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Use of animals in research

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Title: Use of animals in research


1
Use of animals in research Charlotte
Bonardi
2
Issues Why are animals used in
Psychology? How? What are the
benefits? Ethical issues what are the
safeguards?
3
Who uses animals? Biology study of animals
for their own sake Cognitive psychology study
of common cognitive processes Comparative
psychology compare cognitive skills in animals
Neuropsychology which bits of the brain are
involved? Medical psychology animal models of
mental illness
4
Who uses animals? many involve the study of
learning (i.e. memory) in animals... but how
can you do this? and why even think of
using animals in the first place?
5
Issues whether you can study learning in
animals depends on - what you think learning
is - whether we all learn in the same
way Philosophical position on this has
changed over time
6
learning a rule-based mental process -
information encoded can't see inside the mind..
but can see information input
7
learning a rule-based mental process -
information encoded can't see inside the mind..
but can see information input ..and a
predictable change in behaviour results --
output animals probably do something similar,
maybe less well...
8
but this is a modern view..... relatively
recently (1500s) people used to think of even
non-living things animistically with desires
and so on -- in the same way as humans e.g.
magnets attraction/repulsion moving together
in voluntary union
9
....superseded by mechanistic view Descartes
(1596 - 1650) - dualist distinguished mind and
body. Man has mind which interacts with body in
pineal gland. because he is sceptical about the
external world, much knowledge comes from
deduction not perception... i.e. learning
unobservable Animals explicable in terms of
physical principles robots
10
Locke (1632-1704) All ideas originate in
experience. Idea is unit of mind, simple ones
make up complex ideas association of ideas - a
learning rule Hume (1711-1776) - distinguish
impressions (sensations) and ideas (experienced
in absence of object). Laws of association
resemblance, contiguity, cause and effect
(correlation). Psychological processes are
analysable learning comes from experience --
input is observable
11
James Mill (1773-1836) refined the idea of the
association of ideas, that mirror sensations
that we experience Empiricist/Associationist
approach forms basis of psychology as an
experimentally tractable subject Can study mind
by relating external stimuli (input) to
psychological output (e.g. report, or other
behaviour)
12
Introspectionism mainly Germans e.g. Fechner,
Weber, Wundt Fechner (1801-1887) pioneered
psychophysics - study of sensations evoked by
physical stimuli - using techniques like
measuring just noticeable differences and
relating them to physical stimulus
magnitude Würzburg School - highly trained
observers used for psychological
experimentation used introspection
and report as measure ..which rules
out use of animals...
13
Behaviourism Reaction to introspection data
must be publically observable and so
independently verifiable. relate external
stimuli to behaviour, not psychological report.
obvious? maybe not... e.g work on
stereotyping - get different results from self
report and affective priming measures... "I
love Norwegians!" but Norwegian - happy
slower than Norwegian - dreadful
14
Darwin (1809-1882) - theory of evolution,
implies continuity between man and animals So
theoretically in a position to study animals...
study of learning involves looking at
information input and measuring behaviour
output and rats and man are on a
continuum but what of the theories?
15
Radical Behaviourists Only deal with S and R -
no unobservable mental events e.g. Skinner
(1904-1990) attempted a complete account of
behaviour - response either elicited by a
stimulus or controlled by a consequence... but...
. what is a response? If rats learn a maze,
and then it is flooded, do they try and walk? If
it's S--gtR they should.....! Tolman (1886-1959)
better to think of responses at molar level e.g.
approach end of maze, not reflexes involved in
walking
16
Radical Behaviourists S?R cant do
goal-directed behaviour many of these theories
see reinforcement as a glue cementing S?R
relationship cat in puzzlebox (Thorndike)
makes lots of responses until one allows it to
escape. Frequency of this response increases
because it has been rewarded. BUT Lever?food
then food? illness strict S?R says you should
keep on pressing the lever
17
Cognitive Behaviourists cumbersome e.g. cat in
front of barking dog... arches back, hisses, hair
on end, etc... cat--gtR1 cat--gtR2
cat--gtR3 cat--gtR4 etc... instead e.g. cat
in front of barking dog... --gt fear --gt arches
back, hisses, hair on end etc fear is an
intervening variable not directly observable,
but useful if strongly tied to observable events
- what causes it and what effect it has. And can
be linked to internal states sometimes e.g.
