cocaine Flashcards
(137 cards)
1
Q
Stimulants
A
Psychoactive drugs producing a
temporary increase in mental function
2
Q
Psychostimulants
A
Alertness, wakefulness, and
locomotion
3
Q
Psychomotor stimulants
A
Cocaine, amphetamines, caffeine,
nicotine
4
Q
Cocaine Primary psychoactive component has
moderate bioavailability by
A
oral
administration
5
Q
Cocaine is sensitive to
A
acid hydrolysis
6
Q
Coca leaves traditionally chewed with lime
to
A
decrease acid hydrolysis in the GI
7
Q
cocaine administered via
A
oral, IV, or intranasal routes
8
Q
cocaine is Susceptible to breakdown by
A
heating
9
Q
cocaine Can be precipitated by heating with
A
baking soda - crack cocaine
10
Q
Freebase and crack cocaine delivered by
A
inhalation
11
Q
Cocaine is purified by
A
acid-base
extraction
12
Q
Illicit cocaine is purified by
A
partially
drying leaves
13
Q
Inhalation (smoking) or intranasal (snorting)
result in
A
in rapid access to the CNS
14
Q
Half-life in circulation
A
30-90 minutes.
15
Q
cocaine Metabolized by
A
esterases, CYP450 in liver
16
Q
Cocaethylene is an
A
active metabolite formed in the presence of alcohol – longer lasting than cocaine and greater cardiotoxic effects.
17
Q
Methylecgonidine
A
produced by heating of cocaine and is detectable in urine
18
Q
Cocaine is amphipathic – meaning it has
A
both hydrophilic and lipophilic nature
19
Q
Cocaine is amphipathic Subsequently cocaine is very rapidly absorbed
A
across the BBB and measurement of cocaine in circulation does not effectively convey the psychoactive levels
20
Q
Inhalation and intranasal admin both result in
A
rapid uptake into brain and pronounced psychoactive effects
21
Q
Rapid uptake into brain and short duration of ‘high
A
(5-30 minutes) thought to contribute to addictive potential
22
Q
Effects of cocaine “positive” (7)
A
Euphoria
Increased alertness
Increased self-confidence
Increased sociability
Heightened sexual interest / performance
Motor stereotypies
Anorexia
23
Q
Effects of cocaine “negative” (9)
A
Dysphoria
Irritability, hostility, anxiety
Psychosis
Impulsivity
Increased heart rate
Increased blood pressure
Hyperthermia
Seizures
Stroke / Intracranial haemorrhage
24
Q
Psychomotor stimulation (7)
A
locomotor
hyperactivity
head bobbing,
pacing,
repetitive rearing,
excess grooming.
compulsive activities such as obsessive cleaning, sorting, organizing
25
Animal models
Animal models will rapidly acquire self-administration of cocaine
26
Cocaine administration causes
hyperactivity in rodents – simple measurement of intoxication
27
Animals will self-administer to the
point of
personal neglect, anorexia, and increased mortality
28
Cocaine is an
SNDRI
29
SNDRI
serotonin, norepinephrine, and dopamine reuptake inhibitor)
30
Cocaine blocks neurotransmitter reuptake such as at the
dopamine transporter (DAT).
31
Cocaine blocks neurotransmitter reuptake such as at the
dopamine transporter (DAT) This leads to accumulation of
neurotransmitters in the synapse and excessive downstream signalling.
32
At elevated doses cocaine blocks (N)
Na+ channels and can be used as a topical anaesthetic
33
Cocaine Also causes decrease in
monoamine synthesis through presynaptic autoreceptors.
