Midterm 1 Flashcards
Cocaine withdrawal often has ____ physical symptoms but ___ psychological ones
Cocaine withdrawal often has no physical symptoms but intense psychological ones
With withdrawal long-term DAT efficiency ____, may explain ____ ___ episodes
With withdrawal long-term DAT efficiency increases, may explain common depressive episodes
Withdrawal symptoms include…
depression, anxiety, appetite changes
Intermittent use of cocaine associated with strong behavioural sensitization, ___ locomotor activity
Intermittent use of cocaine associated with strong behavioural sensitization, increased locomotor activity
Reverse tolerance
Increased susceptibility to hyperthermia, convulsions, stereotyped movements
Altered opioid-ergic signaling → ___ ____ expression is induced (generated)
Altered opioid-ergic signaling → striatal dynorphin expression is induced
When there is reduced euphoria by cocaine that is because ___ DA and ___ DAT efficiency
When there is reduced euphoria by cocaine that is because depleted DA and increased DAT efficiency
After cocaine binds the same site as dopamine it locks transporter in ___ conformation which ___ the transporter
After cocaine binds the same site as dopamine it locks transporter in stable conformation which inactivates the transporter
cocaine binds ___ ___ as dopamine
cocaine binds same site as dopamine
___ % of cocaine users combine their use with alcohol, this causes ___ ____ leading to the byproduct ____ being produced which is a potent ____
30-60 % of cocaine users combine their use with alcohol, this causes altered metabolism leading to the byproduct cocaethylene being produced which is a potent vasoconstrictor
cocaine causes ___ acute infections in GI tract which leads to ___ blood flow causing ____ ___ ___
cocaine causes increased acute infections in GI tract which leads to reduced blood flow causing tissues to die
Another adverse effect of cocaine use include formication which is …
the delusion of crawling insects under skin
Some adverse affects of acute cocaine use include irritability, ____, ____, ___ and ___
Some adverse affects of acute cocaine use include irritability, hostility, anxiety, fear and restlessness
After cocaine use NE excess underlies ___ effects, which enhances ___ sensitivity to ___ and ___
After cocaine use NE excess underlies sympathomimetic effects, which enhances VTA sensitivity to Glu and reward
After cocaine use 5HT excess underlies ___, ____,____ and __
After cocaine use 5HT excess underlies mood, sleep ,appetite and temperature
After cocaine use DA is in ___ in the ____, ___, ____ and ___
After cocaine use DA is in excess in the basal ganglia, PFC, VTA and NAc
The neurotransmitters affected by cocaine are
NE, DA, 5HT
The ____ and ____ of cocaine mimics NTs
The aromatic ring and amine group of cocaine mimics NTs
A high dose of cocaine can affect the medulla which in turn can lead to..
respiratory and circulatory failure
Cocaine’s effects on NAc make it
extremely rewarding
Cocaine effects on the PFC
influences planning, problem-solving and social behaviours
___ onset= ___ euphoria
faster onset= greater euphoria
cocaine causes ___ movements
cocaine causes repetitive, compulsive movements
Because of the excess neurotransmitters : ___, ___, ___ and ___ cocaine causes sympathomimetic effects like ___ heart rate, ___ blood pressure, ____, ____, ____ and ___
Because of the excess neurotransmitters : dopamine, serotonin, norepinephrine and epinephrine cocaine causes sympathomimetic effects like increased heart rate, increased blood pressure, anorexia, insomnia, agitation and hyperthermia
The anaesthetic effects of cocaine in the heart causes ____
The anaesthetic effects of cocaine in the heart causes dysrhythmias
cocaine is an anaesthetic as it blocks ___ channels which blocks ____ leading to no pain
cocaine is an anaesthetic as it blocks Na channels which blocks neuotransmission leading to no pain
Cocaine can be detected in the urine ___ days and __ ___ in chronic users
Cocaine can be detected in the urine 4 days and 2 weeks in chronic users
When an individual uses alcohol and cocaine at the same time, ____ develops in the liver
When an individual uses alcohol and cocaine at the same time, cocaethylene metabolite develops in the liver
Liver/plasma esterases generate ___ ___ which is a marker for crack cocaine use
Liver/plasma esterases generate ecogonine methylester which is a marker for crack cocaine use
Major metabolite of cocaine is benzoylecgonine → 40% is
