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Drugs and Behavior: Exam 3 > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

Nicotine

A

the psychoactive ingredient in tobacco (natural source)

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2
Q

dried tobacco leaves contain ___% nicotine?

A

5

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3
Q

tobacco smoke is a very complex mixture that contains….

A

tar - carries nicotine to lungs

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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

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5
Q

currently, about ___% of US population are smokers

A

15

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6
Q

routes of nicotine administration

A
  • smoking/vaporizing (“vaping”)
  • by mouth (chew, dip, snus)
  • by nose (snuff)
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7
Q

pharmacokinetics: smoking/vaporizing (vaping)

A
  • nicotine carried on tar or other particles
  • absorbed via lungs
  • provides highest blood nicotine
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8
Q

pharmacokinetics: by mouth (chew, dip, snus)

A
  • absorbed by membranes in mouth

- strong first pass metabolism

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9
Q

pharmacokinetics: by nose (snuff)

A

absorbed by membranes in nose

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10
Q

E-cigarettes

A

electronic devices that vaporize

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11
Q

smoking/vaping causes nicotine to hit the brain how fast?

A

in 7 seconds

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12
Q

how is nicotine metabolized?

A

metabolized into cotinine by a cytochrome P450 enzyme

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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

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14
Q

the pharmacodynamic action of nicotine

A

nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs), which are ionotropic receptors

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15
Q

acetylcholine receptors (nAChRs), are ionotropic receptors found where?

A
  • brain
  • autonomic nervous system
  • neuromuscular junction (NMJ)
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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
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17
Q

nicotine effects on mood

A
  • relaxing, alleviates stress, helps concentration

- hypothesized to be partially associated with relief from withdrawal

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18
Q

a high dose of nicotine

A

produces unpleasant symptoms

-largely due to autonomic actions of nicotine. But, strong tolerance to these actions

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19
Q

lethal dose of nicotine (rare)

A

kills through depolarization block of muscles involved in respiration

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20
Q

nicotine withdrawal symptoms

A

opposite to acute drug effects

-irritability, stress, difficulty concentrating when they don’ smoke

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21
Q

nicotine: acute tolerance

A

develops over the course of the day due to desensitization of nicotinic receptors (nAChR)

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22
Q

nicotine: chronic tolerance

A

over long time periods

-pharmacodynamic tolerance: nAChR upregulation

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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
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24
Q

the precursor for acetylcholine (ACh)

A

choline, a vitamin found in many foods

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25
Q

the enzyme that synthesizes ACh

A

Choline acetyl-transferase (ChAT)

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26
Q

what metabolizes ACh into choline and acetic acid?

A

acetylcholinesterase

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27
Q

vesicular acetylcholine transporter (VAChT)

A

packages ACh into vesicles

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28
Q

ACh (degradation and metabolism)

A

ACh undergoes rapid degradation/metabolism by AChE, converting it back to choline

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29
Q

Choline (reuptake)

A

choline is then taken up by the choline transporter and reused to make more ACh

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30
Q

Muscarinic ACh receptors (mAChRs)

A

metabotropic (GPCRs)

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31
Q

Nicotinic ACh receptors (nAChRs)

A

ionotropic (ion channels)

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32
Q

nicotinic ACh receptors (structure)

A

pentameric (5 subunits) ligand-gated cation channels

-brain and muscle

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33
Q

Brain nAChRs (structure)

A

consist of 2 alpha subunits and 3 beta subunits or 5 alpha subunits
-higher affinity

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34
Q

Muscle nAChRs (structure)

A

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!***
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35
Q

nicotinic ACh receptors

A

cation channel

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36
Q

nicotine postsynapse

A

rapid depolarization, which can increase neuronal firing or contract muscle

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37
Q

nicotine presynaptic (axon terminal):

A

enhance release of neurotransmitters

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38
Q

nAChRs desensitization

A

nAChRs desensitize with continuous exposure to agonist (the channel closes); this is reversible. Causes acute tolerance to nicotine.

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39
Q

Acetylcholine: autonomic nervous system

A

sympathetic: fight or flight
parasympathetic: rest and digest

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40
Q

acetylcholine: somatic nervous system

A

neuromuscular junction (NMJ)

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41
Q

acetylcholine: somatic nervous system

A

neuromuscular junction (NMJ)

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42
Q

animals and nicotine

A

nicotine is self-administered by animals

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43
Q

nicotine reinforcement

A

systemic nicotine increases activity of VTA dopamine cells –> more dopamine release at terminals in nucleus accumbens

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44
Q

what nAChR subtype is involved in the rewarding effects of nicotine?

