Latent Inhibition & Schizophrenia

Question 1

Schizophrenia background

Answer 1

Schizophrenia is a serious mental disorder, characterised by hallucinations and delusions
Dopamine (DA) is implicated based on evidence that
(1)DA agonists can induce schizophrenic-like symptoms
(2)Schizophrenia is treated with DA antagonists

Question 2

Better drugs are needed to treat SZ

Answer 2

• Cases worldwide: 24 million
• Lifetime risk: 2-10 per 1000
• Poor prognosis (< 25% recover; 20-30% don’t respond at all to existing drugs)
• Existing drugs mostly ineffective for negative symptoms
• Unacceptable incidence and severity of side effects
• Suicide risk: 10%, 25% sufferers attempt

Question 3

Cognitive and attentional problems in SZ

Answer 3

• “The basic cognitive defect… is an awareness of automatic processes which are normally carried out below the level of consciousness” (Frith, 1979)
• Schizophrenics show a “failure of attentional focusing to respond to stimulus redundancy” (Maher, 1983)
• “Schizophrenics are less able to make use of the redundancy and patterning of sensory input” (Hemsley, 1987)
• Schizophrenics “concentrate on detail at the expense of theme” (Cutting, 1985)

Question 4

Amphetamine psychosis (Griffith et al. ,1972)

Answer 4

Participants (n = 7) users but no prior history of psychosis
Given 10 mg dextroamphetamine every hour for up to 5 days
All became psychotic within 2-5 days
Delusions mostly auditory, also included poisoning by experimenters and electric dynamo thought control

Question 5

Pro- and anti-psychotic drug actions

Answer 5

Amphetamine is psychotomimetic
Amphetamine is an indirect dopamine (DA) agonist
Typical antipsychotics are DA D2 antagonists (e.g. haloperidol)
Atypical antipsychotics have different DA D2 affinity, block also D4 and 5-HT2
D1 agonists to boost DA hypo-function in frontal cortex? (Goldman-Rakic, 2004)

Question 6

How the model came about and continues to develop…

Answer 6

Better drugs are needed for schizophrenia (SZ)
SZ is characterised by attentional problems, some of which can be measured in animals
Amphetamine is a drug model for SZ

LI is impaired in SZ and by amphetamine
Model extends to studies of individual differences (psychoticism, schizotypy)

Rat model is now used to identify neural substrates
Effects on LI are compared to those seen using other methods to weaken associative learning

Question 7

Latent inhibition (LI)

Answer 7

Pre-exposure (PE) Control (NPE)
Stage 1: CSa->nothing [CSb->] nothing
Stage 2: CSa->US CSa->US

Stimulus pre-exposure (in stage 1) reduces later learning (in stage 2) when the stimulus is now relevant
LI can apply to both excitatory and inhibitory stimuli, i.e. LI of a potential inhibitor

Question 8

Basic experimental design for LI

Answer 8

• Degree of LI assessed by comparing learning in PE and NPE groups
• Follow-up test of associative learning
• Experimental effects (of drug or lesion treatments or in different patient populations) can be measured in 2 x 2 designs
• Degree of LI is assessed by comparing PE and NPE groups in each experimental condition
• Comparing NPE groups to determine effects on conditioning

Question 9

LI in rats is abolished under amphetamine

Answer 9

Suppression ratio

0.5 = no learning

Question 10

Testing for LI in human participants

Answer 10

• Methods first developed in Lubow’s laboratory
• Task should not be too obvious
• US = counter increment
• Task to work out which of a series of nonsense syllables (e.g., pev, jic) predicts the counter increment
• CS in fact a white noise

Question 11

. LI deficits in participants with SZ

Answer 11

• Link between the loss of LI and SZ shown using the counter increment variant (Baruch et al., 1988)
• LI is reduced or abolished in acute (but not chronic) SZ
• Since the failure of LI is expressed as a relative learning increase, it can’t be due to non-specific features of the disease process

