, chewed raw or cooked
210
history of psilocybin/psilocin
magic mushrooms used for >5,000 years
211
history of use: mescaline
- mescaline used by indigenous people for >5,000, possibly >20,000 years
- potent visual hallucinogen, can produce feelings of spiritual insight
- peyote and mescaline are both Schedule I
- some exemptions for religious and ceremonial use by Native American church
212
history of use: LSD
- the structure of LSD is based on a family of fungal alkaloids
- ergot fungus
- Albert Hofmann synthesized several compounds including: LSD-25: d-lysergic acid diethylamide
- he had the first LSD trip (1943)
213
history of psychedelic use (1940s-50s)
- 1940s-50s: psychedelics were used for therapeutic treatment and research. They had not yet acquired the cultural and political stigmas
- Aldous Huxley (Brave New World) tried mescaline
- Life magazine article "Seeking the Magic Mushroom"
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psychodelic: psychotherapy tool (1940-50s)
potential miracle drugs for psychiatric illness and alcohol addiction
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pschodelic: psychosis research (1940s-50s)
hypothesized to be a good model for psychosis/schizophrenia
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history of psychedelic use (1960s)
some therapists wanted psychedelics to be available to all of society (not just those needing treatment)
- Timothy Leary eats magic mushroom
- Harvard Psychedelic Drug Research Program
- began experimenting with LSD also and giving students and faculty, became leader of psychedelic movement
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1950s-60s: research by US government as potential psychological weapon
- MK-ULTRA program (mind control agent)
| - secret tests by CIA on unknowing citizens and employees
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history of psychedelic use (1960s-70s)
profound effect on art, music and culture
| - hippie culture as part of nonconformist
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profound shift in political and cultural opinions on LSD
by 1966
- banned in 1967
- all psychedelic research and therapy halted
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oral psychedelics
- onset 30-90 minutes
| - duration is 6-12 hours for LSD or mescaline, shorter for psilocybin
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smoked DMT
- onset in seconds
- peak within minutes
- duration 30-60 minutes
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major effects of psychedelic: sensory perceptual
- visual illusions
- time distortion
- synthesias
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major effects of psychedelic: psychological
- depersonalization (loss of ego)
- emotional shifts
- disruption of logical thought
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major effects of psychedelics: physiological
activation of sympathetic nervous system
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early research into therapeutic treatment (1950s-60s) revealed that:
- set and setting are very important to the patient's experience
- volunteers who had a "complete mystical experience" showed lasting improvements in well-being
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psychedelics: possible adverse effect
```
"bad trip"
- dose, personality, expectations, previous drug experience, physical and social setting
Flashbacks
- re-experiencing perceptual symptoms
Psychotic reactions
- pre-existing condition
Overdose
- virtually impossible to overdose
```
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Tolerance and dependence (psychedelic drugs)
Tolerance
- rapid tolerance with repeated use but reverse with time
- pharmacodynamics tolerance: down-regulation of serotonin 5-HT2a receptors
- multiple mechanisms of tolerance
Dependence/Withdrawal
- none
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Addiction (psychedelics)
Humans: little to no evidence of addiction (and may be anti-addictive)
Animals: typically will not self-administer
WHY?
- only weak rewarding properties
- long duration of action
****despite no dependence or addiction, these are all Schedule I drugs: LSD, mescaline, DMT, and psilocin
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effects of chronic psychedelic use
no evidence of psychological or cognitive impairments after chronic use
- "no evidence of psychological or cognitive deficits among Native Americans using peyote regularly"
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potential medical uses: psilocybin
- can produce long-lasting increases in openness
- sustained (>6 month) decreases in depression and anxiety, and increased quality of life and optimism in cancer patients
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potential medical uses: LSD
- enhanced optimism and openness
| - recent trend of "LSD micro-dosing"
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Potential psychedelic medical use: Breakthrough Therapy Designation
- for drugs that treat a serious or life-threatening disease and show preliminary clinical evidence of substantial improvement over existing therapies
- include ketamine, MDMA, and psilocybin
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Psychedelic: mechanism of action
- acting on serotonin (5-HT) system
| - the 5-HT2a receptor is particularly important for hallucinations
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pharmacodynamic action for hallucinations
binding to a receptor complex of 5-HT2a and mGluR2 (a glutamate receptor)
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hallucinations require activation of a receptor complex involving:
5-HT2a (serotonin receptor, Gq) and mGluR2 (glutamate receptor, Gi)
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psychedelics interact with what system?
the serotonin system
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What receptor is particularly important for hallucinations?
