Animal models in psychological disorders

Question 1

What makes an animal model valid?

Answer 1

Face validity - does the model look like the disorder? are the symptoms equivalent?
Predictive validity - can the model predict effective treatments for the disorder? Hard to test if no treatments have progressed to clinical trials
Construct validity - Does the model have the same functional basis as the disorder? Same mechanisms? Same neurological and psychological basis, at least for the aspects you’re trying to address?

Question 2

What is PTSD?

Answer 2

The prototypical example of maladaptive memory disorder.
Caused by witnessing or experiencing an event involving threat of death, actual or threat of serious injury, or injury to the physical integrity of self or others. The event normally causes intense fear, horror or hopelessness.
50% of female and 60% of male survivors of sexual assault develop PTSD.
Gold standard treatment is cue-exposure therapy

Question 3

Diagnostic criteria of PTSD

Answer 3

For at least one month after event:
1. Re-experiencing the traumatic event - recurrent and invasive memories, nightmares, flashbacks, psychological and physiological distress in response to stimuli associated with the event
2. Avoidance - refusing to talk about the event, avoiding stimuli associated with the event, inability to remember aspects of the event, reduced range of affect, disinterest in life, detatchment from other people, sense of a foreshortened future
3. Persistent increased arousal - sleep problems, difficulty concentrating, increased startle
((4. negative alterations in cognition and mood - amnesia for the trauma, anhedonia))

Question 4

Conditioning account of PTSD

Answer 4

Keane et al 1985 - during the event itself, an association is formed between stimuli involved and the fear experience. This part can be adaptive. But because of the intensity of the fear response, there is generalisation of the CS to other stimuli and contexts, which becomes maladaptive. This generalisation causes hypervigilance and hyperarousal. The avoidance behaviour ensures that extinction cannot occur.

Question 5

Alternative account of PTSD

Answer 5

Brewin 2001 - there are two types of memory, ‘verbally accessible’ (episodic, hippocampus-dependent) and ‘situationally accessible’ (emotional, amygdala dependent). In high emotional intensity, the hippocampus is essentially inactive and the amygdala is super active, so memories are preferentially encoded in the amygdala. These emotional memories have no involvement of time, and are not context dependent, so are preferentially retrieved when similar cues or stimuli are later experience (generalisation).

Question 6

Why is it hard to cure PTSD?

Answer 6

Bouton and Bolles 1979 - Renewal - if you put conditioned and extinguished rats in a new context, the conditioned fear comes back. Happens regardless of ABA, ABC, or AAB patterns of conditioning, extinction, test context. Thus context-dependence of extinction must be stronger than that of conditioning. Happens even when extinction is really strong. True for ‘interoceptive contexts’ too, cf state-dependent learning.
Spontaneous recovery - if you leave extinguished PTSD patients for a while, the fear comes back. This may be the renewal effect, but using temporal context rather than spatial/interoceptive.
Reinstatement - reexposure to the US and then testing of the extinguished CS in the same context leads to reinstatement. THere is no reinstatement if you expose to the US in an irrelevant context then test the CS again in a different context. This suggests it’s another type of context-conditioning.

All of these boil down to - extinction is not unlearning. The original fear memory is still there.

Question 7

PTSD - What animal models do we have? Are they any good?

Answer 7

Single Prolonged Stress
Predator Scent Stress
Stress Enhanced Fear Learning
Pavlovian conditioning

Measures of PTSD include elevated plus maze, enhanced startle.

BUT none of these can assess cognitive impacts.

Question 8

PTSD - Cue-exposure therapy

Answer 8

Exposure to the CS with no aversive outcome, typically while using relaxation techniques so the patient can manage stress.
d-cycloserine increases efficacy and duration of extinction, in people where extinction therapy works.

BUT renewal etc
Craske et al 2014 - The patient may develop an association between e.g. the therapist and safety, so the extinction only holds in the therapy context.
Cue-exposure therapy only works for 50% of patients

Question 9

PTSD - Disruption of memory consolidation

Answer 9

Consolidation ultimately requires protein synthesis, but PSIs are inappropriate for routine use in humans.
Quevedo et al 1999 - administering anisomycin immediately prior to or 3 hours after inhibitory avoidance training leads to amnesia (but not immediately of 6 hours after).