adrenaline
18
eating dry food runs maze for
water deprive of water drinks
water inject with saline presses lever for
water
19
eating dry food runs maze for
water deprive of water
thirst drinks water inject with saline
presses lever for
water From Hall 1983
20
Modern Cognitive Behaviourism mental
representations activated by presentation of
environmental events associations form between
representations of two events that are reliably
paired, so presenting one will activate the
other....
tone
tone ? food
response ? food
21
Modern Cognitive Behaviourism Associative
learning allows us to learn causal relationships
in our environment - found in all vertebrates -
very general mechanism explains much learning in
animals and also people e.g. connectionist
networks - explain complex human cognitive skills
in terms of associations
22
Cognitive Psychology So modern theories of
animal learning will work for humans too.. But
why still bother?!! why not cut to the chase and
test humans?
23
Because... Huge existing research base on
associative learning in animals and associative
theory is the most comprehensive theory of
learning we have...
24
Very high levels of experimental control
possible prior experience - e.g. stimulus
novelty current experience - stability of
conditions motivational control Interference
of higher level processes experimenter
demands higher level reasoning prior
knowledge context effects
25
So this is why we study animals for cognitive
psychology... for comparative psychology its
obvious how about neuropsychology?
26
Neuropsychology aim is to understand how the
brain works - how it produces psychological
phenomena can't we study the behaviour of the
organism without knowing how it is
produced? data can aid theoretical development -
if theory says skills a and b depend on the same
process, but lesion affects only skill a, theory
wrong.... understanding underlying systems can
help deal with pathology parallels can lend
credence to theory - e.g. associations and neurons
27
Issues with studying neuropsychology in
animals assumes homology of anatomy, if
knowledge is to apply to man assumes mapping of
psychological/behavioural phenomena - cf.
hippocampus
28
  • Advantages - Techniques available!
  • compared to techniques available in humans, where
    until recently only had patients with brain
    damage - uncontrolled, no idea what they were
    like before, etc
  • more modern imaging techniques vary in
    definition, scope etc
  • e.g. fmri supposedly measures neural activity
    while doing a task
  • but actually measures oxygenation of blood
  • indirect
    measure of neural activity
  • and which neurons? excitatory? inhibitory?
  • which neurotransmitter system? etc etc...

29
Advantages - Techniques available! techniques
available now in humans very important but not
perfect the range of different techniques
available in animals offer powerful complementary
strategies to understand how the brain works
30
Lesions - selective anatomically, and in
neurotransmitters targeted lesion cell bodies
leaving fibres of passage intact - e.g. ibotenic
acid, NMDA can target specific neurotransmitter
systems - e.g cholinergic denervation by e.g.
192IgG-saporin (SAP)
31
Lesions - selective anatomically, and in
neurotransmitters targeted lesion cell bodies
leaving fibres of passage intact - e.g. ibotenic
acid, NMDA can target specific neurotransmitter
systems - e.g cholinergic denervation by e.g.
192IgG-saporin (SAP) disconnection lesions -
destroy half of two structures, thus destroying
communication between them, but leaving them
functioning independently. If function depends
on interaction, it will be impaired Disconnection
of the anterior cingulate cortex and nucleus
accumbens core impairs Pavlovian approach
behaviour (Parkinson et al., 2000)
32
Lesions -- limitations lack of precision --
collateral damage confounding behavioural
effects e.g. activity limitations of
histological assessment where is it?