spontaneously____ by ____ within ___ hours of use
Major metabolite of cocaine is benzoylecgonine →40% is spontaneously produced by hydrolysis within 4 hours of use
___ is an enzyme that is mainly located in the liver and controls the metabolism of cocaine
CYP3A4
3 main consumable forms of cocaine
1) Coca leaves
2) Cocaine hydrochloride
3) Free-base cocaine= crack
Half-life
time to remove 50% of the concentration of drug from circulation
Drug half-lives indicate ____
Drug half-lives indicate how long the drug remains in circulation
bioavailability of ingestion
5-99%
duration of ingestion
6+ hrs
onset of ingestion
20-45 min
insufflation has ____ pathway to the BBB
insufflation has long pathway to the BBB
bioavailability for insufflation
up to 80%
duration of insufflation/snorting
5-8 hr
onset for insufflation/snorting
10-45 min
routes of administration with first-pass metabolism
ingestion
routes of administration with no first-pass metabolism…
injection and insufflation
Routes of administration
inhalation, injection, insufflation, ingestion
Injection has ___ circulatory path to brain from ___ –> ___–> left side of heart –> ___
Injection has 2nd shortest circulatory path to brain from right side of heart –> lungs–> left side of heart –> BBB
Duration for injection
2-4 hr
onset for injection
10-20 seconds
____ has shortest circulatory path to brain from ___ –> ___ –> _____
inhalation has shortest circulatory path to brain from lungs –> left side of heart –> BBB
Bioavailability of inhalation
5-99%
Duration of inhalation
2-4 hr
Onset of inhalation
7-10 seconds
Bioavailability is…
the amount of administered drug reaching systemic circulation i.e. unchanged
Slower absorption routes:
- ____ peak
- correlate with ___ ____ reported high
- ____ duration in the brain
Slower absorption routes:
- lower peak
- correlate with less intense reported high
- prolonged duration in the brain
Faster absorption routes= ___ delivery to the brain:
- ___peak
-correlate with ___ reported high
- drug ___ ____ remain in brain very long
Faster absorption routes= faster delivery to the brain:
- higher peak
-correlate with stronger reported high
- drug does not remain in brain very long
Predispositions
A tendency/vulnerability to suffer from a particular condition
Polygenicity
multiple genes are involved in addiction
___ D2/D3 receptor expression in NAc of drug- naïve high- impulsive rats
Reduced D2/D3 receptor expression in NAc of drug- naïve high- impulsive rats
High impulsive rats display ___ cocaine self- administration
High impulsive rats display greater cocaine self- administration
Submissive monkeys display ___ D2 receptor levels and ___ vulnerability to cocaine self-administration
Submissive monkeys display lower D2 receptor levels and higher vulnerability to cocaine self-administration
D2 level differences are ___ in socially- housed monkeys
D2 level differences are amplified in socially- housed monkeys
In humans, individual characteristics predict high vulnerability to drug addiction, these include:
• sensation- and novelty-seeking
• trait impulsivity
• anti-social conduct disorder (especially in
adolescence)
In animal models, individual characteristics that predict high vulnerability to drug-seeking behaviour include…
• high reactivity to stress
• high novelty-induced locomotor activity
• high novelty-seeking
• high trait impulsivity
Subjects with deficits in striatal D2 levels report a ___ experience with methylphenidate
Subjects with deficits in striatal D2 levels report a pleasurable experience with methylphenidate
Healthy male subjects with robust striatal DA levels report ___ experience with methylphenidate
Healthy male subjects with robust striatal DA levels report displeasurable experience with methylphenidate
Causes of reward deficiency hypothesis
1) Deficiency of D2 receptors in the reward circuit
2) An aberration in D3 receptors in the reward circuit
3)Due to a deficiency in presynaptic DA levels in the NAc
Adoption studies→more likely to display ___ family than ____ family habits
Adoption studies→more likely to display birth family than adopted family habits
Twin studies→ ____ twins have more similar rates of addiction than ____ twins
Twin studies→ monozygotic twins have more similar rates of addiction than heterozygotic twins
All drugs are ___ – ____
All drugs are pleiotropic – cause multiple physiological effects
ACh activates ___ responses, plays a major role in ____ and ___