A

alpha4beta2-containing receptors

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45
Q

what nAChR subtype is involved in cognitive effects (attention) of nicotine?

A

alpha7-containing receptors

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46
Q

smoking leads to occupancy of ______ nAChRs

A

alpha4beta2

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47
Q

Nicotine reinforcement in mice:

A

IV nicotine self-administration impaired in mutant mice with genetic knockout of either alpha4, alpha6, beta2, BUT NOT alpha7

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48
Q

alpha7-containing receptors are important for nicotine effects on __________?

A

attention

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49
Q

psychological (cue-induced craving) and pharmacological (dependence) nicotine treatment options

A

-Nicotine replacement therapy (NRT) helps with dependence /withdrawal

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50
Q

withdrawal and craving treatment options (nicotine):

A

Bupropion - weak nAChR antagonist
Varenicline - partial agonist at alpha4/beta2
-most effective treatment

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51
Q

opioids

A

analgesic and sedative-hypnotic

  • at high doses can lead to coma and death
  • best painkillers known
  • produce a sense of euphoria
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52
Q

“opiates”

A

naturally occurring alkaloids found in the sap of the opium poppy

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53
Q

raw opium contains….

A

about 10% morphine, about 0.5% codein

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54
Q

opium routes of administration:

A

oral, smoking

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55
Q

since before recorded history, opium has been used in….

A

many medicinal preparations

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56
Q

history of opium medical use

A

primarily for pain; also diarrhea, coughing

-laudanum: tinctures of opium

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57
Q

recreational use of opium

A

raw opium is usually smoked

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58
Q

principal active ingredients in opium:

A

morphine and codeine (natural source)

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59
Q

Morphine

A

medical use as analgesic

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60
Q

codeine

A

medical use: some analgesic effects, really good for cough

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61
Q

opiod form (semi-synthetic)

A

heroin (diacetylmorphine)

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62
Q

heroin

A

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
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63
Q

street heroin purity

A

it varies

-adulterants to enhance the effects (e.g. fentanyl, which is more potent

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64
Q

creating heroin by adding two acetyl groups to morphine

A

increases lipid solubility and speed to brain

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65
Q

potency of heroin

A

2-4x more potent than morphine when take intravenously

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66
Q

most “harmful” abused drug

A

heroin

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67
Q

desomorphine (“krokodil”)

A

opioid form

  • “flesh-eating” drug
  • 8-10x more potent than morphine
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68
Q

opiates vs. opioids

A

opiates: natural opioids derived from opium poppy
opioides: all ligands for opioid receptors

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69
Q

prescription opioids

A

are used for severe pain (analgesic) and cough (antitussive)

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70
Q

chronic opioid use

A

seems to increase potential for abuse, addiction, and overdose

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71
Q

There has been a large increase in opioid overdose deaths (prescription, heroin, synthetic opioids) T/F

A

TRUE!!

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72
Q

what factor contributed to the prescription opioid and heroin epidemic?

A

Purdue aggressively marketed Oxycontin (controlled release oxycodone)

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73
Q

what percent of people with opioid prescriptions for pain become addicted?

A

about 3%

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74
Q

Factors leading to opioid crisis:

A
  • chronic use of Rx opioids

- lacing of heroin with fentanyl

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75
Q

opioid recreational routes of administration

A
  • IV injection
  • SC injection
  • smoking/inhalation
  • snorting
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76
Q

IV heroin reaches the brain much ________ than morphine due to ______ ________.

A

faster, lipid solubility

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77
Q

opioid drugs differ in onset and duration, how?

A

half life:

  • morphine and most oral Rx: 2-4 hours
  • methadone (oral): 24 hours due to depot binding
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78
Q

Effects of opioids: Low to moderate doses

A

-analgesia
-suppression of cough reflex
-reduced gastrointestinal (GI) motility (constipation)
-euphoria
-some dysphoria
-nausea/vomiting
Also: slow respiration, pupil constriction, drowsiness, decreased concentration

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79
Q

effects of opioids: high doses

A
  • unconsciousness
  • pinpoint pupils
  • reduced temperature and blood pressure (clammy)
  • respiratory depression
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80
Q

respiratory depression (opioids)

A

main cause of death due to overdose

-reversed rapidly by naloxone (antagonist)

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81
Q

withdrawal symptoms (opioids)

A

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
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82
Q

how does the duration of opioids effect withdrawal and intensity of withdrawal?

