Conference 2002

Workshop I
Workshop II
Workshop III
Workshop IV
Final Group Discussion and Summary
Schedule

Photos of the June 2002 Meeting

Workshop IV: Translational and Cross-Disciplinary Integration
Chair: S. Grant; Scribe: R. Kortekaas; Spokesperson; M. Delgado

SG: intro: How should we translate back and forth between any of the fields of clinical observations, anatomy, function and animal experimentation?

We only discussed these two questions:

1. IS DEPRESSION AN ACTIVE STATE?
C: Depression is a group of syndromes, some patients are anxious and active, others sad and passive.
C: When looking at animal models e.g. forced swim test, they suggest that depression is a loss of an active coping response. [A brief discussion about the validity of animal tests follows.]
SH: Mother-infant separation in non-human primates is a good depression model. Here we don't see passivity in the infant.
[Comment about maternal deprivation in rats, but we agree that this is a completely different model.]
JF: The effects of reserpine resemble depressive symptoms.
RK: Yes they do, but should we conceptualise depression as a disorder of incentive or consummatory neural processes i.e. do patients initially stop wanting or enjoying? Or maybe they stop wanting because they don't enjoy?
SN: So if we remember that reserpine potently reduces dopamine function in the brain and also that dopamine is involved in responding to reward-indicating cues, maybe depression is merely that lack of responding to reward cues.
C: And an accentuation of responding to negative cues!
SG: Normal people were found to have an unrealistic bias towards the positive, while depressed people are more realistic.
C: If this dopamine theory is true, why is the accumbens never implicated in models and theory about depression?
C: It ought to be.
C: The cortex is more important.
JF: What about the autonomous nervous system in depression?
C: It is roughly normal.
SH: The way to go is to start with a primate model, because we know that these animals can develop real depressive symptoms. Then this should be transferred to rats.
C: Recovery from depression may lead to suicide. Also sleep may improve first, then eating patterns normalise and finally mood is improved. So we're looking at different systems with varying sensitivity.
SG: We need to lose these self-report measures like Hamilton if we intend to do drug screening.
JF: What good monkey model could we use for depression?
SH: Show the monkey pictures of other monkeys. If there is a shift in responding towards negative responses e.g. aggressive grimacing to a picture of an infant, this could indicate a depression-like state.
Gr comments on the involvement of the 5-HT system in depression.
C: Why not use a depression model in an animal and record units from VTA or Acb while the animal responds to various stimuli?
SG: Or is depression an inability to switch between emotions?
C: But in bipolar affective disorder there is too much switching.
SH: What is actually the difference between major depression and the depressive state in bipolars?
SG appeals to the clinicians to keep us realistic, since we know no better.
C: Clinically it looks the same, but from twin studies, genetic studies and population studies there is evidence that the mechanism is probably different.
C: The response to antidepressants is different in bipolars and major depressive disorder: the formers only switch faster while in the latter mood improves towards normalcy.
SN: Maybe DA is for the short-term switching and 5-HT for longer term emotional switching.
SG: If rats, after an aversive event, take longer to start responding for a reward (e.g. nose-poking), this may be a good depression model.
Gr: Phosphoinositide response to anti-bipolar drugs is on a similar time scale as the mood response.
SG: But what is the connection? […] Affective perseveration?
RK: This could very well be the case, since all cortico-striato-thalamo-cortical (CSTC) loops are organised similarly irrespective of whether they deal with motoric, limbic, cognitive or oculomotor domains. Depression could be much like the classical frontal perseveration syndrome, but then in the limbic domains.
MK: Parkinson's patients show depression and motor perseverance in addition to the classic cognitive perseverance (card sorting). Since they have a lack of dopamine, this may be prerequisite for any switching of activity in CSTC loops.
SG picks up the 'vague' hypothesis launched by SN: maybe the biogenic amines only differ in time scale but not in function.
JF: The amygdala habituates easily to happy faces, but not to sad ones.
LP: is there a transmitter or structure that is tightly bound to sadness?
C: TMS has implicated the prefrontal cortex.
C: Subgenual cingulate cortex.
C: Amygdala!
C: Just below the STN there is an area that, when stimulated, produces intense sadness.
SN: Is L-DOPA effective in relieving a non-parkinsonian depression?
C: No, none of the dopaminergic drugs have any beneficial effect on non-parkinsonian depression.
SG: bingeing on food or drugs can also be seen as perseveration.

