Serotonergic Modulation of Cognition, Emotion and Brain Activation in Healthy Volunteers

The aim of this project is:

* To apply a pharmacological tool of selective serotonin (5-hydroxytryptamine, 5-HT system) reuptake inhibition in healthy humans. Specifically:
* To investigate how sub-chronic administration of 20 mg of escitalopram affects cognitive performance ('cold' cognition) and social-emotional functioning ('hot' cognition) compared with placebo; and
* To investigate how sub-chronic administration of 20 mg of escitalopram affects functional brain activation during a paradigm of reinforcement learning following drug administration compared with placebo, and how activation relates to cognitive performance and social-emotional functioning.

The aim of this project is:

* To apply a pharmacological tool of selective serotonin (5-hydroxytryptamine, 5-HT system) reuptake inhibition in healthy humans. Specifically:
* To investigate how sub-chronic administration of 20 mg of escitalopram affects cognitive performance ('cold' cognition) and social-emotional functioning ('hot' cognition) compared with placebo; and
* To investigate how sub-chronic administration of 20 mg of escitalopram affects functional brain activation during a paradigm of reinforcement learning following drug administration compared with placebo, and how activation relates to cognitive performance and social-emotional functioning.

Serotonin is a monoamine neurotransmitter implicated in diverse cognitive and affective brain functions. Serotonin has a significant role in the regulation of cognition and mood, including emotional appraisal, perception and flexible behaviour, with 5-HT receptors found in the cortex, amygdala and hippocampus. The investigators have previously shown that in healthy human experimental studies, acute dietary tryptophan depletion induces 'waiting' impulsivity and impulsive behaviours, impairs goal-directed behaviour and shifts behavioural control toward habitual responding when appetitive, but goal-directed when aversive. Reduced availability of forebrain serotonin has also shown to impair a range of cognitive processes, such as psychomotor processing, episodic memory, attention and executive function. Recently, the research team have shown that using an acute and clinically relevant dose (20 mg) of escitalopram impaired learning and cognitive flexibility, but improved response inhibition in healthy humans, suggesting a dissociation of effects possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

The investigators now aim to investigate the effects of sub-chronic administration of 20 mg of escitalopram (i.e. three weeks) in healthy volunteers using sophisticated neuropsychological testing (Cambridge Neuropsychological Test Automated Battery and EMOTICOM) and functional magnetic resonance imaging (fMRI). Whereas 'cold' cognition refers to the use of non-emotional processing (e.g. episodic memory; spatial working memory), 'hot' cognition is emotion-laden and used in response to stimuli with affective salience (e.g. decision-making under high levels of risk of uncertainty). It has been suggested that cognitive-emotional effects, such as the re-appraisal and re-evaluation of emotions underlying learning mechanisms, may mediate improvements in mood associated with SSRI treatment. This project will help further the understanding of the role of serotonin in the regulation of cognitive and emotional processes, as well the neural correlates underlying reinforcement learning, in healthy humans.

Eligibility Criteria:
Inclusion Criteria:

* Healthy volunteer (male or female) between 18 and 45 years.

Exclusion Criteria:

* Current or former primary psychiatric disorder (DSM IV Axis I or WHO ICD-10 diagnostic classification).
* Current or previous neurological disease, severe somatic disease, or the consumption of drugs likely to influence the test results.
* Non- fluent in Danish or pronounced visual or auditory impairments.
* Current or past learning disability.
* Pregnancy (females).
* Lactation (females).
* 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).
* Nicotine addiction.
* Current psychoactive medication.
* Severe physical impairments affecting eyesight or motor performance.
* Hamilton-6 depression scale score \> 5.