33
Neurotransmitters and drugs -- cannulate specific
agonists or antagonists into specific brain
areas Double dissociation of the behavioural
effects of R() 7OHDPAT infusions in the
central and basolateral amygdala nuclei upon
Pavlovian and instrumental conditioned appetitive
behaviours (Hitchcott Phillips, 1998) can
investigate the degree to which these effects are
influenced by other drugs in other areas Effects
of intra-amygdala R() 7-OH-DPAT on
intra-accumbens d-amphetamine-associated learning
(Hitchcott Phillips, 1998)
34
Neurotransmitters and drugs - limitations problem
s with spread of neurotransmitters do you need
control infusions in other areas that don't show
the effects? confounding behavioural effects
again
35
Transgenics -- strains of mice have been
developed in which genes are modified - knockout
and knockin MANY types e.g. Tg 2576
develops plaques similar to those seen in
Alzheimer's disease
Transgenic animals are frequently created by
either microinjection of DNA sequences into the
chromosomes of fertilized eggs, or genome is
modified in embryonic stem cells, and then inject
into embryo, where they are assimilated. Latter
technique allows addition as well as removal of
sequences.
36
Zhuo et al., (2007) Early discrimination
reversal learning impairment and preserved
spatial learning in a longitudinal study of
Tg2576 APPsw mice. Transgenics - limitations
some of these gene replacement techniques are
not as clean as they sound many types of
transgenic animals are they always good
analogues of what you think they
are? confounding physiological/behavioural
effects
37
c-fos expression - fMRI for rats? -- Measure
expression of c-fos as an indirect marker of
neuronal activity - c-fos often expressed when
neurons fire action potentials. "Occasionally
when a neuron is stimulated a reaction cascade
occurs that affects the expression of genes. One
gene that is often immediately induced is c-fos.
This is followed by an increase in c-Fos protein,
that reaches peak concentrations approximately 90
minutes after stimulation." Give critical
behavioural experience, remove brain, isolate
relevant area and then using c-Fos antibody
evaluate level of c-Fos protein in target (and
control) areas Patterns of brain activation
associated with contextual conditioning to
methamphetamine in mice. Rhodes et al., 2005
38
c-fos expression - limitations even if an
accurate measure of neuronal activity in a
particular area, which neuron? excitatory or
inhibitory? sometimes identifying adequate
control procedure very difficult - how can you do
within subject design? not temporally specific
39
Reversible inactivation -- can temporarily
inactivate certain brain areas with various types
of anaesthetic e.g. lidocaine Partial
hippocampal inactivation Effects on spatial
memory performance in aged and young rats. Poe
et al., 2000 can do within subject designs
40
Reversible inactivation - limitations leaves no
trace so have to rely on other evidence to be
sure of spread
41
  • In vivo microdialysis -- can measure levels of
    neurotransmitter activity in a specific area of
    the brain while animal is engaged in task
  • Enhanced dopamine efflux in the amygdala by a
    predictive but not a nonpredictive stimulus
    facilitation by prior repeated d-amphetamine.
    Harmer Phillips., 1999

42
  • In vivo microdialysis - limitations
  • limited by size of probe
  • no fine temporal discrimination - looking at
    release over a long period in each sample

43
Animal models of pathological states, to
understand them further and devise treatments.
Various types complete model of syndrome
actually reproduce syndrome (but how do you know,
given most are subjectively defined e.g.
depression, and definition always changing DSM
97 etc) e.g. learned helplessness partial model
of syndrome (based on objective symptoms)
concentrate on one specific and easily identified
symptom e.g. amphetamine model of schizophrenia
based on fact it produces symptom-like
behaviour http//www.acnp.org/g4/GN401000076/CH.h
tml
44
models that only predict treatment efficacy -
pharmacological isomorphism implies no real
understanding, and no ability to develop new
treatment... e.g. train animal to recognise one
effective drug, and then see which others will
substitute models based on operationally defined
psychological construct that is supposedly
affected by disorder e.g. anhedonia core symptom
of depression and schizophrenia, modelled by less
tendency to eat sucrose http//www.acnp.org/g
4/GN401000076/CH.html
45
Topical examples transgenic models e.g of
schizophrenia various dopamine knockout
mice Alzheimers disease that reproduce
characteristic plaques and tangles can look for
cognitive deficits that occur before b-amyloid
neuropathology kicks in critical for early
diagnosis
46
  • Animal models should have
  • predictive validity - allows accurate predictions
    in human analogue?
