Genetic moderation of CO2-induced fear by 5-HTTLPR genotype.
Inhalation of an increased concentration of carbon dioxide (CO(2)) has been shown to induce a state of negative affect in healthy subjects that is closely related to the clinical phenomenon of panic. It has been suggested that the vulnerability to CO(2) is moderated by differences in serotonin (5-HT) activity, caused by a functional polymorphism in the promoter region of the 5-HT transporter (5-HTTLPR) gene. Our aim was to examine the relationship between bi- and tri-allelic 5-HTTLPR genotype and the affective response to different dosages of inhaled CO(2) in healthy volunteers. Ninety-six subjects performed a double inhalation of four mixtures containing, respectively, 0%, 9%, 17.5% and 35% CO(2), following a double-blind, cross-over, randomized design. Affective responses were measured with a visual analogue scale for fear and the Panic Symptom List. 5-HTTLPR genotype was expressed as LL, SL and SS. Subjects with the SL and SS genotype reported less fear than LL subjects. A significant interaction effect was found between genotype and CO(2) dosage: the SS genotype showed lower fear scores than the LL genotype, particularly in the 17.5% CO(2) dose condition. The present study suggests that the dose-dependent fear reaction to CO(2) is moderated by a polymorphism in the 5-HT transporter gene, particularly at intermediate CO(2) dosages. It also underscores the usefulness of the introduction of an intermediate phenotype related to panic to reveal an underlying genetic vulnerability otherwise staying elusive. These results are in line with current theories on the role of 5-HT in both panic and respiration.
Schruers
Koen
K
Academic Anxiety Center, Maastricht University, Maastricht, The Netherlands. koen.schruers@pn.unimaas.nl
Esquivel
Gabriel
G
van Duinen
Marlies
M
Wichers
Marieke
M
Kenis
Gunter
G
Colasanti
Alessandro
A
Knuts
Inge
I
Goossens
Lies
L
Jacobs
Nele
N
van Rozendaal
Jalet
J
Smeets
Hubert
H
van Os
Jim
J
Griez
Eric
E
D000328:Adult; D000483:Alleles; D002245:Carbon Dioxide / Q000008:administration & dosage / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005239:Fear; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016584:Panic Disorder / Q000235:genetics; D011110:Polymorphism, Genetic; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D002245:Carbon Dioxide