Question 12

Translational evidence

Answer 12

•Amphetamine treatment abolishes LI in ‘normal’ human participants
(single 5 mg dose, Gray et al., 1996)

•Haloperidol can reduce LI in humans (Williams et al., 1997, 1998)
•But any beneficial effect might be expected to depend on baseline DA activity
•Haloperidol effects in healthy humans depend on Psychoticism scores
(single 5 mg dose, Kumari et al., 1999)

Question 13

Haloperidol effects depend on P

Answer 13

Kumari et al 1999

Question 14

Measuring schizotypy in normal participants (O-LIFE)

Answer 14

• Are the sounds you hear in your daydreams really clear and distinct?
• Do your thoughts sometimes seem as real as actual events in your life?
• Does it often happen that nearly every thought immediately and automatically suggests an enormous number of ideas?
• Do you believe in telepathy?
• Are your thoughts sometimes so strong that you can almost hear them?
• Do your thoughts ever stop suddenly causing you to interrupt what you are saying?
• Do you think you could learn to read others’ minds if you wanted to?

Question 15

LI reduced with schizotypy

Answer 15

Shrira & Kaplan, 2009
Two procedures (1) without masking and (2) with masking

Question 16

Low latent inhibition featured in Prison Break

Answer 16

a fictional character and one of the two main protagonists of the American TV series Prison Break.
As the principal character, Michael has been featured in every episode of the series…

Michael has been clinically diagnosed with low latent inhibition, a condition in which his brain is more open to incoming stimuli in the surrounding environment. As a result of this condition, he is unable to block out periphery information and instead processes every aspect and detail of any given stimulus. This, combined with a high IQ (as a psychiatrist explains) theoretically makes him a creative genius.

Question 17

19. Translating back to animal models

Answer 17

• Loss of the “selectivity which normal attention ordinarily exercises among the sensory impressions” (Bleuler, 1911; Hemsley, 1987, 1993; Gray et al., 1991; Kapur, 2004)
• Core deficit suggests use attentional measures, e.g., LI
• Low LI = openness to environmental stimuli irrespective of their past significance
• Rat model to tell us which neurotransmitter systems and brain structures are important
• Translational research, with humans too..

Question 18

LI in rats is modulated by

Answer 18

Amphetamine

Haloperidol

Question 19

Brain circuitry of interest (Cassaday & Moran, 2010)

Answer 19

LI is reliably reduced by excitotoxic lesions to the shell region of nucleus accumbens

Question 20

Other selective learning tasks (Cassaday & Moran, 2010

Answer 20

Rescorla-Wagner (1972)
: reflects salience of CS
•Schizophrenics show a “failure of attentional focusing to respond to stimulus redundancy” (Maher, 1983)
•“Schizophrenics are less able to make use of the redundancy and patterning of sensory input” (Hemsley, 1987)

Question 21

Systemic amphetamine abolished LI not overshadowing

Answer 21

Nelson, A.J.D., Thur, K.E., Marsden, C.A. & Cassaday, H.J. (2011). Dopamine in nucleus accumbens: Salience modulation in latent inhibition and overshadowing. Journal of Psychopharmacology, 25, 1649-1660.

Question 22

Amphetamine in nucleus accumbens core abolished LI

Answer 22

Nelson, A.J.D., Thur, K.E., Marsden, C.A. & Cassaday, H.J. (2011). Dopamine in nucleus accumbens: Salience modulation in latent inhibition and overshadowing. Journal of Psychopharmacology, 25, 1649-1660.

Question 23

Theoretical framework

Answer 23

Cassaday & Moran, 2010
D1 agonists based on known therapeutic effects? OR
D1 antagonists based on direction of effects in overshadowing?

Question 24

makes sense to restrict learning to events that are

Answer 24

likely to indicate the causes of important events
•Some are irrelevant (as in LI)
•Amphetamine mimics the dopaminergic hyperactivity seen in schizophrenia
•LI is reduced in both humans and rats under amphetamine
•LI is reduced in human participants with SZ or high schizotypy scores
•LI is a translational model for aspects of schizophrenic attention deficit