34
Tolerance
Cocaine tolerance develops acutely and transiently
35
Subjective and cardiovascular effects develop tolerance
quickly
36
* Intermittent use produces
sensitization rather than tolerance
37
In animal models Continuous infusion via minipump results in
tolerance to the effects of cocaine
38
Daily use (intermittent) sensitizes the
psychomotor and reinforcing effects
39
Both animals and humans show
cross-sensitization to other stimulants (esp. amphetamines)
40
Withdrawal
No medically serious withdrawal syndrome develops with cocaine use
41
* Three phases observed in binge users of cocaine
1. Crash (15-30 minutes following final dose)
2. Withdrawal (hours-days after final dose)
3. Extinction
42
Binge use refers to
episodic use for extended periods (hours or days) without interruption (or sleep)
43
Cocaine crash (7)
Dysphoria
agitation
anxiety
depression
strong craving
fatigue after brief period
Exhaustion results in hypersomnolence (prolonged sleep)
Sleep can be interrupted by brief periods of waking and hyperphagia
44
Withdrawal and Extinction
Withdrawal is a period of relatively normal function
Extinction is a gradual return to normal function
45
Withdrawal is a period of relatively normal function
Hours or days of normal mood, sleep, little anxiety
* Little craving for cocaine
* Some report mild cognitive impairment
* Gradual onset of a dysphoric syndrome
46
dysphoric syndrome (5)
boredom, anergia, anhedonia, anxiety, and increased craving
47
Extinction is a gradual return to normal function
Normal mood, normal hedonic function
* Intermittent cravings may occur – particularly in response to emotional or environmental
cues
48
Toxicity Acute overdose results from several main effects
Reduced seizure threshold
Cardiovascular effects
Hyperthermia
49
Reduced seizure threshold
Due to general increase in neurotransmitter release
50
Cardiovascular effects
* Increased heart rate and blood pressure can increase risk of stroke, cerebral hemorrhage, tachycardia
and arrhythmia
51
* Treatment of overdose is administration of
sedative (typically a benzodiazepine) to decrease heart rate and BP, and use of ice or cooling blankets for hyperthermia
52
Cocaine is the
second most popular illicit drug in the USA second to cannabis
53
(PCE)
Prenatal cocaine exposure`
54
* In utero exposure to crack-cocaine was
correlated (in early studies, mostly case studies
or small cohorts) with
* Premature birth
* Lower birth weight
* Mental and physical defects
55
Public opinion formed around the risks of
PCE leading to prosecution of
mothers who
tested positive for cocaine or metabolites
56
Experts predicted a ‘biological underclass’ of delinquents affected by PCE
Crime rates were predicted to rise
* Children were predicted to be a burden on school and health care systems
57
Crack cocaine can be explicitly tested by the presence of
methylecgonidine
58
Effects of PCE
Cocaine readily crosses the placental barrier
59
Animal studies do not support long-term effects of
PCE
60
animal studies and cocaine Studies support moderate decreases in
learning in the presence of distractions
61
Most described effects of PCE in humans can be attributed to confounding factors
Prenatal nutrition
pre- and post-natal care
additional drug use environmental
risks
increased rates of STI
62
Most described effects of PCE in humans can be attributed to confounding factors - Child more likely to be exposed to
maternal depression, domestic violence, ‘deadbeat’ parenting – all
affect early childhood development
63
* Most described effects of PCE in humans can be attributed to confounding factors - Small increased risk of
ADHD or increased impulsivity/distractibility
64
Cocaine is
sympathomimetic
65
Cocaine elevates NE signalling at
noradrenergic
locations
66
Cocaine exerts activating effects on the
sympathetic nervous system
67
Cocaine exerts activating effects on the
sympathetic nervous system - Increased
heart rate, vasoconstriction,
hypertension, hyperthermia
68
Many adverse effects of cocaine are due to
sympathetic activation (stroke, heart failure,
seizure, intracranial hemorrhage)
69
* Central noradrenergic effects contribute to the
psychostimulant effects of cocaine
70
Dopaminergic effects ad cocaine
Dopamine plays a central role in the
psychostimulant response to cocaine
71
Dopaminergic effects Two key pathways
Nigrostriatal
Mesolimbic
72
Nigrostriatal pathway
substantia nigra to the
striatum
73
Mesolimbic pathway
ventral tegmentum to
nucleus accumbens
74
Behavioural effects in rodents can be
examined using
microinjection and
lesions
75
Microinjection of cocaine into striatum
elicits (Substantia nigra - striatum)
stereotyped behaviours
76
Lesion with 6-OHDA antagonizes (substantia nigra - striatum)
psychostimulant-induced stereotypies
77
Microinjection of cocaine into NAc elicits (ventral tegmentum to
nucleus accumbens)
hyperactivity
78
(ventral tegmentum to
nucleus accumbens)
* Lesion with 6-OHDA blunts
psychostimulant-induced hyperactivity
79
lesion of the mesolimbic system
diminishes reinforcing effects of
cocaine administration
80
Basal ganglia and affects of dopamine of the direct and indirect pathways
Dopamine balances activity between the
direct and indirect pathways
81
Activation of nigrostriatal dopamine
pathways promotes the
direct pathway (D1 – excitatory) over the indirect
pathway (D2 – inhibitory).
82
Cocaine elevates DA in the striatum and
drives locomotor activity (often
purposeless).
83
Euphoric and
reinforcing
effects
Euphoric effects (subjective ‘high’) has been well
studied by PET imaging
84
cocaine occupies what transporter
DAT occupancy by cocaine
85
D2R occupancy by
DA
86
Rate of onset of DAT occupancy correlates with
intensity of euphoria
87
level of intensity depending on intake
Smoking > IV > Intranasal > Oral
88
Individuals with increased D2 receptor occupancy
prior to cocaine administration have
greater
euphoric effects.