A

longer duration opioids cause longer withdrawal with lower intensity (methadone vs. heroin)

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83
Q

rapid tolerance to some effects of opioids but not others (examples)

A

rapid tolerance: analgesia

NOT: GI effects (constipation), pupil constriction

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84
Q

factors driving opioid tolerance

A
  • metabolic
  • pharmacodynamics
  • psychological (classical conditioning)
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85
Q

controlled, long-term use of opioids effects

A
  • 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
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86
Q

multidimensional support (opioids)

A

-detoxification
-pharmacological support (opioid agonists and antagonists)
-group/individual counseling
reduce injury and crime (harm reduction) not cure

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87
Q

detoxification

A
  • 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
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88
Q

opioid agonists (long-term replacement therapy)

A
  • methadone maintanence

- buprenorphine maintanence

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89
Q

methadone maintanence

A
  • 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)
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90
Q

buprenorphine maintenance

A
  • partial agonist

- longer duration

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91
Q

opioid antagonists

A

naloxone (Narcan) and naltrexone (Trexan)

  • rapidly reverse opioid overdose
  • prevent misuse of opioids
  • addiction treatment
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92
Q

The pharmacodynamic action for ALL opioid drugs…

A

is to bind to opioid receptors in the central nervous system and periphery

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93
Q

first endogenous opioid discovery:

A

beta-endorphin (“endogenous morphine”)

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94
Q

all endogenous opioids are….

A

peptide neurotransmitters

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95
Q

different endogenous opioids and what they act as

A

endorphins, enkephalins, and dynorphins

-they act as neurotransmitters and hormones

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96
Q

all opioid peptides are products of 4 gene families:

A
  • POMC
  • PENK
  • PDYN
  • PNOC/OFQ
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97
Q

the short/long peptides are cleaved to give smaller/longer opioid peptides

A

long, smaller

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98
Q

synthesis, release, and inactivation of peptides (opioids)

A
  • 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)
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99
Q

where are opioid receptors located?

A

CNS: brain, spinal cord
PNS: sensory neurons
Periphery: heart, lungs, liver, etc.

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100
Q

Bioassay for opioids (guinea pigs):

A

ability of opioids to influence contractions of guinea pig intestine (ileum) strongly predicts human analgesic properties

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101
Q

four major types of opioid receptors

A
  • mu (MOR)
  • delta (DOR)
  • kappa (KOR)
  • nociceptin/orphanin FQ (NOPR)
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102
Q

abused opioids all bind to what receptor?

A

mu-opioid receptor

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103
Q

opioid receptors are all:

A
  • 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
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104
Q

endogenous opioids are found in multiple brain regions, especially those involved in….

A

pain and emotion (affect) signaling

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105
Q

Opioid agonists and antagonists

A

agonist: many Rx and abused opioid drugs
competitive antagonists: naloxone, naltrexone
partial agonists: buprenorphine

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106
Q

although they bind to other receptors, all abused opioids are agonists at the _________ receptor

A

mu-opioid receptor

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107
Q

analgesic effects of opioids:

A
  1. spinal cord: opioids inhibit incoming pain signal
  2. periaqueductal gray
  3. forebrain: sensory and emotional response to pain
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108
Q

what causes the release of endogenous opioids?

A

painful stimuli

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109
Q

mu receptors

A
  • strongly implicated in reward and euphoria

- strong self-administration and conditioned place preference for mu receptor agonists

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110
Q

evidence that dopamine does mediate opioid reward: mu agonist

A

mu agonist

  • increase DA cell firing in VTA, and DA release in striatum (NAc)
  • self-administration
  • increase locomotion
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111
Q

evidence that dopamine does mediate opioid reward: dopamine antagonist

A

DA antagonists:

  • block opioid CPP
  • reduce opioid self-administration
  • block increased locomotion
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112
Q

Evidence that DA does not mediate opioid reward:

A
  • DA receptor blockade and 6-OHDA lesions do not affect heroin self-administration
  • DA-deficient mice still show morphine CPP
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113
Q

GI effects of opioids due to…..

