the role of serotonin in compulsive behavior in humans: underlying brain mechanisms

Conditions: Obsessive-Compulsive Disorder/High Compulsive Individuals; Healthy Individuals

Summary: 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.

Eligibility criteria:
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).

Keywords: serotonin cognition emotion neural activation