The Role of Serotonin in Compulsive Behavior in Humans: Underlying Brain Mechanisms

The Role of Serotonin in Compulsive Behavior in Humans: Underlying Brain Mechanisms

The aim of this project is to investigate:

• The status of the central serotonin (5-hydroxytryptamine, 5-HT) system in compulsive behaviour and how it is affected by sub-chronic escitalopram administration
• The mechanisms underlying how sub-chronic administration of escitalopram affects the central 5-HT system
• How changes in cognitive performance, including the balance between habitual and goal-directed mechanisms, are affected in compulsive behaviour by boosting 5-HT function
• How functional brain changes in cognitive function measured with magnetic resonance imaging relate to altered 5-HT function following escitalopram administration.

Previous studies have shown that 5-HT is strongly implicated in compulsive behaviours in experimental animals. Manipulation of 5-HT influences neuronal interactions underlying action selection. Reduced forebrain 5-HT causes perseveration and impairs goal-directed behaviour under reward but not punishment. Dysfunctional 5-HT neurotransmission has also been implicated in Obsessive-Compulsive Disorder (OCD) based on the selective efficacy of relatively high doses of selective serotonin reuptake inhibitors (SSRIs) in treating this disorder. Hitherto, it is unknown whether there is a primary defect in the serotonergic system or whether SSRIs ameliorate symptoms by modulating other brain neurotransmitter pathways. So far, only one study of central 5-HT release in OCD patients has been conducted and its methodology may be questioned.

A number of behavioural and cognitive features of OCD, including endophenotype markers that appear to characterise the disorder have been determined. These include a shift in cognitive control from a goal-directed strategy to a habitual (stimulus-response, S-R) strategy, cognitive rigidity in terms of both reversal learning and attentional set-shifting, impaired response inhibition and planning, and a tendency to over-respond to spurious negative feedback in a probabilistic learning paradigm. Neural substrates of these deficits are being investigated using brain imaging methodologies based on magnetic resonance and preliminary evidence suggests an over-active medial prefrontal cortex-caudate nucleus circuits and underactive lateral prefrontal cortex-putamen circuits. However, little evidence exists that relates to the hypothesis of an over-active habit system in this disorder or to the role of serotonin in all these cognitive and behavioural deficits observed in OCD and compulsivity in general.

Inclusion Criteria:

• Individuals with high scores on obsessive-compulsive traits (with or without a diagnosis of OCD established by a psychiatrist) and healthy volunteers (male or female) between 18 and 70 years. Compulsive individuals without an OCD diagnosis are individuals without a history of psychiatric or other major medical conditions but scoring abnormally high on the Obsessive-Compulsive Inventory (OCI) questionnaire.

Exclusion Criteria:

• Current or previous neurological disease, severe somatic disease, or consumption of medical drugs likely to influence the test results
• Non- fluent in Danish or pronounced visual or auditory impairments
• Current or past learning disability.
• Pregnancy
• Lactation
• Participation in experiments with radioactivity (> 10 mSv) within the last year or significant occupational exposure to radioactivity.
• Contraindications for MRI (pacemaker, metal implants, etc.).
• Allergy to the ingredients in the administered drug.
• Abnormal ECG (e.g. prolonged QT syndrome).
• Dizzy when changing from supine to upright position (e.g. postural orthostatic tachycardia syndrome).
• Mild hypotension (blood pressure below 100/70 mmHg) or hypertension (blood pressure above 140/90 mmHg).
• Head injury or concussion resulting in loss of consciousness for more than 2 min.
• Alcohol or drug abuse
• Drug use other than tobacco and alcohol within the last 30 days.
• Hash > 50 x lifetime.
• Drugs > 10 x lifetime (for each substance).
• Current medication with serotonergic acting compounds. Use of other psychoactive substances must be stable at least one month prior to inclusion and maintained throughout the study.
• Severe physical impairments affecting eyesight or motor performance.
• For the OCD group: other Axis I mental disorder as primary diagnosis according to ICD-10 criteria.
• For healthy volunteers: any current or former primary psychiatric disorder (Axis I WHO ICD-10 diagnostic classification).