The prevalence of stress and anxiety disorders in modern society is increasing, but
the development of new treatments decreasing due to high research costs and low
success rates in clinical trials. The latest type of compounds introduced to treat
anxiety and depression was the specific serotonin reuptake inhibitors (SSRI), which
was introduced in 1987. Since then, no new class of compounds have been
introduced, suggesting that the need to find alternative targets in treating mental
disorders is needed.
In this thesis I have used the zebrafish as a model organism to study the modulation
of behaviours through intracellular signalling pathways, known to be involved in
learning, memory and anxiety.
First, using the pro-convulsant compound, pentylenetetrazole (PTZ), an automated
tracking system was established to quantify and analyse swimming behaviour in
larvae zebrafish. Pentylenetetrazole induces seizures in zebrafish at high
concentrations, however this thesis identifies that the combination of a low level of
PTZ and subjecting the fish to alternating cycles of light and dark induced a reversed
response to light and dark. A group of compounds with known anti-seizure effects
were subsequently screened, which found that a combinational treatment with
diazepam and two types of neurosteroids reversed the PTZ-induced light dark
response.
Secondly, using the same automated analysis setup, the effect of cAMP modulators
was studied on behaviour in zebrafish larvae. Our lab has previously established that
Rolipram, a PDE4 inhibitor, causes anxiety thigmotaxis in zebrafish larvae. In this
thesis we treated zebrafish larvae with Rolipram and other compounds modulating
cAMP, which greatly increased the swimming activity, which was reversed by
subsequently treating with PD0325901. To test if the pharmacological modulation of
cAMP-levels through the inhibition of other PDEs would lead to increased locomotor
activity, a small library of PDE inhibitors was screened, and 4 compounds were
identified that caused an increase in locomotion – three of these compounds were
PDE4-inhibitors.
Finally, by using two behavioural assays, I found that in adult fish Rolipram cause
anxiety-like phenotypes, which is also reversible by MAPK-inhibition