animal models of addiction Flashcards
3 Different types of animal models- construct, face, and predictive
Construct validity
the model has a sound theoretical rationale (neurobiological or psychological mechanisms, aetiology)
Face validity
phenomenological similarity between the model and the disorder being modelled (symptoms)
Predictive validity
manipulations known to influence the pathological state should have similar effects in the model (drugs)
example of construct vadility- in parkinson’s disease there is a lack of dopamine produced by the striatum. If the animal model does not have an intact striatum it may not be wise to use
face validity- eg in parkinson’s disease a cardinal symptom is having tremors/hypokinesia, so having tremors in a mouse is necessary
predictive valitidty- drugs used to help humans should also be somewhat effective in improving symtpoms in the mouse eg. L dopa would have same efficacy in mouse as in humans
we mostly only have 2
animal model for showing substance abuse
Intravenous, usually the jugular vein.
Rat can tap a lever or poke a nose-hole with infra-red beam to get the drug reward.
Also self-admin by oral, in drinking fluid, can be forced (1 bottle) or choice (2 or more bottles)
graph can be plotted to show active or inactive nose pokes in group that were given the drug intravenously in the first place to show whether the drug induces drug seeking behaviour
Number of lever taps?
Schedule achieved?
Post-reinforcement pause?
different ways the drug can be administered
intravenous (not so common)
sub-cutaneous (SC, common)
intraperitoneal (IP, common)
intra-cerebral (quite common)
intramuscular (not so common)
animal model for drug seeking behaviour
Conditioned Place Preference/Avoidance
Initial test for side-preference
Usually give the drug in non-preferred side
Give saline in preferred side
Test for CPP after 5-10 days
Time spent in the heroin paired compartment was measured on day 2 and day 7 (pre-, post- conditioning)
so give drug before day 2 and day 7 and saline in between, measure difference in CPP
measure the time in each compartment at different concentrations of heroin
how can inbred mice strains be used to show drug abuse vulnerability
eg. two different groups of mice- C57BL/6J and DBA/2J
these different groups of mice naturally show different
affinity ie morphine analgelsia, morphine preference, alcohol, amphetamine preference, cocaine preference
how to model increase in tolerance/sensitization
Tolerance is commonly found in people when taking drugs such as opiates, benzodiazapines and psychostimulants
Metabolic tolerance = change in the metabolism of the drug (e.g. enzyme that degrades the drug such as alcohol dehydrogense)
Cellular tolerance = change in a receptor or reuptake site e.g. dopamine transporter
Method: Male 7-8 week old C57BL/6J and DBA/2J mice
Chronic “intermittent” escalating dose heroin (s.c.) treatment of C57BL/6J and DBA/2J mice
Intermittent Heroin: 2 injections daily (9 am and 5 pm)
Total activity measured after injection
model for sensitization- what it is and locomoter sensitization?
sensitization? when a person’s reaction to a drug increases such that smaller doses are needed to achieve the same effect.
Behavioural sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine
Sensitization, which is a long-lasting phenomenon, is thought to underlie drug craving and relapse to drug use
Locomoter experiment to show sensitization:
mouse injected with cocaine at 50mg/kg every hour
at 0 60 and 120 mins
measured locomoter activity
after day 1 increase of locomoter behaviour that increased and then worse off (up and down)
same protocol on day 2 and 3
you can see the same dose of cocaine induces a much higher effect on day 3 compared to day 1
this is experiment showing sensitisation which is what is assocated with drug craving and relapse
Mechanism of sensitization
D1 is post synaptic, D2 is pre and post synaptic, D1 is post synaptic
In sensitization,
Increase in dopamine transmission
Increased D2 receptor activity
Increased D1 receptor numbers and activity
Withdrawal symptoms and how to model them
Physical, characterised by abstinence syndrome (LC)
Sweating, gooseflesh (cold turkey), irritability, aggression
Psychological, craving to avoid withdrawal effects
Physical symptoms of cocaine withdrawal not really obvious in mice and rats
Naloxone precipitated opioid withdrawal
-naloxone injection in chronic morphine treated mice will precipitate acute physical withdrawal
Mecamylamine precipitate nicotine withdrawal
we can model these opioids withdrawal symptoms
by adminstering opioids like morphine or heroine in animals for a period of 2-3 weeks to make the mouse or rat dependent
inject nalaxone which is an opioid receptor antagonist. the mouse would lose weight, shaking, diarrhoea- the same withdrawal symptoms. Mice always get jumping behaviour which doesn’t happen in humans
emotional withdrawal effects and how to model them
Anxiety Irritability Drug craving Cramps Hypo-locomotion Anhedonia Depression
Mouse model of emotional impairment during opioid abstinence- method:
Chronic Saline or Escalating-Dose Morphine administration
Assessed emotional-like behaviour (sociability, anxiety, depression) following protracted morphine abstinence
anxiety, depression, hedonia, social withdrawal last for a long period of time and can cause relapse
we left mouse wihtout drug for 7 days and measured emotive response of anxiety, depression etc
Evidence that long term administration abolishes social preference
3 chambers sociability test!!!!!!