A

mu and kappa binding in stomach and small/large intestine, which decreases GI motility (and causes constipation)

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114
Q

Loperamide

A

is a modified opioid that acts peripherally

-used to slow GI motility and reduce diarrhea

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115
Q

opioids interact on all levels of respiratory control:

A
  1. fundamental drive generated by brainstem
  2. conscious modulations from cortex
  3. subconscious modulations from blood chemoreceptors
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116
Q

codeine

A

is often considered the “gold standard” in antitussive therapy (cough sepression)

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117
Q

opioids probably reduce cough via:

A
  • central actions in the brainstem (cough reflex)

- peripheral actions on sensory nerve endings

118
Q

dextromethorphan

A

was developed as a non-addictive substitute for codeine; it is an opioid derivative but does not act at opioid receptors

119
Q

opioid-induced nausea acts via several mechanisms:

A
  1. area postrema
  2. increased vestibular sensitivity
  3. delayed gastric emptying
120
Q

pupil constriction

A

due to opioid disinhibition of brainstem nuclei

121
Q

Where do opioid drugs act to produce analgesia?

A

spinal cord, periaqueductal gray, forebrain

122
Q

Where do opioid drugs act to produce reward?

A

brain-dopamine neurons (evidence for and against)

123
Q

Where do opioid drugs act to produce gastrointestinal effects?

A

stomach, small/large intestine

124
Q

Where do opioid drugs act to produce respiratory depression?

A

brainstem, cortex, blood chemoreceptors

125
Q

Where do opioid drugs act to produce cough suppression?

A

brainstem, sensory nerves

126
Q

Where do opioid drugs act to produce nausea and vomiting?

A

area postrema, vestibular system, and GI

127
Q

Where do opioid drugs act to produce pupil constriction?

A

brainstem

128
Q

Cannabis contains many ________ (natural)

A

cannabinoids

129
Q

where are cannabinoids concentrated and secreted?

A

they are especially concentrated in the sticky, yellow resin secreted at the flowering top of the female plant

130
Q

cannabis contains…

A

> 110 cannabinoids (many of which are psychotic)

131
Q

what seems to be the most important psychoactive drug??

A

delta9-tetrahydrocannabinol (delta9-THC or “THC”)

132
Q

other cannabinoids besides THC….

A

delta8-THC, cannabinol, cannabidiol (CBD)

133
Q

marijuana

A

refers to dried cannabis and contains a mixture of leaves, small stems, and flowering tops

134
Q

THC content varies with…

A

strain (breeding) and growing conditions

-Ex: if prevent pollination and seeding in female plants, THC contents increase (sinsemilla = “without seeds”)

135
Q

How has content in seized marijuana changed?

A

it has increased over the decades

- 2010: 8-12% typical

136
Q

concentrated forms of THC (3)

A
  • hashish
  • hash oil
  • dab
137
Q

hashish

A

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
Q

hash oil

A

is an alcoholic extraction from hashish

139
Q

dab

A

includes other extractions from cannabis

-can be >90% THC

140
Q

routes of administration (marijuana)

A 
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
Q

cannabis sativa (hemp)

A

is one of the earliest cultivated non-food plant and among the strongest natural fibers

142
Q

history of cannabis use

A
  • 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
Q

current cannabis used

A
  • the most popular US illicit drug

- typically first used in adolescence

144
Q

potential medical uses of marijuana

A
  • 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
Q

legalization status of marijuana

A

many US states have legalized medical marijuana, and some have legalized recreational marijuana. BUT, still. illegal at the federal level (Schedule I)

146
Q

cannabidiol (CBD)

A

thought to have similar benefits as THC without strong psychoactive effects

147
Q

medical cannabinoids

A
  • dronabinol: synthetic THC in pill form
  • Schedule III: treatment of nausea and anorexia
  • cannabis extract mouth spray
  • Nabilone: synthetic agonist
148
Q

pharmacokinetics of marijuana: absorption and distribution

A
  • 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
Q

half life of marijuana

A

LONG, 20-30 hours

150
Q

drug tests detection of marijuana

A

drug tests can detect single-use >2 weeks later (even if longer with repeated use)

