To evaluate whether healthy subjects and cocaine addicts carrying the s-variant of the 5-HTTLPR show improved reversal learning and reduced 5HTT function.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
verslaving
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Vigilance level (an fMRI task): % BOLD signal change in the ventral
frontostriatal circuit (which is associated with reversal learning).
- 5HTT function (a phMRI study): peak amplitude (maximum % change relative to
baseline) in cerebral blood flow (CBF) evoked by an acute pharmacological
challenge with citalopram.
Secondary outcome
none
Background summary
Until now, prevention and treatment of cocaine dependence have been only
moderately successful, suggesting that the critical mechanisms underlying
individual differences in vulnerability to cocaine dependence have not yet been
identified. Cocaine addicts show increased negative emotionality, which is
hypothesized to drive continuation of drug use and compulsivity in drug
addiction. Negative emotional states can be elicited by drug-related
conditioned stimuli, which are notoriously difficult to extinguish. The
serotonergic system plays a key role in the regulation of (conditioned)
emotional responses. We have previously demonstrated that serotonin plays a key
role in vigilance, that is sensitivity to environmental (stress, drug-related)
stimuli, and reduces cognitive flexibility. Interestingly, while such increased
vigilance may predispose to cocaine dependence (cause), it could also be target
for individualized treatments (cure). Thus, cocaine-induced cognitive
inflexibility, which is seen in wild-type rats as well as cocaine addicts
normally makes it difficult to stop responding to drug-related cues. Yet, the
improved cognitive flexibility in serotonin transport knockout (5-HTT-/-) rats
following chronic cocaine self-administration provides the premise that cocaine
addicts characterized by reduced 5-HTT function and high vigilance may benefit
from *reversal learning* behavioural cognitive therapies (BCT) and/or
pharmacotherapy directed towards the 5-HT system. There is extensive evidence
that the 5-HTT-/- rat models the low activity (short; s) variant of the common
5-HTT-linked polymorphic region (5-HTTLPR). Like 5-HTT-/- rat, human s-allele
carriers show impaired emotional control and increased cognitive flexibility.
Yet, whether cocaine addicts carrying the s-variant of the 5-HTTLPR also show
improved reversal learning and reduced 5HTT function has not yet been
investigated. This pilot study should indicate the feasibility and/or improve
the design of the research to come in which we identify novel 5-HT related
genetic, neurochemical and behavioral biomarkers in cocaine dependence.
Ultimately, we expect that these 5-HT biomarkers will better predict both cause
and cure in cocaine dependence than research up to now, which is typically
directed towards the dopaminergic system.
Study objective
To evaluate whether healthy subjects and cocaine addicts carrying the s-variant
of the 5-HTTLPR show improved reversal learning and reduced 5HTT function.
Study design
Cross-sectional pilot study
Study burden and risks
No serious side effects are foreseen. MRI itself is a non-invasive imaging
modality. In this study, a low dose citalopram challenge (7.5 mg injected over
7.5 min.) will be administered during an MRI sequence. There is no risk
associated with participation. Intravenous citalopram (5*10 mg) has been
developed as probe of central 5-HT function by measuring increased prolactin
secretion following its administration and has also been used as a probe for
5-HT modulation in phMRI studies. It is the only SSRI available for intravenous
administration. In fact, * 50% patients report no adverse events during chronic
treatment with i.v. citalopram at much higher doses (20-60 mg) than employed in
this study . The most common adverse events associated with i.v. citalopram are
nausea (13%), headache (6%), tremor (5%), and somnolence (2%). The nature of
the burden is classified as minimal to moderate, considering that subjects will
have to deliver saliva for genotyping and a minority will have to come to the
AMC on 1 occasion for the MRI scan, which involves a venous puncture and i.v.
administration of citalopram. The risks involved are negligible, as all the
agents and techniques employed are registered for their use and/or routinely
performed at the AMC. 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
Meibergdreef 9
1105 AZ
NL
Meibergdreef 9
1105 AZ
NL
Listed location countries
Age
Inclusion criteria
Male subjects with cocaine dependence as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association 1994), and will be determined by a structured interview (Composite International Diagnostic Interview: CIDI) aged 18-40 years.
Controls: male healthy volunteers aged 18-40 years.
Exclusion criteria
No cocaine dependence
Positive DSM-IV/CIDI for any drug other than cocaine, heroin, alcohol or marijuana
Major neurological disorders, claustrophobia, peripheral vascular diseases, current use of respiratory, cardiovascular, anticonvulsant or psychoactive medications (SSRIs), or alexithymia
A positive urine test result for amphetamines, barbiturates, benzodiazepine metabolites, cocaine (metabolite), opiates, alcohol, and marijuana
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL35166.018.10 |