4. WHY ISN'T BASIC RESEARCH INTO DRUG ADDICTION INFORMING THE HUMAN CONDITION (TREATMENT, CRAVING, ETC)?
SN: One of the main reasons may be that we rely too much on self-administration and that the mechanisms behind this are entirely different from human addiction.
JF: Heroin can be replaced by methadone, is there something similar for cocaine?
NM: Amineptine!
SG: Yea, but it doesn't work, though.
SN: How does methadone work anyway?
Gr: It's a partial agonist, right?
RK: It's actually a full opioid agonist with the same euphoric effects and addictive potential as heroin itself. These are only dampened by its slow absorption resulting from oral administration.
Gr: Do people show sensitisation to the effects of stimulants like we see in rat locomotor activity?
SG: No.
C: When cocaine self-administering rats are abstained and then reinstated, they use more cocaine than before.
SG: In the early days rats' relapse could only be induced by stress. Later they found that certain cues could also induce it. Finally a prolongation of the abstinence period turned out to produce a very high rate of reinstatement.
C: A recent paper in J.Neurosci. showed that the incentive value of a drug increases with duration of abstinence.
SG: Are there any clinical correlates to this observation?
C: There may be a correlation between LMA sensitisation and relapse.
[JM and SG exchange comments about the self-administration model]
LP: Drug taking is not always coupled to the intention to feel good.
C: Exactly: as addiction progresses, the motivation to use increases while pleasure drops.

FORMULATE A QUESTION/ISSUE FOR PLENARY MEETING ON TUESDAY MORNING JULY 2.
Is the concept of perseveration useful as an alternative angle on depression, bipolar mood disorder, ADHD and addiction?

C: comment by unnamed participant, Gr: Steve Grace, JF: Julie Fudge, JM: J. McGinty, LP: L. Peoples, MK: Martijn Keitz, NM: N. Mercuri, RK: Rudie Kortekaas, SH: Susanne Haber, SG: Steve Grant, SN: Saleem Nicola

Workshop IV (Group C): Translational and Cross-Disciplinary Integration
Chair: D. Van der Kooy; Scribe: S. Totterdell; Spokesperson; J. M. Deniau

The group focused on: Why isn't basic research into drug addiction informing the human condition (treatment, craving etc.)

Attempting to identify therapies developed in the past 10 years, a number of suggestions were cited from the animal literature.
· CRF antagonists block withdrawal symptoms (Koob et al.,)
· Alpha-2 agonists block stress-induced relapse (Jane Stewart)
· Partial D1 agonists & 5-HT2A/C antagonists block craving, measured as the blocking of cocaine-induced motor sensitisation
· Drugs acting on the dopamine transporter are of interest as they display prolonged effects that peak about 96h after administration
· Cannabinoid receptor antagonists are believed to be undergoing testing in primates

Does block of craving have any clinical relevance with respect to relapse?
· There appear to be no compounds that block craving in animal trials that are suitable for administration to humans so this cannot be addressed.
· The use of Naltrexone was mentioned: alcoholics on Naltrexone still drink but not as much.

How do you measure success in the treatment of addicts?
· In cancer care, survival for an additional 5-10 years is considered a valuable intervention
· In comparison, is an addict 'treated' if they are restored to being able to function in society (work, maintain healthy relationships, refrain from violence)?

In this context, methadone treatment is successful. Nevertheless, there is a moral and social dimension to attitudes to the treatment of addicts. Even more than for cancer in smokers, individuals are blamed for their dependent state and criticized for lacking the will-power to stop drug-taking.

This might be addressed by understanding whether drug addiction is a disorder of affect or motivation or both (Question 2).
· Depression may be a disorder of motivation and affect.
· The motivational element is possibly very important in young people suffering from depression who find it hard to initiate a behaviour that might produce a pleasurable outcome.
· Is it that addicts need something to do to replace drug taking? Those addicts who really need treatment are those whose whole life is spent seeking more drugs.
· There may be a difference between addicts who are self-motivated to recovery and those who are not. They do not appear to suffer any less, as a group, from withdrawal symptoms but they are motivated to persevere.

The group moved on to consider if addiction is primarily liking or wanting or whether learning is more important. It was thought difficult to disentangle learning deficits from motivational deficits. Points made include:
· Motivation is innate but testable
· Are anhedonic people predisposed to drug addiction, making their behaviour a form of self-medication?
· Does motivation, focusing (pathologically) on drug acquisition, or the anhedonic state drive addiction? The consensus was that this is different in different addicts.
· A common cause for addiction may be the need to 'feel better' and addiction is then a maladaptive learning of how to do this.
· In people who do not become addicts there are competing motivations that focus behaviour on other goals or other means to achieve the goals.
· However, once addicted, the hedonic response is reduced. Do addicts continue to take drugs to avoid the ensuing 'down' state provoked by withdrawal from the drug? This anhedonic state can last weeks after withdrawal from a drug.
· Craving is different, being more associated with learned cues of situations in which drug taking has taken place and the hedonistic response has been experienced

The answer to Question 2 was BOTH.