151
Q

pharmacokinetics of marijuana: metabolism and elimination

A
  • 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
Q

THC effects: low to moderate doses on behavior and mood

A
  • 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
Q

THC effect: low to moderate doses on physiology

A
  • 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
Q

THC effects: High doses behavior and mood

A
  • increasingly disorganized thoughts, confusion
  • paranoia, agitation
  • anxiety (dependent on setting)
  • synesthesias and pseudohallucination
155
Q

THC effects: high doses physiological

A

pronounced motor impairment

NOT lethal even at very high doses

156
Q

effects of repeated cannabis: dependence and addiction

A

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
Q

factors that contribute to increased risk of addiction (marijuana)

A
  • early onset of use (young age)

- daily use

158
Q

effects of repeated cannabis use: tolerance

A
  • behavioral tolerance

- pharmacodynamics tolerance: after repeated use, desensitization and downregulation of CB1 receptors in the brain

159
Q

synthetic cannabinoids

A

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
Q

what receptors does marijuana act at?

A

cannabinoid receptors

161
Q

where are CB1 receptors located and for what?

A

presynaptic terminals, for retrograde signaling

162
Q

What are the endogenous ligands for CB receptors (CB1 and CB2)??

A

endocannabinoids

163
Q

endocannabinoids

A

high lipid solubility

164
Q

two endocannabinoids

A

Anandamide
-partial agonist for CB1 receptors
2-AG
-full agonist for CB1 and CB2

165
Q

endocannabinoids: signaling

A

endocannibinoids are lipid neurotransmitters and retrograde messengers

166
Q

why are their no vesicles with endocannabinoids signaling?

A
  • too lipid soluble to be stored in vesicles

- synthesized on demand in the post synaptic side of the synapse

167
Q

endocannabinoids signals travel retrogradely to the…

A

pre-synaptic terminal and bind to the CB1 receptor

168
Q

endocannabinoid signaling deactivation

A

degradation by intracellular enzymes

169
Q

two known cannabinoid receptors

A

CB1 receptor
CB2 receptor
-both metabotropic, coupled Gi proteins

170
Q

CB1 receptor expression

A

mostly in brain and spinal chord

171
Q

CB2 receptor expression

A

mostly in immune system

172
Q

CB1 receptor

A
  • basal ganglia, hippocampus, cerebellum, cortex
  • rewarding effects and “high” from cannabis
  • the most abundant GPCR in mammalian brain
173
Q

Endocannabinoids: function

A
  • 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
Q

endocannabinoids are the principal components of _________ ___________ _________.

A

retrograde synaptic signaling

175
Q

endocannabinoid signaling plays an important role in….

A

long-lasting synaptic plasticity, including long-term depression (LTD)

176
Q

animal studies of cannabinoid effects on:

A
  • reward
  • feeding
  • learning/memory
177
Q

cannabinoid effects: reward (low doses and high doses of THC)

A

low doses of THC:
-conditioned place preference (CPP), self-administration
high doses of THC:
- conditioned place aversion (CPA), no self-administration

178
Q

what mediates the rewarding effects of cannabinoids?

A

dopamine

179
Q

evidence dopamine mediates the rewarding effects of cannabinoids:

A
  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
Q

cannabinoid effects: feeding

A

cannabinoids injected i.v. or into NAc cause pleasurable reactions to tastes

181
Q

cannabinoid effects: memory

A
  • the hippocampus, causes deficits in working memory

- blocked by CB antagonist rimonabant into hippocampus

182
Q

CB1 antagonists or CB1 gene knockout: (endocannabinoid roles: reward)

A
  • 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
Q

how does CB1 antagonist AM6545 affect food consumption?

A

decrease

- reduced motivation and reward

184
Q

CB1 antagonist Rimonabant

A

was used medically in Europe as obesity treatment… but stopped

185
Q

endocannabinoid roles: memory

A
  • 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
Q

THC effects in mice:

A
  • rewarding
  • increased feeding
  • impairs learning/memory
  • hypoalgesic (reduced pain)
  • ALL blocked by CB1 antagonist
187
Q

CB1 antagonist or knockout effects:

A
  • reduces reward
  • decreases feeding
  • impairs extinction learning
  • hyperalgesic (enhanced pain)
188
Q

can cannabis use lead to addiction?