The noradrenergic system is thought to enhance consolidation of emotional episodic memories over neutral episodic memories.
Pitman et al 2002 - administering propanolol for 10 days starting within 6hrs of a traumatic event reduced PTSD score 1 month later

But either way, you’d have to get to everyone exposed to the traumatic event within 6 hours, and you’d be treating people who would never go on to develop PTSD

Question 10

PTSD - Disruption of memory reconsolidation

Answer 10

Pitman et al 2002 - Took people who’d just undergone trauma, gave some propanolol and some placebo. Messy data (perhaps because some of the placebo group would never have gone on to develop PTSD), but suggested propanolol reduced PTSD incidence one month later.
Debiec and leDoux 2004 - either systemic or intra-amygdala propanolol given in conjunction with memory reactivation persistently reduced fear to the CS and prevented the reinstatement of fear by presentation of the US. When the same was done but without memory reactivation, there was no difference between propanolol and saline. So it disrupted memory reconsolidation but not consolidation.
Brunet et al 2008 - PTSD patients were reactivated with a self-generated trauma script. Three groups: reactivated placebo, non-reactivated propanolol, reactivated propanolol. The latter group had reduced SCR and cardiovasc response to subsequent CS exposure, but no reduction in frowning - so they could remember the association, but not the fear of it.
Kindt et al 2009 - Took healthy humans, conditioned scary pictures with electric shock. CS-reexposure plus propanolol reduced fear on re-presentation of the stimulus.

Question 11

Retrieval-extinction aka superextinction aka extinction within the reconsolidation window

Answer 11

Instead of creating a competing CS-noUS memory that competes with CS-US, you replace the CS-US with CS-noUS. It’s a drug-free method, you make the memory labile (by reactivating it), then give repeated exposure to the CS without the US, so that the reconsolidated memory is CS-noUS rather than CS-US.
Monfils et al 2009 - fear-conditioned rats, retrieved the memory, then gave extinction either inside or outside the lability (6hr) window. All groups had the same freezing to CS after 24hrs, but only those that were extinguished within the lability window had reduced freezing one month later.
Shiller et al 2010 - repeated in humans, lasts up to a year

BUT there have been some failures to replicate

Question 12

Interfering with consolidation or reconsolidation of CS

Answer 12

Assuming Brewin’s account is correct, the problem in PTSD is the situationally accessible memories. These should be preferentially disrupted by visuospatial concurrent task.
James et al 2015 - induced flashbacks of traumatic film clips. These were reduced by reactivation then Tetris.
Holmes group - shown that traumatic memory consolidation can be interfered with by Tetris in road traffic accident patients in A&E and in women who’d just had emergency C sections

Question 13

Substance use disorder - what is it?

Answer 13

Aka drug addiction aka substance dependence. Mst exhibit 3 of 7 criteria:
1 - use of drug in larger amounts or over a longer time than intended
2 - persistence desire or unsuccessful attempts to reduce intake of drug
3 - continued use of drug despite adverse consequences
4 - spending a lot of time obtaining, using or recovering from the drug
5 - giving up social or occupational activities in order to spend more time using the drug
6 - drug tolerance
7 - drug withdrawal

Alternatively: Loss of control, high motivation for drug, persistance despite negative consequences, physiological adaptations.

Question 14

SUD - why is it hard to treat?

Answer 14

Easy to get someone to give up the drug, hard to prevent relapse
50% of those who detoxify in professional rehab will relapse. 75% of those who detoxify in prison.
Disulfiram is fine, but requires administration (poor compliance)

Cue-induced relapse occurs in rats after extinction or forced abstinence

Question 15

SUD - maladaptive conditioning theory of addiction

Answer 15

1 - Drugs of abuse increase dopamine in limbic corticostriatal system
2 - Striatonigrostriatal spirals of dopamine pathway enhance consolidation
3 - Habits, or ‘stimulus-response associations’ are formed
4 - Pavlovian conditioning to stimuli and contexts associated with the seeking and taking of the drug, forming CS-drug associations
5 - These CSs activate limbic system, cause craving and relapse.