ACh activates parasympathetic responses, plays a major role in learning and memory circuits
Generally, drugs that target 5HT receptors are ___
Generally,drugs that target 5HT receptors are less addictive
NE plays a major role in ___
NE plays a major role in stress-induced drug relapse
NE innervation activates ___ responses
NE innervation activates sympathetic responses
Lab animals prefer ___ over ___, ____, ___ and ___ even in the presence of aversive and painful consequences
Lab animals prefer drugs over food, water, toys and sex even in the presence of aversive and painful consequences
In the context of addictive drugs, the learning signal leads to drug ___ behaviours leading to ___ drug intake at the expense of all other behaviours
In the context of addictive drugs, the learning signal leads to drug adaptive behaviours leading to compulsive drug intake at the expense of all other behaviours
Once the reward becomes fully predictable, DA- ergic neurons ____ and learning ____
Once the reward becomes fully predictable, DA- ergic neurons are no longer triggered and learning ceases
Phasic firing of VTA DA-ergic neurons generates a ____ signal when an ____ reward occurs
Phasic firing of VTA DA-ergic neurons generates a learning signal when an unexpected reward occurs
NMDAR expressed in ___
NMDAR expressed in hippocampus
mGluR7 is expressed in ___, ___, ___
mGluR7 is expressed in Hippocampus, Amygdala, locus coeruleus
mGluR3 is expressed in ___
mGluR3 is expressed in NAc
____ – potentiation last minutes, weeks, months; unique to LTP
Persistence – potentiation last minutes, weeks, months; unique to LTP
___ – many weak stimuli can induce LTP; constructive interference
Cooperativity – many weak stimuli can induce LTP; constructive interference
___ – sites of LTP are confined to specific contact sites
Specificity – sites of LTP are confined to specific contact sites
LTP = ___ of synaptic transmission between two neurons ___ of glutamate receptors
LTP = strengthening of synaptic transmission between two neurons downstream of glutamate receptors
Group I Gq-linked – ____
excitotoxicity risk
Group I Gq-linked – increase
excitotoxicity risk
Glutamate receptors (mGlu-R) are involved in__
synaptic plasticity
NMDAR has ___ signalling
Ca2+ (calcium)-dependent
NMDAR is critical for ___
NMDAR is critical for synaptic plasticity (LTP/LTD)
NMDAR is co-activated by ___ and ___
NMDAR is co-activated by glutamate and Serine/Glycine
NMDAR is ___
ionotropic
AMPAR has a major role in ___
long-term depression (LTD)
AMPAR is ___ and forms __
AMPAR is ionotropic and forms tetramers
Hedonic dopamine tone is reduced during ___, causing___
Hedonic dopamine tone is reduced during withdrawal, causing dysphoric state
After drugs wear off, addicts experience ____ and ____ within this circuit leading to ___
After drugs wear off, addicts experience post-use dysphoria and depressed activity within this circuit leading to further drug use to avoid unpleasant feelings
Tolerance to some drugs leads to ___ of hedonic tone (___ euphoria) during chronic use causing addicts to use ___ doses to ____
Tolerance to some drugs leads to lowered elevation of hedonic tone (lowered euphoria) during chronic use causing addicts to use higher and higher doses to restore homeostatic dopamine levels to ‘get straight
Antagonists produce subjectively ___ effects in humans,___ of drug-taking behaviours
Antagonists produce subjectively aversive effects in humans, extinction of drug- taking behaviours
Dopamine antagonists are __ reinforcers that enhance behaviours to ___
Dopamine antagonists are negative reinforcers that enhance behaviours to reduce administration
Intracerebral microinjections of nicotine produce ___ and ___
Intracerebral microinjections of nicotine produce conditioned place preference and voluntary self-administration
All addictive drugs cause lab animals to ___and enhance ___
All addictive drugs cause lab animals to self- administer frequently and enhance functioning of the reward circuitry
Dopamine is the neurotransmitter of __
Dopamine is the neurotransmitter of reward
Addictive drugs induce ___ firing in the __
Addictive drugs induce phasic DA firing in the NAc
You can measure neurotransmitter levels in specific nuclei directly via ___
You can measure neurotransmitter levels in specific nuclei directly via microdialysis