The three-chambered box as it can be seen on the screen assesses social interaction behaviours in rodents. The whole test consists of 3 phases.
During the habituation phase the mouse had free access to explore the three empty chambers for 10 minutes.
During the second phase, called the social interaction phase, two identical small cages were placed in each of the end-chambers and an unfamiliar mouse, called the stranger 1, was placed in one of the two small cages while the other cage remained empty. The test mouse was allowed to explore the whole apparatus for a period of another 10 minutes.
During the last phase, the preference for novelty phase, another unfamiliar mouse, the stranger 2, was introduced in the previously empty cage while the now familiar “stranger 1” remained in its original cage. The test animal was permitted to explore the box for another 10 minutes.
Social interaction was determined by calculating the time that the test mouse spent in the chamber containing the unfamiliar mouse (stranger 1) vs. the chamber containing the empty cage. Saline withdrawn mice, shown with the clear bars, exhibited a significant preference for the chamber containing stranger 1 vs the empty chamber as you can see here. Morphine withdrawan animals did not show any preference between the chamber containing the stranger 1 and the empty chamber demonstrating a lack of social preference.
Similarly, saline withdrawn animals showed significant preference for the chamber containing the unfamiliar mouse (stranger 2) vs the now familiar stranger 1 demonstrating social novelty preference. However, morphine withdrawn mice did not show any preference between the 2 chambers demonstrating a luck of social novelty preference.
Therefore, morphine withdrawal induced social interaction deficits in mice which is in agreement with the situation of opioid abstinent humans. This data clearly shows clear causality btween opioid abstinence and social impairment
Evidence for increased anxiety like behaviour in long term opioid abstinence (animal model)
We then assessed anxiety-related behaviour with the use of the elevated plus-maze. This plus-shaped apparatus consisted of two open arms and two closed-arms and it was elevated 40cm from the floor. This test measures the conflict between the natural tendency of mice to explore a novel environment versus the tendency to avoid exposed areas.
The animals were positioned in the centre of the apparatus and left to explore for 5 mins. Anxiety-like behaviour was determined by calculating the amount of time spent and the number of entries each mouse made in the open and closed arms.
Morphine withdrawn animals spent significantly less time and entries in the open arms compared to saline withdrawn animals. These data clearly show that prolonged withdrawal from morphine induces anxiety-like behaviour. Consisten in humans
Evidence for Increase in depressive-like behaviour following long-term opioid abstinence (animal model)
SENSITIVE TO ANTIDEPRESSANTS
Forced swim test:
5 litre beaker, put water into out at specific temperature
place mouse in water and let it swim
after a period of time it likes to get out
some keep their head above the water and doesn’t bother moving- forced- swim test
gives the despair like behaviour
what is relapse and reinstatement
In drug abuse/dependency this means that a person starts taking the drug again after a period of abstinence
Cue could be a light that comes on when they get i.v cocaine.
Drug could be a small dose of cocaine or similar drug.
Stress could be tail pinch, foot shock, food or water restriction
stress induced reinstatement (animal model)
Stress-induced Reinstatement:
Saline or Carbetocin injection (6.4mg/kg, i.p.)
Forced-swim stress (6 minutes)
Test for place preference
animal model of stress induced relapse:
first condition animal to be dependent on drug
give period of absitinence
re-introduce a trigger such as stress that re-introduces the strug starting behaviour
conditioning, extinction (only give saline), trigger re-instatement behaviour
eg. the forced swim test for 6 mins
can do similar experiment with morphine:
during pre-conditioning- spends about 350 seconds in the morphine compartment
following extinguishing goes back to pre-conditioning levels
but stress completely re-instates and the mouse relapses towards morphine