  • e.g. does it predict therapeutic value of drugs
    in humans?
  • e.g. do other variables affect animal model and
    humans the same?
  • http//www.acnp.org/g4/GN401000076/CH.html

47
construct validity - does it do what it says
on the tin? often don't know - because don't
understand the condition yet - that's the point
of the exercise! thus hard to know - constant
refinement http//www.acnp.org/g4/GN401000
076/CH.html
48
aetiological validity - is cause of effect the
same as in humans but often don't know aetiology
of conditions in man - that may be what the
animal model is designed to establish transgenics
help http//www.acnp.org/g4/GN401000076/CH
.html
49
convergent/discriminant validity - defined with
relation to other tests does it agree with
tests for the same thing, and differ from tests
for different things? http//www.acnp.org/g
4/GN401000076/CH.html
50
face validity - does it look right? poor
criterion - species differences very superficial
and possibly irrelevant features
emphasised http//www.acnp.org/g4/GN4010
00076/CH.html
51
Ethical Issues Peter Singer "Animal Liberation"
(1975). Argues on basis of utilitarian
philosophy - the morality of action depends on
whether it results in pain or pleasure. Whether
an organism's feelings should be considered in
this way depend on the concept of "personhood" -
"A thinking intelligent being that has reason and
reflection and can consider itself as itself, the
same thinking thing, in different times and
places." (from John Locke's Essay on Human
Understanding, 1689). As animals are sentient
beings, then it is species-ist to omit them from
this equation - their feelings count too. Thus a
healthy nonhuman primate could be considered a
person in this sense -- whereas a brain damaged
human infant cannot. "Should the baby live the
problem of handicapped infants" Not all his
views are popular...
52
Ethical Issues Note the alternative
"contractarian" moral view, according to which
only those who have the ability to enter into a
moral contract can be considered within the moral
framework. This would exclude animals from this
analysis. I can agree with my human enemy that
we will not kill each other, but cannot enter
into such an agreement with an animal. So given
they will kill you if they can, is it OK to kill
them? Singer's way of thinking now influences
the legislation on animal experimentation in many
countries, including the UK. Animal suffering is
taken into account when giving permission to
undertake experiments. but remember much
research does not cause suffering
53
Legislative Framework in UK The use of animals
in scientific procedures is regulated by the
Animals (Scientific Procedures) Act 1986, which
is widely viewed as the most rigorous piece of
legislation of its type in the world. Under the
1986 Act, both personal and project licences are
required. These ensure that those doing the work
are qualified and suitable that alternatives to
animals are used wherever possible that the
number of animals used is minimised and that any
suffering or other harmful effects experienced by
the animals have been weighed against the
potential benefits (to humans or animals).
Special conditions control and minimise any pain
or suffering. In addition, work can only be
carried out at designated establishments which
meet high standards and which have suitable
veterinary and animal welfare personnel. http/
/scienceandresearch.homeoffice.gov.uk/animal-resea
rch/animal-testing-faqs/)
54
Legislative Framework in UK If you want to work
on a project involving animals using a protocol
that is classified as an experiment (as mild as
maintaining a rat at less than 85 of its ad lib
body weight) then you must hold a Personal
Licence To obtain one of these you must possess
knowledge of the legislation governing animal
use, and be competent in the relevant procedures,
including euthanasia. To attain this you
must (i) go on a Home Office Training course
(four levels depending on what skills you
need (ii) pass an assessment and exam
55
Legislative Framework in UK In order to be
responsible for a research programme using
animals on a licenced protocol, a researcher must
apply for a Project Licence, which lasts for
five years. To obtain one of these you must go
on another course (1-2 days) and pass an extended
assessment. Then you must submit an application
for a Project Licence. Bottom line is that
project licence holder is legally responsible for
welfare of animals in his experiments.
56
Legislative Framework in UK Project Licence
Application requires the following
information Background of work, objectives
potential benefits Justification of
research project is done on the basis of a
cost-benefit analysis - basically research that
is unpleasant for an animal is only permitted if
there is a very good reason for it.
