Serotonin transporter gene variation and sensitivity to
conditioned cues: cause and cure in cocaine dependence

Until now, prevention and treatment of cocaine dependence has been only
moderately successful, suggesting that the critical mechanisms underlying
individual differences in vulnerability to cocaine dependence have not yet been
identified. The failure to extinguish (drug-related) conditioned behaviour in
response to conditioned stimuli is suggested to be a major factor in the
continuation of drug administration and relapse in cocaine dependence. This
conditioned behaviour is the target of exposure therapy, in which cocaine
dependent patients learn to extinguish drug-related conditioned behaviour.
Unfortunately, a substantial part of the patients respond poorly to this type
of therapy. A key factor in extinction failure is impaired PFC top-down control
over the amygdala, which is suggested to be related to abnormalities within the
serotonergic system. Serotonin transporter (SERT) knockout rats show
impairments within the PFC-amygdala circuit as well as heightend sensitivity as
evidenced by increased cognitive flexibility and a failure to extinghuis drug
and fear related behaviour. In humans, the s-variant of the 5-HTTLPR
polymorphism is associated with reduced SERT function, functional and
structural abnormalities within the PFC-amygdala circuits as well as impaired
fear extinction. These studies suggest that the s-allele of the polymorphism
may predispose to the development of cocaine addiction and poor responding to
exposure thearpy. However, a direct link between this polymorphism and cocaine
dependence have not yet been demonstrated. The first objective of this study is
to investigate how the 5-HTTLPR polymorphism affects the PFC-amygdala circuitry
and (related) cognitive processes in healthy controls and cocaine dependent
patients. The hypothesis is that inherited serotonin transporter down
regulation predisposes to cocaine dependence due to impaired prefrontal (PFC)
top-down control over the amygdala and heightened sensitivity for negative and
drug related information. In addition, there are several other genetic
polymorphisms that are suggested to affect the sensitivity to conditioned
stimuli, including the genes encoding for the serotonin 2C receptor, de GRIN2A
subunit in NMDA receptor, the dopamine D2 receptor,
catechol-O-methyltransferase and Brain-derived neurotrophic factor.

The objective of this study is to evaluate whether healthy subjects and cocaine
dependent patients carrying the s-variant of the 5-HTTLPR, show functional and
structural impairments within the PFC-amygdala circuit and (related)
abnormalities in the neurocorrelates of behavoural conditioning and cognitive
processing. More exploratory, the influence of 5 other polymorphisms will be
investigated.

The aim of the study is to investigate how the 5-HTTLPR polymorphism affects
the PFC-amygdala circuitry and related cognitive processes in healthy controls
and cocaine dependent patients. More exploratory, the influence of 5 other
polymorphisms will be investigated..This study follows a cross-sectional
design.

No adverse events are foreseen. Saliva-derived genotyping and MRI itself are
non-invasive. In this study, DCS will be orally administered as a challenge on
the first testing day. There is no risk associated with participation. The
nature of the burden is classified as minimal to moderate, considering that
subjects will have to deliver saliva for genotyping and will have to come to
the Spinoza Center for one session. The risks involved are negligible, as all
the agents and techniques employed are registered for their use and/or
routinely performed at the Spinoza Center. There is no direct potential benefit
for the participants, other than indirect benefits as the current pilot study
ultimately will hopefully to be able to better predict both cause and cure in
cocaine dependence.