89
Reinforcing effects of cocaine - Cocaine use in humans leads to
addiction in
10-15% of users
90
Several studies have shown that
given free choice rats will choose
sweetened water over cocaine
infusion
91
Cocaine psychosis
transient paranoid psychosis with delusions and hallucinations
92
Cocaine psychosis Occurs more frequently over
time
93
Cocaine psychosis Similar to psychosis in
Schizophrenia
94
Cocaine psychosis Similar to psychosis in Schizophrenia Sensitive to
antipsychotics – mesolimbic DA
95
Acute tolerance
Chronic cocaine infusion reduces the locomotor effects of a single cocaine injection
96
Chronic sensitization
Daily injection of cocaine results in increased stereotypic behaviours in rats over time (head bobbing, corner-to-corner motion, and vertical rearing/nose poking).
97
Tyrosine hydroxylase regulates overall rate of
catecholamine
synthesis
98
Phosphorylation Activity-dependent activation
(CaM-kinase
phosphorylation)
99
Acute tolerance results in large part from
inhibition of
dopamine biosynthesis
100
Presynaptic autoreceptors respond to prolonged
DA in the synapse to inhibit TH
101
Phosphorylation Modulatory activation
(such as PKC signalling
)
102
Adverse effects of cocaine use
Chronic, heavy cocaine use is associated with a mild cognitive impairment
103
mild cognitive impairment
Verbal memory, attention, and motor function
104
mild cognitive impairment and grey and white matter
Correlated with gray and white matter abnormalities in the cortex and striatum
105
Cardiotoxic effects of chronic use
Arrhythmia, cardiac myopathy, myocardial infarct
106
Administration-dependent effects - intranasal
– Perforation of the nasal septum (cocaine HCl)
107
Administration-dependent effects - Smoking
‘crack lung
108
‘crack lung
scarring and damage to lung tissue due to vasoconstriction
of vessels in lung
109
Addiction treatment
Animal work has been used to
evaluate the usefulness of dopamine
receptor antagonists as treatment for
cocaine addiction
110
D1- and D2-family receptor
antagonists can reduce
reinforcing
effects of cocaine
111
Specific D3 antagonists (SB-277011-
A) or partial agonists (BP897)
decrease
SA or CPP
112
Administration of ecopipam, a D1-
family antagonist, in cocaine users has
had mixed results
Reported to reduce high in IV trials
Reported to increase high in freebase
smoking trial
113
Trials of selective DAT inhibitors or D1
agonists as replacement therapeutics
have been limited by
decreased seizure
thresholds
114
Some studies have used disulfuram to
treat cocaine abuse due to the high
coincident use of
alcohol and cocaine
115
Disulfuram is a common treatment for
alcohol abuse
116
Disulfuram is a common treatment for
alcohol abuse – it inhibits
aldehyde dehydrogenase and causes an acute aversive reaction
117
most common treatments of cocaine use are
antidepressants
118
Fluoxetine (SSRI) treatment for cocaine addiction
increases 5-HT
119
Desipramine (TCA) - treatment for cocaine addiction
increases NE
120
Vaccination
Vaccination against small molecules is technically
possible
121
Circulating antibodies would be capable of
inactivating
cocaine before it reaches the brain
122
vaccination - Lack of effect would lead to extinction of
drugseeking behaviours
123
vaccination - Drug molecules are covalently attached to the
surface of an immunogenic protein
124
Immune system develops antibodies against
drug
molecules
125
Vaccine efficacy - In animal trials cocaine vaccination
reduces response to drug (locomotion,
stereotypies)
126
In clinical trials vaccination reduced
the number of cocaine users
127
Vaccine efficacy Reduces effects without
altering
craving or impulse to use
128
Vaccine efficacy Requires regular
boosters as cocaine is
not itself immunogenic
129
Requires regular boosters as cocaine is
not itself immunogenic
need to
maintain high antibody levels
130
While dopamine is known to regulate reinforcement in addictions, and cocaine strongly affects DAT function, dopamine transporter knockout mice (DAT -/-) still
readily acquire cocaine self-administration
131
5-HT compensates for
DAT -/-
132
5-HT is proposed to play a role in
modulating reinforcement
133
DAT and SERT double knockouts abolished the
reinforcing effects of cocaine
134
Both DAT and 5-HT can play a role in reinforcing behaviours via
NAc DA release
135
In the DAT -/- (but not wild-type) mice, fluoxetine, citalopram (SSRI), and cocaine were shown to
increase VTA activity leading to NAc DA release
136
developmental alterations of dopamine function lead to
compensatory changes in 5-HT in reinforcement
137
Collectively this suggests that developmental alterations of dopamine function lead to compensatory changes in 5-HT in reinforcement
Function switches from aversive to rewarding in the DAT -/-