So it’s hijacking adaptive instrumental and pavlovian conditioning (normally needed in the wild so we remember where the berry bush is etc)

Question 16

Animal models of SUD

Answer 16

Conditioned place preference - experimented administered drug is associated via training with one compartment of a two-compartment cage, then the rat’s preference for that compartment is tested. BUT the drug administration is non-contingent, and usually administered less than 4 times.
Intra-Venous Self Administration - Rats have a chronic indwelling catheter, and perform an instrumental action to get a shot of the drug, with a ceiling to prevent OD. Often the instrumental action is paired with a pavlovian cue, e.g. a light comes on, so better construct validity. Self-administration is key.

Question 17

Three routes to relapse

Answer 17

Everitt et al 2001 review:
1 - conditioned approach - animal involuntarily approaches a CS associated with the behaviourally noncontingent presentation of an appetitive reinforcer. Dependent on dopaminergic signalling in CeN.
2 - conditioned reinforcement - the CS becomes a secondary reward, capable of supporting the acquisition of a novel skill. Also allows maintenance of motivation over an unpredictable or long interval between stimulus and reward. The reinforcer is resistant to extinction and maintains its value even when the primary reward has been devalued. Dependent on BLA.
3 - conditioned motivation - same as PIT. ‘Potentiates instrumentalactions’. Specific requires BLA, general requires CeN.

Question 18

Pharma interventions for SUD

Answer 18

Milton et al 2008, 2010 - NMDAR antagonist MK-801 impairs conditioned approach (rats approached CS+ and CS- nondiscriminatively), abolishes conditioned reinforcement (rats that received MK-801 just before reactivation NEVER learnt to lever press for the reinforcer), and impairs conditioned motivation (rats pressed the alcohol-lever as much without as with the alcohol-cue).
Propanolol only disrupted conditioned reinforcement.

Abstinent addicted rats given MK-801 before relapse have a less severe relapse - they still lever press for CS+ more than CS-, but not by as much. Propanolol had no effect.

Lonergan et al 2016 - Giving humans propanolol at reactivation reduced cravings, but sample sizes small and error bars huge and no non-reactivation control group

Saladin et al 2014 - propanolol reduced subjective craving measures and physiological responses to cocaine-related cues 1 week later, but not enough power to look at real-life cocaine use

Bernardi et al - betablockers disrupt CS-drug association underlying place preference for drug.

Lee et al 2005 - knockdown of zif268 disrupts conditioned reinforcement

Question 19

Summary of which drugs affect which relapse route

Answer 19

Conditioned reinforcement - beta blockers, NMDAR antagonists, zif268 knockdown

Conditioned approach - NMDAR antagonist

Conditioned motivation - NMDAR antagonist

There’s been less work on the latter two because they’re harder to study with IVSA - Kearns and Weiss showed that rats do not sign-track for IV cocaine.
Studies looking at propanolol and craving/relapse in humans have had mixed results, possibly because of differences in reactivation protocol - Xue et al 2017 found subjects needed to smoke 2 cigs in 10 mins to sufficiently reactivate+destabilise memories for propanolol to have an effect.
Most studies find NMDAR antagonist more effective at disrupting drug memories than propanolol, but Wouda et al showed that propanolol was more effective at preventing reinstatement after a long post-training window.

Question 20

Non-drug potential SUD treatments

Answer 20

Superextinction - Xue et al 2012 daily retrieval of drug-associated memories 10 mins or 1 hr but not 6 hrs before an extinction session reduced reinstatement, renewal and spontaneous recovery. Heroin addicts that retrieved memories 10 mins before extinction session had reduced craving to CSs up to 180 days later
Germeroth et al 2017 - same shown in nicotine addicts
Counter-conditioning in the reconsolidation window - shown effective for alcoholics. Violate expectation, then associate alcohol CS with a bitter drink or aversive image.

Disruption of instrumental drug-seeking memories - we used to think instrumental memories don’t reconsolidate, but recent work in rodents suggests otherwise. Exton-McGuinness et al 2014 showed that it requires switching from a predictable to a less predictable reinforcement schedule, rather than simply performing the action with no reinforcement (equivalent to pavlovian reactivation session)