57
  • Legislative Framework in UK
  • 2. Description of plan of work, including
  • (i) justification of research methods
  • (ii) justification of particular animal model
    employed
  • (iii) explanation of how proposed experimental
    protocols will allow research objectives to be
    achieved
  • (iv) an illustrative experiment
  • (v) explanations of how you are addressing the
    issues of reduction, refinement and replacement

58
Legislative Framework in UK 3. Description of
each experimental protocol employed,
including (i) number of animals ("experiments")
employed (ii) estimate of severity (iii)
precise description of what happens to
animal Following is an excerpt from a project
licence protocol to induce mild food deprivation
(different from what you would impose on a pet?)
59
Food Deprivation schedule Each animal is
weighed, normally daily, and given a restricted
amount of food (approximately 5g of standard
diet this is sufficient to ensure a gradual
decline in body weight so that the target weight
is achieved over no less than seven days.
Thereafter the daily ration is increased to
approximately 5g/100g body weight, so that the
target weight is maintained. In no case is body
weight allowed to fall below 80 of the ad
libitum level of an age- and sex-matched control.
If the animal is not in an experiment, or about
to start one, ad lib food will be
given. Appetitive behavioural training and
testing. Animals receive normally daily sessions
in the operant chambers multiple daily sessions
will be separated by at least an equivalent
period of time in the home cage. The maximum
session duration in a 24-hour period would be 14
hours. For sessions longer than three hours
water will be made available in the chambers.
Two paradigms are used. In instrumental tasks
the animal operates a manipulandum (e.g., a
response lever) for a reward. In classical
conditioning similar rewards are delivered
without any response being required. In both
cases various stimuli or combinations of stimuli
(e.g., auditory, visual or thermal cues, or
contextual cues provided by the experimental
chamber see section 18a) may signal the
occurrence or nonoccurrence of reward. Behaviour
in the presence of these cues is monitored by a
computer and recorded. The maximum duration of
this protocol would be one year.
60
Legislative Framework in UK 3. Description of
each experimental protocol employed,
including (i) number of animals ("experiments")
employed (ii) estimate of severity (iii)
precise description of what happens to
animal (iv) description of possible adverse
effects, likely incidence, and proposed methods
of prevention
61
Food deprivation. Food deprivation procedures
produce weight loss that is monitored by weighing
(normally daily) and regulated by controlled
feeding. The deprivation levels used are enough
to ensure that the animals will work for food
reward and produce no adverse effects (life
expectancy of laboratory rats maintained at 80
ad lib weight is longer than that for rats
maintained on ad lib feeding -- cf., Vitousek,
Gray Grubbs, 2004). As rodents continue to
increase in weight throughout life, the target
weight for experiments that take longer than
three weeks to perform is adjusted for the
projected increase in the 100 weight, at
two-three weekly intervals over the course of the
experiment the projected increase in ad lib
weight is added to the original ad lib weight,
and a new 80 value is calculated. In all cases
the motivation of the animals will be carefully
monitored if their performance is satisfactorily
motivated for the purpose of the experiment with
a deprivation régime bringing the animals to 85
rather than 80 of their ad libitum weight, (a
non-regulated procedure) then this less stringent
deprivation schedule will be employed. Rat
weights are measured to an accuracy of 10g. If an
animal's weight falls below its target level, it
will be fed more than the maintenance ration
until its target weight is re-attained. If this
fails to produce a satisfactory increase in
weight in three days, then veterinary advice will
be sought, or the animal killed by a Schedule 1
method.
62
Appetitive behavioural training and testing.
The behavioural tests employed in this protocol
do not have any adverse effects (and indeed may
be regarded as a form of environmental
enrichment). The only possible adverse effect
is that the animals might become thirsty over the
course of the session. In my experience animals
do not show signs of thirst (i.e. immediate
drinking on return to the home cage) after
shorter sessions (three hours or less).
Accordingly water will be provided in the
chambers for sessions of longer than three hours.
If animals show signs of thirst after shorter
training sessions, then water will be provided in
the chambers for these shorter sessions durations
also.