___ (CPP) is when pairing an __ with stimulation of ___projections causes ____that persists for several days
Conditioned place preference (CPP) is when pairing an environment with stimulation of VTA DA-ergic projections causes immediate place preference that persists for several days
Effort exerted to self-administer is related to _____
Effort exerted to self-administer is related to degree of reward experienced
Self-administration in animal studies is via ___, e.g. __, __
Self-administration in animal studies is via instrumental behaviour, e.g. lever-press, nose poke
Animal tests assess ___ of a drug and ___
Animal tests assess addictiveness of a drug and translate well to humans
D2-like type ___ cytoplasmic (cAMP) via adenylyl cyclase
decreases
D2-like type are couple to ___
Giα
D2-like type are ___
D2, D3 and D4
D1-like type (D1 and D5) ___ cytoplasmic (cAMP) via adenylyl cyclase
increases
D1-like type (D1 and D5) receptors are coupled to __
Gsα
There are __ dopamine genes which are ___ that encode for __ dopamine receptors (DRs) which are ___
There are 5 dopamine genes which are DRD1-DRD5 that encode for 5 dopamine receptors (DRs) which are D1-D5
There is a link between low 5-HT and ___ and ____
There is a link between low 5-HT and impulsivity and violence in addicts
__ is the major source of serotonin
raphe nuclei
5-HT (seretonin) is a ___
monoamine indole
___receptors are involved in LTD and LTP
glutamate
Glu has a major role in ___
Glu has a major role in cue-triggered relapse
Glu (glutamate) is an ___
amino acid
ACh is central to ____
ACh is central to learning/memory
the major inhibitory neurotransmitter is ___
GABA
NE has a big role in ____
NE has a big role in stress-induced relapse
Major source of NE projections in the brain come from the ___
Major source of NE projections in the brain come from the locus coeruleus
NE (norepinephrine) is a ___
catecholamine
DA is the primary ____in particular during the ____phase
DA is the primary driver of reward circuit in particular during the VTA→NAc 2nd phase
Dopamine (DA) is a __
catecholamine
Withdrawal is the generally ___ affective ___ and ___ due to ____/___
withdrawal is the generally unpleasant affective mood and symptoms due to tolerance/dependence
Tolerance is taking ___ drug __ feeling effects or needing ___
Tolerance is taking more drug without feeling effects or needing more drug to feel the same effect
The change from __-driven to ____-driven drug-seeking behaviour correlates with a ____ ___ mediated shift in control of ____ behaviour
The change from reward-driven to goal-driven drug-seeking behaviour correlates with a ventral striatum-to-dorsal striatum- mediated shift in control of drug-seeking behavior
Addiction starts as ___use then ___ use then ____ use
Addiction starts as occasional recreational use then impulsive use then habitual compulsive use
____ and ___ are critical neurotransmitters
Dopamine and glutamate are critical neurotransmitters
When dendrites or soma reach threshold, nerve
fires = ____
When dendrites or soma reach threshold ,nerve
fires = action potential
An ability to form new connections, change wiring patterns and establish new pathways = ____
An ability to form new connections, change wiring patterns and establish new pathways = neural re-wiring
Amygdala inputs are at the core of ___/___ circuits
Amy inputs are at the core of reinstatement/relapse circuits
Frontal inputs are at the core of ___, e.g. PFC
Frontal inputs are at the core of anticipation circuits, e.g. PFC
Many addictive drugs lose their ___ effect
Many addictive drugs lose their euphoric effect
VTA→NAc DA-ergic projections are at the core of ____
VTA→NAc DA-ergic projections are at the core of the reward circuit
All drugs of abuse elevate ___which reinforces drug-___ behaviours
All drugs of abuse elevate striatal dopamine which reinforces drug-taking behaviours
Repeated administration of addictive drugs can lead to ____ drug-seeking behaviour
Repeated administration of addictive drugs can lead to compulsive drug-seeking behaviour
Compulsivity results in decreased ___ over ___, diminished ability to ____ or ___ _____ behaviours and a tendency to perform ____ in a ___ or ____ manner
Compulsivity results in decreased voluntary control over urges, diminished ability to delay or inhibit compulsive behaviours and a tendency to perform repetitive acts in a habitual or stereotyped manner
Compulsivity refers to a tendency toward ___, ___, repeated despite ___
Compulsivity refers to a tendency toward repetitive, habitual actions, repeated despite adverse consequences
Impulsivity results in ___ and ___ before acting