A

yes

189
Q

individuals with cannabis addiction often report:

A
  • social problems
  • financial difficulties
  • poor general life satisfaction
190
Q

treatment options for cannabis addiction:

A

mostly centered around psychotherapy

  • cognitive behavioral therapy
  • relapse prevention (high relapse rates)
191
Q

what are the long lasting effects of repeated cannabis use?

A

remain long after abstinence/withdrawal period

  • lung damage? NO
  • reduced cognitive function? maybe (adolescent use)
  • increased risk for psychosis
192
Q

lung damage from long term cannabis use?

A

no clear evidence of long-term lung problems with heavy marijuana use

193
Q

cannabis use effects on cognitive function (negative)

A

evidence of reduced cognitive function (IQ) following weekly adolescent use

194
Q

cognitive function (marijuana affect on brain makeup)

A

reduced gray matter in areas of orbitofrontal cortex (even with smaller IQ)

195
Q

rats were exposed to synthetic CB agonist (CP) only during adolescence. In adulthood they showed (as well as the conclusion):

A
  • reduced cognitive (memory) function
  • reduced dendritic complexity in prefrontal cortex
    Conclusion: CB1 receptors are important in neurodevelopmental changes during adolescence
196
Q

adverse affects of cannabis use: increased risk for psychosis

A
  • increased incidence of psychosis among cannabis users

- establishing a causal link is very difficult

197
Q

comprehensive report on cannabis

A

comprehensive review of recent research on health effects of recreational and therapeutic use
- cannabis users in US (age >12) increased

198
Q

comprehensive report on cannabis: therapeutic effects (conclusive evidence)

A
  • reduced pain

- reduced nausea/vomiting

199
Q

comprehensive report on cannabis: risks (conclusive evidence)

A

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
Q

drug categories of hallucinogens:

A
  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
Q

psychedelics

A

produce hallucinations and an altered state of consciousness

  • only weak rewarding properties, not considered addictive
  • psychedelic = alters perception and cognition
  • hallucinogen = hallucinations
202
Q

dissociatives

A

distort perceptions and produce feelings of detachment (dissociation) from the environment and self
- depressant properties

203
Q

deliriant

A

produce a state of delirium, including stupor, confusion, and distorted memory

204
Q

two main classes of psychedelics

A
  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
Q

psilocybin/psilocin

A
  • numerous mushrooms produce alkaloids with hallucinogenic properties (magic mushrooms, shrooms)
  • dried mushrooms are eaten
  • major ingredient is psilocybin and the related compound psilocin
206
Q

psilocybin/psilocin after ingestion

A

psilocybin is converted (dephosphorylated) to psilocin (aka 4-HO-DMT). Psilocin is the active psychoactive agent

207
Q

DMT and 5-MeO DMT

A
  • 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
Q

LSD

A

semi-synthetic compound derived from fungal alkaloids

  • taken orally
  • VERY POTENT
209
Q

Mescaline

A
  • 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
Q

history of psilocybin/psilocin

A

magic mushrooms used for >5,000 years

211
Q

history of use: mescaline

A
  • 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
Q

history of use: LSD

A
  • 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
Q

history of psychedelic use (1940s-50s)

A
  • 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”
214
Q

psychodelic: psychotherapy tool (1940-50s)

A

potential miracle drugs for psychiatric illness and alcohol addiction

215
Q

pschodelic: psychosis research (1940s-50s)

A

hypothesized to be a good model for psychosis/schizophrenia

216
Q

history of psychedelic use (1960s)

A

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
217
Q

1950s-60s: research by US government as potential psychological weapon

A
  • MK-ULTRA program (mind control agent)

- secret tests by CIA on unknowing citizens and employees

218
Q

history of psychedelic use (1960s-70s)

A

profound effect on art, music and culture

- hippie culture as part of nonconformist

219
Q

profound shift in political and cultural opinions on LSD

A

by 1966

  • banned in 1967
  • all psychedelic research and therapy halted
220
Q

oral psychedelics

A
  • onset 30-90 minutes

- duration is 6-12 hours for LSD or mescaline, shorter for psilocybin

221
Q

smoked DMT

A
  • onset in seconds
  • peak within minutes
  • duration 30-60 minutes
222
Q

major effects of psychedelic: sensory perceptual

A
  • visual illusions
  • time distortion
  • synthesias
223
Q

major effects of psychedelic: psychological

A
  • depersonalization (loss of ego)
  • emotional shifts
  • disruption of logical thought
224
Q

major effects of psychedelics: physiological

A

activation of sympathetic nervous system

225
Q

early research into therapeutic treatment (1950s-60s) revealed that:

A
  • set and setting are very important to the patient’s experience
  • volunteers who had a “complete mystical experience” showed lasting improvements in well-being
226
Q

psychedelics: possible adverse effect

A 
"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
227
Q

Tolerance and dependence (psychedelic drugs)

A

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

228
Q

Addiction (psychedelics)

A

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

229
Q

effects of chronic psychedelic use

A

no evidence of psychological or cognitive impairments after chronic use
- “no evidence of psychological or cognitive deficits among Native Americans using peyote regularly”

230
Q

potential medical uses: psilocybin

A
  • 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
231
Q

potential medical uses: LSD

A
  • enhanced optimism and openness

- recent trend of “LSD micro-dosing”

232
Q

Potential psychedelic medical use: Breakthrough Therapy Designation

A
  • 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
233
Q

Psychedelic: mechanism of action

A
  • acting on serotonin (5-HT) system

- the 5-HT2a receptor is particularly important for hallucinations

234
Q

pharmacodynamic action for hallucinations

A

binding to a receptor complex of 5-HT2a and mGluR2 (a glutamate receptor)

235
Q

hallucinations require activation of a receptor complex involving:

A

5-HT2a (serotonin receptor, Gq) and mGluR2 (glutamate receptor, Gi)

236
Q

psychedelics interact with what system?

A

the serotonin system

237
Q

What receptor is particularly important for hallucinations?

A

Seretonin 5HT2a

238
Q

hallucinations require activation of a receptor complex involving both:

A

5HT2a and mGluR2 (Gq-coupled serotonin receptor and Gi-coupled glutamate receptor)

239
Q

catecholamines

A

dopamine, norepinephrine, and epinephrine

240
Q

indolamines

A

seretonin

241
Q

serotonin is synthesized from…

A

amino acid precursor tryptophan

242
Q

tryptophan is converted to ______ by __________ ___________ ___________.

A
  • 5-HTP
  • enzyme tryptophan hydroxylase (TPH)
  • TPH is the rate-limiting step
243
Q

5-HTP is converted to 5-HT (serotonin) by _________ ?

A

AADC, the same enzyme that converts DOPA to dopamine

244
Q

Serotonin: Synaptic transmission

A
  • 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
245
Q

serotonin receptors

A
  • 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
246
Q

serotonin receptors: 5-HT2a (expression, agonists, antagonist)

A

expressed in cerebral cortex, striatum, and other brain areas

agonist: some are hallucinations
antagonists: some are antipsychotic

247
Q

serotonin nuclei and pathways

A

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

248
Q

Serotonin: key drugs

A
  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
249
Q

____% of serotonin in the body is found in the gut and enteric nervous system.

A

90

250
Q

functional roles of serotonin in CNS

A

mood (depression, anxiety), hunger, pain sensitivity, learning and memory, addiction

251
Q

functional serotonin roles: anxiety

A

5-HT1a agonists reduce anxiety

252
Q

Functional roles of serotonin: depression

A

SSRIs used to treat depression and mood regulations in humans

253
Q

Where are LSD and other psychedelics agonists? Evidence?

A

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
254
Q

Affinity for 5-HT receptors

A
  • common affinity for 5HT2a and 5HT2c receptor among hallucinogens
  • significant correlation between 5HT2a binding affinity and psychedelic effects
255
Q

effects of 5-HT2a antagonists

A
  • 5-HT2a antagonists block subjective effects of hallucinogens in humans
  • 5-HT2a antagonists dose-dependently reduce responding
256
Q

effects of 5-HT2a knockout

A
  • hallucinogen-evoked behaviors (head twitch) are also missing in the 5-HT2a knockout mice
  • selective restoration of 5-HT2a receptors in cortex only
257
Q

5-HT2a receptors expressed in cerebral cortex

A

expression particularly robust in layer V (output layer) of cerebral cortex

258
Q

psychedelics increase excitation in cortex (explain)

A

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

259
Q

psychedelics reduce cortical organization/coupling (psilocybin)

A

psilocybin disrupts coupling of certain cell types and rhythmic oscillations among populations of neurons –> disorganizing influence on cortex that allows greater flexibility

260
Q

psychedelics reduce activity in the….

