Role of 5-ht2c receptor density on behaviour in mice
Stevenson, Paula Louise
The neurotransmitters serotonin (5-HT) and dopamine (DA) play roles in eating disorders, mood disorders, such as depression and anxiety, and in the regulation of locomotion. The 5-HT2C receptor is one of fourteen 5-HT receptor subtypes that is expressed in regions of the brain including the hippocampus, amygdala, dorsal striatum, nucleus accumbens (NA) and substantia nigra, and is therefore implicated in behaviours and disorders associated with these regions. 5-HT has been shown to exert both a tonic and phasic inhibitory control, through the 5-HT2C receptor, on the firing rate and bursting activity of DA-containing neurones in the ventral tegmental area which enhances DA release in the NA and prefrontal cortex. In addition, the 5-HT2C receptor is under the control of a monophasic diurnal rhythm and is in a position to alter circadian regulation and behaviour due to its expression in the suprachiasmatic nucleus (the light entrainable oscillator (LEO)). It was hypothesised that elevating expression of the 5-HT2C receptor would have a detrimental effect on mood and cause hypolocomotion while reducing 5-HT2C receptor expression would improve mood, cause hyperphagia, obesity and hyperlocomotion. In order to investigate these hypotheses mouse models that either over- or under-expressed the 5-HT2C receptor were implemented. The 5-HT2C receptor expression pattern and levels were confirmed in all mouse lines. A behavioural phenotype of hypolocomotion and increased anxiety in the 5-HT2C receptor over-expressing mice and hyperphagia, obesity and hyperlocomotion in the 5-HT2C receptor under-expressing mice were found the latter is conistent with current literature. During backcrossing of the mouse lines onto the C57Bl/6 genetic background the abnormal behavioural phenotypes were lost suggesting that 5-HT2C receptor function is particulary sensitive to the genetic background on which it is being expressed. In response to altered expression levels of 5-HT2C receptor, compensatory alterations were found in the 5-HT system, with an inverse relationship existing between both the 5-HT1A receptor mRNA expression levels and 5-HT release in the hippocampus with the expression levels of the 5-HT2C receptor. Over-expression of 5-HT2C receptor appears to inhibit DA release in the cortex. The circadian experiments showed that under-expressing the 5-HT2C receptor did not alter the regulation of the food entrainable oscillator and there was a suggestion that the regulation of the LEO was affected. In summary, these results demonstrate that altered expression of 5-HT2C receptors results in abnormal behaviours consistent with its role in psychiatric disorders, but that the outcome is dependent on the genetic background.