Supervisors: Professor Veiko Vasar (University of Tartu), Professor Eduard Maron (University of Tartu), Assistant Professor Jakov Šlik (University of Ottawa, Canada).
Opponent: Professor Michael Kellner, Dr. med. (University of Hamburg, Germany)
Panic disorder (PD) characterized by recurrent unexpected panic attacks (PA) and persisting fear of their recurrence, is a frequent mental health problem, often associated with serious impairment.
Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a valid experimental model of human panic attacks. Several studies have investigated the interaction patterns between CCK and other (most intriguing among these probably serotonin (5-HT)) neurotransmitter systems. Earlier studies have suggested that patients with panic disorder and healthy controls differ in their sensitivity to CCK-4 challenge as well as in their responsiveness to serotonergic modulation of this sensitivity. Studies suggest that these dissimilarities may at least partly be explained by the differences in the brain 5-HT receptor and transporter systems as well as in the genes regulating 5-HT system.
The general objective of the present work was to study the modulating role of the 5-HT system on CCK-4-induced panic response. Apart from the effects of direct pharmacological manipulation of synaptic 5-HT levels, some factors of hypothetical importance, such as gene polymorphisms and binding properties of 5-HT transporter system were investigated.
The main findings of the present study were as follows:
1. Acute decline in the central availability of 5-HT by means of tryptophan depletion did not reverse the protective effect of SSRI treatment on CCK-4-induced panic.
2. On a panel of candidate genes, only rs1386494 A/G polymorphism in TPH2 gene was associated with CCK-4-induced panic attacks in HV with the frequencies of G/G genotype and G allele significantly higher in panickers.
3. Serotonin transporter non-displaceable binding potential (5-HTT BPND) was significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in 5-HTT BPND were observed between female patients and controls.
4. The treatment with an SSRI escitalopram did not reduce the CCK-4-induced PA in CCK-4-sensitive HV beyond the effect of placebo in contrast to the findings in patients with PD
To conclude, it would apparently be an oversimplification to consider 5-HT system as the single or primary modulatory factor in determining the CCK-4-induced panic response as well as to assume a direct modulatory effect of 5-HT on CCK-4 induced panic. The molecular and receptor mechanisms behind the 5-HT effects on panic manifestations observed in the context of CCK-4 challenge warrant further studies.