Seretonin 5HT2a
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hallucinations require activation of a receptor complex involving both:
5HT2a and mGluR2 (Gq-coupled serotonin receptor and Gi-coupled glutamate receptor)
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catecholamines
dopamine, norepinephrine, and epinephrine
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indolamines
seretonin
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serotonin is synthesized from...
amino acid precursor tryptophan
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tryptophan is converted to ______ by __________ ___________ ___________.
- 5-HTP
- enzyme tryptophan hydroxylase (TPH)
- TPH is the rate-limiting step
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5-HTP is converted to 5-HT (serotonin) by _________ ?
AADC, the same enzyme that converts DOPA to dopamine
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Serotonin: Synaptic transmission
- packaged into vesicle by VMAT2
- inactivation primarily released via rapid reuptake (serotonin transporter, SERT)
- Metabolism is secondary mechanism of inactivation; via monoamine oxidase (MAO) to yield 5-HIAA
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serotonin receptors
- 14 5-HT receptor subtypes
- all metabotropic except 5-HT3
- 5-HT terminal autoreceptor (located on axon terminals): 5-HT1b or 5-HT1d
- 5-HT somatodendritic autoreceptor (located on soma and dendrites): 5-HT1a
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serotonin receptors: 5-HT2a (expression, agonists, antagonist)
expressed in cerebral cortex, striatum, and other brain areas
agonist: some are hallucinations
antagonists: some are antipsychotic
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serotonin nuclei and pathways
most 5-HT cell bodies (nuclei) are found along midline of brainstem (medulla, pons, midbrain), loosely associated with raphe nuclei
- widespread innervation of 5-HT projections to brain
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Serotonin: key drugs
1. Drugs that inhibit SERT: more 5-HT available in synapse
- selective serotonin reuptake inhibitors (SSRIs)
- cocaine
2. Drugs that inhibit 5-HT synthesis: less 5-HT overall
3. Drugs that are 5-HT neurotoxins: destroy 5-HT axons and terminals
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____% of serotonin in the body is found in the gut and enteric nervous system.
90
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functional roles of serotonin in CNS
mood (depression, anxiety), hunger, pain sensitivity, learning and memory, addiction
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functional serotonin roles: anxiety
5-HT1a agonists reduce anxiety
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Functional roles of serotonin: depression
SSRIs used to treat depression and mood regulations in humans
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Where are LSD and other psychedelics agonists? Evidence?
postsynaptic 5-HT2a receptors
EVIDENCE!!
- affinity for 5-HT2a receptors
- effects blocked by 5-HT2a antagonists/knockout
- expression of 5-HT2a and mechanisms in cortex
- effects of other 5-HT2a agonists
- interactions with 5-HT2a and mGluR2 receptors
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Affinity for 5-HT receptors
- common affinity for 5HT2a and 5HT2c receptor among hallucinogens
- significant correlation between 5HT2a binding affinity and psychedelic effects
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effects of 5-HT2a antagonists
- 5-HT2a antagonists block subjective effects of hallucinogens in humans
- 5-HT2a antagonists dose-dependently reduce responding
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effects of 5-HT2a knockout
- hallucinogen-evoked behaviors (head twitch) are also missing in the 5-HT2a knockout mice
- selective restoration of 5-HT2a receptors in cortex only
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5-HT2a receptors expressed in cerebral cortex
expression particularly robust in layer V (output layer) of cerebral cortex
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psychedelics increase excitation in cortex (explain)
5-HT2a receptor stimulation enhances glutamate-mediated excitation of neurons in prefrontal cortex (PFC)
- this interferes with gating of sensory information from other parts of cortex
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psychedelics reduce cortical organization/coupling (psilocybin)
psilocybin disrupts coupling of certain cell types and rhythmic oscillations among populations of neurons --> disorganizing influence on cortex that allows greater flexibility
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psychedelics reduce activity in the....
default mode network (DMN)
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psychedelics reduce cortical organization/coupling (LSD)
LSD causes increased cerebral blood flow (CBF) to visual cortex
- decreased organization of cortex
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Effects of 5-HT2a agonists
not ALL 5-HT2a agonists are hallucinogens (graph on slides)
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interactions with 5-HT2a and mGluR2 receptors
different intracellular signaling
- ALL 5-HT2a agonists --> involve G1 signaling
- hallucinogenic 5-HT2a agonists --> ALSO involve Gi signaling
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a receptor complex formed by 5-HT2a and mGluR2 (glutamate GPCR) triggers...
unique cellular responses when targeted by hallucinogenic drugs
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psychedelics binding to receptor complex increase.... and decrease....
