addiction in animals

Question 1

what are models of addiction

Answer 1

non contingent

self administration (contingent)
either operant or non operant

Question 2

what is addiction

Answer 2

a brain disorder characterised by compulsive engagement in rewarding stimuli despite adverse consequences

addiction exacts an “astoundingly high financial and human toll” on individuals and society as a whole through:

adverse effects of drugs and associated healthcare costs

long term complications (e.g lung cancer with smoking tobacco, liver cirrhosis with alcohol, and meth mouth from intravenous meth)

functional consequences of altered brain function and consequent loss of productivity

Question 3

what characteristics of animal drug studies resemble human behaviour

Answer 3

both humans and labratory animals will voluntarily take drugs by different routes (orally, iv etc)

if unlimited intravenous heroin or cocaine is provided both humans and animals can easily overdose

mice and rats voluntarily drink large quantities of alcohol leading to strong intoxication

Question 4

what is a main question of validity of animal models of drug addiction

Answer 4

do animals really engage in human like drug taking or are we anthropomorphosising

need a strong scientific definition of drug taking behaviour

Question 5

what are assumptions of animal models of addiction

Answer 5

it is widely assumed that the neurochemical and neuroanatomical substrates involved in drug taking behaviour are similar in rodents and humans however this is quite an assumption

most research is based on cocaine or amphetamine addiction due to mix of historical and practical reasons

Question 6

how do cocaine and amphetamine act

Answer 6

they are the most commonly studied drugs

cocaine acutely blocks dopamine reuptake

amphetamine enters presynaptic terminal and causes vesicular monoamine transporter VMAT to release dopamine intracellularly; results in dopamine being reverse transported; acts on endogenous dopamine terminals to increase the level of dopamine

Question 7

what is non contingent drug exposure

Answer 7

experimenter administered usually via intraperitoneal injection

can measure stimulant induced increase in locomotion, increases with additional injections (sensitisation), conditioned place preference

Question 8

what are pros and cons of non contingent drug exposure

Answer 8

pros:
easy to perform

results in high volume of data

makes it amenable to complex molecular cellular and circuit integration not possible with more complex models

cons:

it is highly unlikely that someone will give you a surprise injection of cocaine into your stomach

thinking psychologically about it, we are missing key aspects of behaviour; seeking, motivation, working for the reward

all of which are key especially in terms of addictive behaviour as these are the behaviours that become compulsive

Question 9

what is non operant contingent exposure

Answer 9

in rodents this is restricted to oral self administration

translationally this should only be used with alcohol, MDMA, and cannabinoids as other drugs are rarely taken via this route; however this has not stopped lots of people studying cocaine and heroin etc

despite the fact that this route is very different pharmacokinetically than that used by humans

Question 10

what are benefits of non operant self administration

Answer 10

rodents typically do not drink alcohol when first exposed to it (much like humans)

they are weaned onto it either through sweetening or by gradually increasing the concentration of alcohol (like humans)

after such training mice and rats can readily and voluntarily drink up to 40% alcohol solutions

will readily drink to intoxication (like humans)

Question 11

what are cons of non operant self administration

Answer 11

often “sped up” by exposure of highly concentrated alcohol vapour

results in high levels of voluntary drinking but is essentially non contingent

Question 12

what is operant self administered exposure to drug

Answer 12

rodents work to administer drug eg via nose poke or lever press

usually via and iv catheter

a model of the acquisition of self administration

Question 13

what are ways of measuring operant self administration of drugs in animal studies

Answer 13

fixed ratio: after a certain number of work (e.g lever presses) the drug will be given, an FR5 would mean the drug would be given every 5 lever presses

measures the motivation to get the drug

progressive ratio:
where each drug delivery the number of lever presses is increased; e.g 1,2,4,8,16

used to measure the breakpoint; maximum drive to get the drug

Question 14

what are benefits of operant self stimulation

Answer 14

we have now regained some important aspects of behaviour

the rodent has to work for the drug, it has to approach the lever of its own will (goal directed behaviour)

also some consitencies with human behaviour; need to enforce timeout periods or the rodent will overdose

while difficult it is high throughput enough to do complex cellular molecular and circuit investigations

allows the identification of risk factors for acquisition that opposed to epidemiological studies can be causally tested

examples are:
sex F>M
impulsivity H>L
sweet preference: H>L
stress H>L
exercise L>H

Question 15

how is impulsivity tested in rats and how does it effect studies

Answer 15

rodents are given a choice:
one lever gets 1 pellet immediately
the other gets 4 pellets after a delay up to 20s later

rats split into 2 groups; impulsive (small immediate reward) or low impulsive (bigger delayed rewards), can be used to test for risk in drug studies

Question 16

what are cons of operant self administration

Answer 16

very rarely are we given what we want just by pressing a lever

operant self stimulation can be supported by many non addictive substances; food, water, even lights

is it addiction or just reward learning

not as simple as it sounds; requires a lot of training (auto shaping, sucrose fading)

only 20% of individuals that regularly take drugs become addicted

this is a good model of acquisition of drug taking

Question 17

what is relapse

Answer 17

drug addiction can be conceptualised as a chronic relapsing disorder characterised by recurrent bouts of drug use with intervening periods of withdrawal and abstinence

relapse may in fact represent the single most predictive outcome of a diagnosis of addiction

one of the greatest challenges for treatment

Question 18

how is relapse modeled in animals

Answer 18

the resumption of a previously reinforced response when the unconditioned reinforcer or reward is presented non contingently after a period of extinction training

Question 19

what are benefits of animal models of relapse

Answer 19

seems to capture a key aspect of addiction

anthropomophically mimics the human problem

has helped to identify causally specific events or drugs that can induce relapse:
the drug itself
cues associated with drug use (for rat a lever, for humans a lighter/ needle etc)
stress (mild foot shock, food deprivation and social isolation can all induce relapse in rats)

Question 20

what are cons to animal models of relapse

Answer 20

all animals exposed to cocaine relapse; this is not the case with humans; something is missing

this model requires extinction of the response; rarely happens in humans and so is of limited value

however some treatment centres have started using behavioural extinction as a means to treatment

Question 21

what are benefits of a multidimensional study for addiction

Answer 21

the animal models examined so far investigate a specific aspect of drug taking, seeking or relapse which are helpful but not necessarily a model of addiction

there is need for a multidimensional model incorporating all of these aspects

e.g addicted individuals not only consume large amounts of drugs but are also unable to repress their drug use regardless of its consequences

also drug seeking is not the same as drug taking, seeking requires many steps such as finding money, implements and tools and purchasing the drug

a “ true model should also take into account the small proportion of individuals who regularly use drugs that transition to addiction”

Question 22

what is a DSM compatible model of addiction

Answer 22

DSM requires 3 out of 7 criteria to be present in the last 12 months;

most notably;
inability to refrain from drug seeking
high motivation for the drug
maintained drug use despite negative consequences

these can be modelled in rodents:
drug seeking periods when the drug is not available and signalled as such
high break points during progressive ratio schedules of reinforcement

persistence of self administration despite punishment by contingent electric foot shocks