A

default mode network (DMN)

261
Q

psychedelics reduce cortical organization/coupling (LSD)

A

LSD causes increased cerebral blood flow (CBF) to visual cortex
- decreased organization of cortex

262
Q

Effects of 5-HT2a agonists

A

not ALL 5-HT2a agonists are hallucinogens (graph on slides)

263
Q

interactions with 5-HT2a and mGluR2 receptors

A

different intracellular signaling

  • ALL 5-HT2a agonists –> involve G1 signaling
  • hallucinogenic 5-HT2a agonists –> ALSO involve Gi signaling
264
Q

a receptor complex formed by 5-HT2a and mGluR2 (glutamate GPCR) triggers…

A

unique cellular responses when targeted by hallucinogenic drugs

265
Q

psychedelics binding to receptor complex increase…. and decrease….

A

increase Gq signaling (5-HT2a) and decrease Gi signaling (mGluR2)

266
Q

activation of mGluR2 blocks….

A

hallucinogenic effects

- antipsychotics cause opposite effects

267
Q

PCP: History of Medical Use

A

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

268
Q

PCP: recreational use

A

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

269
Q

a safer alternative to PCP, and why?

A

ketamine, less potent and shorter acting

270
Q

Ketamine: medical use

A
  • still used as a valuable anesthetic for certain medical procedures (particularly in children) and vetrinary procedures
  • some postoperative adverse reactions
271
Q

depression treatment: ketamine (esketamine)

A
  • shows rapid results (2 hours)

- FDA approved ketamine for treatment-resistant depression

272
Q

ketamine: recreational use

A
  • ketamine use and abuse is smuch greater than PCP
    Liquid: injectable liquid
    Powder or pills: powder for snorting or compress into pills
273
Q

ketamine: low (sub-anesthetic) doses

A
  • feeling of being detached from body, sensations of floating, numbness, dreamlike state
  • euphoria
  • cognitive disorganization
274
Q

ketamine: higher (anesthetic) doses

A
  • dissociative: loss of all mental contact with environment; detachment
  • “k hole”: slang for dissociated state caused by ketamine
275
Q

chronic ketamine users effects

A
  • ketamine bladder syndrome
  • memory and cognitive impairments
  • evidence of gray and white matter abnormalities
276
Q

dextromethorphan (DM)

A

over the counter cough suppressant

- ssubstitute for codeine

277
Q

dextromethorphan: recreational use (at high doses)

A
  • at high doses acts as a dissociative anesthetic
    Effects at high doses:
  • impaired balance, hallucinations, intoxication, euphoria, cognitive impairment, dissociation, delusions
278
Q

promethazine/codeine

A

purple drank

  • abused
  • an opioid agonist (codeine), not a dissociative
278
Q

Salvinorin A: Recreational use

A

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
279
Q

Salvinorin A: acute effects

A

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

280
Q

pharmacodynamic actions: PCP, ketamine, and dextromethorphan

A
  • noncompetitive antagonists for NMDA glutamate receptor

- DA and non-DA mechanisms

281
Q

Pharmacodynamic actions: Salvinorin A

A

agonist at kappa (k) opioid receptor (KOR)

282
Q

glutamate

A

an excitatory amino acid neurotranmitter. The MAJOR transmitter for fast excitatory signaling
- found throughout the brain

283
Q

glutamate synthesis

A
  • glutamate precursor is present in the brain

- glutamine is converted to glutamate via the enzyme glutaminase

284
Q

glutamate: synaptic transmission

A
  • 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)
285
Q

three ionotropic receptors for glutamate

A

each comprised of 4 subunits

  • AMPA receptor
  • Kainate receptor
  • NMDA receptor
286
Q

NMDA receptor requires:

A
  • 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
287
Q

how many metabotropic receptors (GPCRs) for glutamate are there?

A

8

288
Q

Glutamate is important for…

A

synaptic plasticity, learning, and memory

- AMPA and NMDA receptors: important role in synaptic plasticity (LTP)

289
Q

Ketamine: reward mechanism

A
  • rewarding in humans
  • self-administered by animals
  • BUT ketamine/PCP self-administration is not affected by dopamine antagonist (SUL)
290
Q

Salvinorin A: Reward mechanism

A
  • 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

Drugs and Behavior: Exam 3 (1 decks)

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