increase Gq signaling (5-HT2a) and decrease Gi signaling (mGluR2)
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activation of mGluR2 blocks....
hallucinogenic effects
| - antipsychotics cause opposite effects
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PCP: History of Medical Use
PCP synthesized as potential anesthetic agent
Problem: did not provide relaxed anesthetic state
- trance-like state with vacant facial expression, fixed and staring eyes, and maintenance of muscle tone
Problem: postoperative issues
- agitation instead of relaxation
- blurried vision, dizziness, mild disorientation
- more serious: hallucinations, severe agitation, violence
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PCP: recreational use
low levels of abuse, mostly regarded as unpleasant
Powder or pills: taken orally, snorted, i.v., or smoked
Liquid: tobacco or marijuana cigarettes dipped in a liquid containing PCP and embalming fluid
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a safer alternative to PCP, and why?
ketamine, less potent and shorter acting
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Ketamine: medical use
- still used as a valuable anesthetic for certain medical procedures (particularly in children) and vetrinary procedures
- some postoperative adverse reactions
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depression treatment: ketamine (esketamine)
- shows rapid results (2 hours)
| - FDA approved ketamine for treatment-resistant depression
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ketamine: recreational use
- ketamine use and abuse is smuch greater than PCP
Liquid: injectable liquid
Powder or pills: powder for snorting or compress into pills
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ketamine: low (sub-anesthetic) doses
- feeling of being detached from body, sensations of floating, numbness, dreamlike state
- euphoria
- cognitive disorganization
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ketamine: higher (anesthetic) doses
- dissociative: loss of all mental contact with environment; detachment
- "k hole": slang for dissociated state caused by ketamine
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chronic ketamine users effects
- ketamine bladder syndrome
- memory and cognitive impairments
- evidence of gray and white matter abnormalities
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dextromethorphan (DM)
over the counter cough suppressant
| - ssubstitute for codeine
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dextromethorphan: recreational use (at high doses)
- at high doses acts as a dissociative anesthetic
Effects at high doses:
- impaired balance, hallucinations, intoxication, euphoria, cognitive impairment, dissociation, delusions
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promethazine/codeine
purple drank
- abused
- an opioid agonist (codeine), not a dissociative
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Salvinorin A: Recreational use
salvinorin A is the psychoactive ingredient in Salvia divinorum
- chew, smoke, or extract through sublingual/buccal absorption (inactivated in GI tract)
- low toxicity; low abuse potential
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Salvinorin A: acute effects
most potent naturally-occurring hallucinogen. Short-lasting effects
- speech and coordination effects
- out-of-body experiences and hallucinations
BUT no actions at 5-HT2a receptors
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pharmacodynamic actions: PCP, ketamine, and dextromethorphan
- noncompetitive antagonists for NMDA glutamate receptor
| - DA and non-DA mechanisms
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Pharmacodynamic actions: Salvinorin A
agonist at kappa (k) opioid receptor (KOR)
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glutamate
an excitatory amino acid neurotranmitter. The MAJOR transmitter for fast excitatory signaling
- found throughout the brain
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glutamate synthesis
- glutamate precursor is present in the brain
| - glutamine is converted to glutamate via the enzyme glutaminase
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glutamate: synaptic transmission
- packaged into vesicles by VGLUT1, 2,3 (different expressions throughout the brain)
- following release, inactivation primarily via uptake transporters: EAAT 1-5 ( excitatory amino acid transporters; in neuron and glia)
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three ionotropic receptors for glutamate
each comprised of 4 subunits
- AMPA receptor
- Kainate receptor
- NMDA receptor
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NMDA receptor requires:
- binding of both glutamate and a co-agonist
- depolarization to remove magnesium. Glutamate acting at AMPA receptors causes necessary depolarization
- NMDA receptor also has a separate "PCP binding site" - all noncompetitive antagonists
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how many metabotropic receptors (GPCRs) for glutamate are there?
8
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Glutamate is important for...
synaptic plasticity, learning, and memory
| - AMPA and NMDA receptors: important role in synaptic plasticity (LTP)
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Ketamine: reward mechanism
- rewarding in humans
- self-administered by animals
- BUT ketamine/PCP self-administration is not affected by dopamine antagonist (SUL)
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Salvinorin A: Reward mechanism
- other KOR agonists are aversive and not hallucinogenic
- Salvinorin A is rewarding (CPP) and reinforcing (self-administration) in animals
- self-administration blocked by KOR antagonist or cannabinoid CB1 antagonist