However, addiction may reflect habit without either motivation or improved affect and learning this habit may be 'better' with drugs than with natural reinforcers. Nevertheless, to drive a craving so strong that it interferes with other aspects of life may require some affective change.

The discussion around this question moved to smoking and addiction.
· Tobacco is very addictive but multiple cigarettes in a day do not all produce a hedonic response
· Nevertheless, each cigarette follows a period of withdrawal, reinforcing the notion that smoking 'makes you feel better'. Each smoker experiences this thousands of times. Is the addiction also linked to a search for the high that follows the first cigarette of the day?
· Smoking is also a cued behaviour. At the end of a meal, or in a bar, you need a cigarette but on an aeroplane, where smoking is not possible, craving is apparently absent.
· The importance of the 'high' was questioned since ex-smokers still crave a cigarette, despite 'knowing' that is will taste awful.

NB self-reporting of state is notoriously unreliable, especially if retrospective.

We moved on to discuss whether there are common mediators of addiction pathways that could lead to therapies that might be beneficial as early interventions, preventing the learning of 'pathological' associations.
The criteria for such a therapy is that it should:
· Be readily accessible and instant
· Produce a positive affective response
· Be under the control of the subject.

Is there a genetic predisposition for compulsion?
· There are distinct behavioural profiles for different drugs, but there is evidence for predispositions and for some co-morbidity of drug taking with other disorders.

Addiction eventually undermines judgement producing a compulsive state. In that case why do SSRIs treat Obsessive-Compulsive Disorder (OCD) but not addiction?
· A compulsion was defined by reference to an intrusive itch. The desire to scratch it can be resisted by cognitive control but the pull to do it becomes overwhelming, producing a brief period of relief (improved affect?), even if the physical experience is unpleasant.
· In addiction you get transient relief on taking the drug but very rapidly there is a return of the 'sensation'.
· Orbito-frontal cortical (OFC) circuitry and the striatum are implicated in OCD but not, apparently, in addiction.
· Nevertheless, on withdrawal of the drug, acutely there is an increase in OFC activity but over time this is replaced by a hypoactivity which can last for weeks (measured by 2-deoxy-glucose metabolism).

What brain structures underly relapse?
· The striatum has been implicated in relapse.
· In cue-induced relapse there are roles for PFC and amygdala since muscimol or lidocaine in the mPFC prevents reinstatement of drug taking.
· Nevertheless, flupenthixol given to humans does not treat craving, but this may be because it was administered peripherally rather than locally.
· Gaps in our knowledge of this field in humans remain since early imaging studies, which suffered from poor spatial resolution, have not yet been repeated.
· Perhaps in the pathological state, the PFC has been hi-jacked to display an exaggerated response to drug-taking cues, although there is no evidence for an increase in activity in resting states.
· In support of this idea, drug addicts are intolerant antipsychotic drugs finding them extremely anhedonic.

Discussion moved to adaptive and maladaptive aspects of stress responses (Question3).

· Human beings evolved to be part of small (familial) groups which afforded them a degree of security. Rejection by this group was a greater threat to survival than the threat of individual predators.
· Hence social pressure to conform is still a very strong influence on behaviour.
· With respect to the question, stress is a good adaptation from an evolutionary viewpoint, but society has changed. Children these days are often brought up in smaller groups without the large supportive network which was probably more normal in the distant past.
· Sleeplessness due to anxiety is regarded as a maladaptation, but in the past this may have been a positive feature so that predators could not catch you unawares.
· Maladaptations to stress may include: depression, drug taking, OCD but ulcers and heart disease are probably more of a threat to survival.
· With respect to OCD, new parents (human) are found to be quite compulsive about the care of their offspring, with regard to frequency with which parents report thinking about their child during the day but this could be interpreted as a positive adaptive response.
· Similarly in new relationships, thoughts stray to the new partner. There are physiological changes when pairs bond. In voles, pairing results in increased release of oxytocin and in its receptors. Oxytocin levels are also increased at parturition. It is not clear if this is related to some adaptive change.
· However, there is no real evidence a role for oxytocin in OCD.

We briefly touched on the brain regions and neurotransmitters that might be implicated in all of these responses and the usual candidates, PFC and catecholamines, were mentioned.