63
Legislative Framework in UK Most licenced work
must take place in a designated
establishment Conditions of animal welfare -
including cage size, numbers of animals permitted
per cage (depending on animals' weight),
acceptable ranges of temperature and humidity,
are specified. Home Office inspectors can arrive
unannounced at any time to ensure that
legislation is being adhered to. They are
responsible to the Home Secretary that the
establishments under their jurisdiction conduct
research properly. If the project licence holder
violates his licence, the Home Office inspector
is implicated. Thus the Home Office inspector
can shut a lab down if he deems it necessary.
64
Legislation Issues arising Many "experiments"
are realistically not very aversive, and yet are
legislated as stringently as those that
are Transgenic animals are regarded as
experiments regardless of whether you do anything
with them at all. System of licencing based
heavily on the medical model of animal research,
and does not readily accommodate work in
biological sciences, whose focus of interest is
the animal itself Some biologists argue that the
metrics used to estimate animal unhappiness are
not ethologically appropriate
65
Legislation Issues arising Some biologists
(e.g. Barnard, 2007) argue that this approach is
not appropriate cannot replace if you are
studying the animal itself if performing a field
study, reduction may be inappropriate if this
involves disrupting the "ecological integrity" of
the system refinement -- what is unpleasant for
an animal? Complex -- needs to take
reproductive benefit into account e.g. if give
immunosuppressant to male mice, will sleep more
and be less aggressive, as this boosts their
immune system. If introduce female odour, this
protective mechanism overridden.
66
Legislation Issues arising Barnard argue that
as long as animal has the required freedom to act
in accordance with its tendencies, suffering (in
this case immunosuppression) should not be
regarded as bad, because animals will naturally
choose this state in order to increase
probability of mating sometimes counterintuitive
results observed e.g. environmental enrichment
increases aggression, and susceptibility to
infection in mice. But for an alternative
argument see Cuthill, 2007
67
References Harmer, C.J., Phillips.G.D. ,
(1999) Enhanced dopamine efflux in the amygdala
by a predictive but not a nonpredictive stimulus
facilitation by prior repeated d-amphetamine.
Neuroscience, 90, 119-130. Hitchcott, P.K.,
Phillips, G.D. (1998) Effects of intra-amygdala
R() 7-OH-DPAT on intra-accumbens
d-amphetamine-associated learning.
Psychopharmacology, 140, 300-309. Hitchcott,
P.K., Phillips, G.D. (1998) Effects of
intra-amygdala R() 7-OH-DPAT on intra-accumbens
d-amphetamine-associated learning.
Psychopharmacology, 140, 458-469. Parkinson,
J.A., Willoughby, P.J., Robbins, T.W.R.,
Everitt, B.J. (2000) Disconnection of the
anterior cingulate cortex and nucleus accumbens
core impairs Pavlovian approach behaviour
Further evidence for limbic cortical-ventral
striatopallidal interactions. Behavioural
Neuroscience, 114, 42-63. Rhodes, J.S.,
Ryabinin, A.E., Crabbe, J.C. (2005) Patterns of
brain activation associated with contextual
conditioning to methamphetamine in mice.
Behavioural Neuroscience, 119, 759-771. Zhuo et
al., (2007) Early discrimination reversal
learning impairment and preserved spatial
learning in a longitudinal study of Tg2576 APPsw
mice. Neurobiology of Aging, 28, 1248 -1257
68
References Barnard, C. (2007) Ethical
regulation and animal science why animal
behaviour is special. Animal Behaviour, 74,
5-13. Boakes, R (1984). From Darwin to
Behaviourism. Cambridge University
Press. Boring, E.G. (1950) A History of
Experimental Psychology. New York
Appleton-Century-Crofts. Cuthill, I.C. (2007)
Ethical regulation and animal science why animal
behaviour is not so special. Animal Behaviour,
74, 15-22. Dickinson, A. (1980) Contemporary
Learning Theory. Cambridge University
Press. Hilgard E.R Bower, G.H. (1966) Theories
of Learning New York Appleton-Century Crofts.
Singer, P. (1975) Animal Liberation A New
Ethics for our Treatment of Animals, New York
Review/Random House, New York.
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