Animal models of addiction

Question 1

Things to consider when choosing an animal model

Answer 1

Do you just want to model a condition?
Are you interested in only certain symptoms/pathologies?
Are you interested in treatments?
Do you want to examine the disease process?

Question 2

Validity of animal models

Answer 2

Construct validity = the model has a sound theoretical rationale (neurobiological/psychological mechanisms, aetiology)
Face validity = phenomenological similarity between the model + the disorder being modelled (symptoms)
Predictive validity = manipulations known to influence the pathological state should have similar effects in the model (drug efficacy)
Rare to have all 3, usually has good face or predictive

Question 3

A good model follows…

Answer 3

addiction patterns closely + diagnostic criteria, or stages of the addiction cycle

Question 4

What can we model? The different stages of addiction

Answer 4

Substance abuse- drug taking
Drug seeking behaviour
Drug addiction/drug dependence
Increase in tolerance/sensitisation
Acute withdrawal symptoms
Compulsion to use
Relapse
Context dependency
Genetic models- KO mice
Neurochemical models?
Other models?

Question 5

Substance abuse- drug taking

Answer 5

Taken by the animal- self-administration
Intravenous, usually the jugular vein, or brain
Rat can tap a lever or poke a nose-hole w 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)
What to measure in self-admin? Number of lever taps? Schedule achieved? Post-reinforcement pause?

Question 6

How are drugs given by the scientist

Answer 6

Intravenous (not so common)
Sub-cutaneous (SC, common)
Intraperitoneal (IP, common)
Intra-cerebral (quite common)
Intramuscular (not so common)

Question 7

Drug seeking behaviour- conditioned place preference/avoidance (CPP)

Answer 7

Initial test for side-preference
Usually give the drug in the non-preferred side
Give saline in preferred side
Test for CPP after 5-10 days

Question 8

Increase in tolerance/sensitisation

Drug addiction /dependence:

Answer 8

Length of time? 15 mouse days = human time needed for addiction
Can we model dependence? Compulsive drug taking/tolerance?

Question 9

Tolerance

Answer 9

Metabolic tolerance = change in the metabolism of the drug (e.g., enzyme that degrades the drug, like alcohol dehydrogenase)

Cellular tolerance = change in a receptor/reuptake site e.g., DA transporter

Question 10

Method

Answer 10

chronic intermittent escalating dose heroin. Measure total activity after injection. Increases w escalation of administration

Question 11

Sensitisation

Answer 11

when a person’s reaction to a drug increases such that smaller doses are needed to achieve the same effect

Behavioural sensitisation is the augmented motor-stimulant response that occurs w repeated, intermittent exposure to most drugs of abuse, inc. cocaine
Long lasting phenomenon thought to underlie drug craving + relapse drug use
Method = measure locomotor activity after binge doses over a few days. The same dose induces higher affect on day 3 vs day 1

Question 12

Molecular mechanism of sensitisation

Answer 12

Increase in DA transmission
Increased D2 receptor activity
Increased D1 receptor numbers + activity

Question 13

Acute withdrawal symptoms and method

Answer 13

Physical, characterised by abstinence syndrome (LC)
Psychological, craving to avoid withdrawal effects
Method = make animals dependent by injecting opioids over a period of time (few weeks). To induce physical withdrawal, inject naloxone (opioid receptor antagonist). Weight loss, diarrhoea, shaking, paw tremor, jumping behaviour (mice)
But physical symptoms of cocaine withdrawal not v obvious in mice + rats

Question 14

Chronic withdrawal

Answer 14

Emotional withdrawal effects: anxiety, irritability, drug craving, cramps, hypo-locomotion, anhedonia, depression (?)
Method = chronic saline/escalating dose morphine administration to make them opioid dependent, followed by chronic withdrawal. Assessed emotional-like behaviour (sociability, anxiety, depression).

Question 15

Chronic withdrawal:, method:

Answer 15

Assess social interaction using 3-chambered box- one chamber has a cage w another rat in it, the other has a cage w an object inside, the 3rd is empty. Take the opioid abstinent rat and place it in the box + see which chamber it spends the most time in. Opioid withdrawal mice show no social preference

Assess anxiety using elevated plus maze- 2 open arms, 2 closed arms + elevated from the floor. Control mice spend 30% time in the open arms, but OW mice only spend 5% time in open arms. Induction of anxiety-like behaviour following withdrawal

Assess depressive-like behaviour using forced-swim test. Mice will swim for a period of time, before becoming immobile, associated w depressive state/despair. Control mice 125s/7 mins immobile, OW mice spend 200s. Opioid withdrawal induces depressive-like phenotype
But is immobility a good indicator of despair? Debated but many anti-depressants use this method to test efficacy

Question 16

Compulsion to use

Answer 16

Compulsive drug taking after prolonged cocaine use
Method = set up self-administration for a prolonged period of time to ensure dependency. Introduce an electrical shock- in order to obtain cocaine, has to undergo shock. See whether the rat continues to self-admin.

Question 17

Relapse

Answer 17

In drug abuse/dependency, this means that a person starts taking the drug again after a period of abstinence
Relapse triggers/stress induced reinstatement
Cue- could be a light that comes on when they get i.v. cocaine
Drug- could be a small dose of cocaine/similar drug
Stress- could be a tail pinch, foot shock, food or water restriction
Method = need to establish dependence + then have a period of abstinence. Re-introduce a trigger (e.g., stress cue or drug priming) which will induce reinstatement of drug administration or drug seeking behaviour
Mice given morphine every morning for 5 days, and then only saline for another 5. Test for abstinence and then induce stress to see if they relapse. So pre-conditioning, only spend 350 seconds in one side of the CPP. Morphine is then associated w one side of CPP. Post conditioning = 500s. Post abstinence = back down to 350s. but after 6 min forced swim test, back up to 500s. Big reinstatement of drug seeking behaviour.

Question 18

Link behaviour with neurobiology (with microdialysis)

Answer 18

Measuring NT release in vivo
Association w behaviour parameters
Method = implant a probe in specific brain region of animal. Probe is connected to a HPLC, so whatever is released from brain region is recorded.

Question 19

Brain imaging

Answer 19

MRI scan- brain activity
Positron emission tomography- receptors
Receptor autoradiography, immunocytochemistry, in situ hybridisation

Question 20

Genetic models- KO mice: animal models used in addiction research

Answer 20

Wild type animals
Comparison of different strains of animals w different vulnerability to addiction
Gene knockout/knock in mice

Question 21

Contribution of mouse genetics in the field of drug addiction

Answer 21

Identified + confirmed the role of genes in addiction
Help w the development of novel pharmacotherapy for the treatment of addiction + relapse
Identified genes involved in the vulnerability to develop addiction + relapse

Question 22

Limitations & validity of animal models-knockouts

Answer 22

Rat vs mouse
Majority of knock out data only conducted on mice
Mice only have small prefrontal cortex
Developmental compensation
Brain plasticity means that some pathways may be compensated for others
Creation of a new brain pathway to compensate for the one that was knocked out
Phenotype is not due to the knockout, but due to the compensation created for the knockout instead
Background strain + the transgene
Many knockouts are genetically different