Impulsivity results in reduced thought and judgement before acting
___activity is mainly involved in impulsivity
Dorsolateral prefrontal activity is mainly involved in impulsivity
Deficient __ cognitive control- an inability to ___
Deficient frontostriatal “top-down” cognitive control- an inability to override thoughts that lead to actions
Measures of impulsivity rely on__, ___and ___
Measures of impulsivity rely on self-reports, behavioural scores and electrophysiology
Initially, drug-taking behaviour is ___
Initially, drug-taking behaviour is reward-driven
__→__ projections have implicated __ in neuropsychiatric disorders; OCD, ADHD, schizophrenia and others
RN projects to ____, ___, ___ and ___
RN projects to hypothalamus, limbic system, brainstem and spine
RN (raphe nuclei) regulate __, __, ___, ___, __, __, ___, ___ and ___
RN (raphe nuclei) regulate mood, emotion, aggression, sleep, anxiety, memory, appetite, pain and temperature
RC is located in
the dorsal medulla oblongata, multiple nuclei
LC projects to __, __, ___, ___, __, ___, ____,
___, ___ and __
LC projects to VTA, brainstem, cerebellum,
thalamus, hypothalamus, hippo, Amy,
basal ganglia, cortex and spine
LC (locus coeruleus) regulates ___, ___, ___, ___, ___, ___, ___
LC regulates arousal, cognition, memory,
sleep-wake, attention, emotion, stress
Locus coeruleus (LC) is located in __
the dorsal pons
VTA has reciprocal projections with _, _, _, _, basal ganglia and others
VTA has reciprocal projections with NAc, Amy, RN, PFC, basal ganglia and others
Drugs accumulate in the ___ binding to the transporters
Drugs accumulate in the CN, binding to the transporters
CN has reciprocal connections with ___, ___, ___, ___
CN has reciprocal connections with VTA, NAc, Hippo, Amy
CN is involved in ___, ___, ____, ___, ___, ___
CN is involved in voluntary movement, learning, memory, sleep, pain, social behaviour
Basolateral amygdala permits ___, ____by medial PFC
Basolateral amygdala permits emotional regulation, decision making by medial PFC
Chronic drug abuse disrupts ___ →____connections
Chronic drug abuse disrupts Amy →PFC connections
Amygdala associates cues with ____, ___, ____
Amygdala associates cues with drug consumption, conditioning, reinstatement
Amygdala has key involvement in ____, most disabling symptom in addicts
Amygdala has key involvement in emotional reactivity, most disabling symptom in addicts
Amygdala has role in ___, ___, ____, ____, ___, __, ____
Amygdala has role in emotions (fear, pleasure), learning, memory, reward, attention, arousal, stress
VTA→____ projections modulate plasticity and learning/memory
VTA→Hippo projections modulate plasticity and learning/memory
Hippocampus contains___ cells, ____ by drugs of abuse
Hippocampus contains neuronal stem cells, suppressed by drugs of abuse
Hippocampus has role in __, ____and ____ information
Hippocampus has role in memory formation, processing novel and contextual information
Location of hippocampus
para-saggital plane, caudal amygdala
PFC has reciprocal connections with multiple regions involved with ___, ___, ___
PFC has reciprocal connections with multiple regions involved with attention, action, cognition
PFC → ___ + ___ expression of behaviours trained by chronic drug abuse
PFC → VTA + Amygdala expression of behaviours trained by chronic drug abuse
PFC has role in ___, __, ___, ___, ___, ___, ___, ____, ____
PFC has role in self-awareness, planning, problem solving, learning, memory, executive functions, personality, decision making, social behaviour
PFC is located in the
frontal lobe and extends into medial regions
VTA is the main driver of _
VTA is the main driver of rewarding feelings
VTA is involved in _, _, _
VTA is involved in cognition, motivation, locomotor activity
VTA is located in the _
midbrain
NAc has reciprocal projections with _, _, _, _, _
NAc has reciprocal projections with VTA, PFC, Amy, Hippo, basal ganglia
NAc is the __ centre, involved in _ , cognitive processing of __, ___ of drug-taking, translating emotional stimulus into __
NAc is the pleasure centre, involved in motivation, cognitive processing of aversion, reward/reinforcement of drug-taking, translating emotional stimulus into behaviour/action
Nucleus accumbens (NAc) location
basal forebrain striatum
PFC has reciprocal connections with multiple regions involved with ___, ___, ___
PFC has reciprocal connections with multiple regions involved with attention, action, cognition
