Bibliography: leaves 221-270.Serotonin neurones have been implicated in the pathophysiology and treatment of clinical depression to a greater degree than any other neurotransmitter. Additionally, serotonin pathways may playa role in the pathophysiology and treatment of eating disorders, anxiety states and schizophrenia. Molecular biological studies have confirmed pharmacological evidence suggesting the existence of multiple serotonin receptor subtypes and the genes for these receptors, as well as that of the serotonin transporter, have common polymorphic variants. To investigate the effect of repeated treatment with selective serotonin fe-uptake inhibitors (SSRI's) on the function of central 5-HT2C receptors. To assess the effect of polymorphic variation in the 5-HT2c receptor and serotonin transporter on functional responses to selective pharmacological challenge. To determine whether polymorphic variation in the 5-HT receptor and serotonin transporter influence the clinical response of patients with major depression to treatment with serotonergic antidepressants. To assess the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRI's) on the function of central 5-HT2c receptors I used the 5-HT2C receptor agonist, m-chlorophenylpiperazine (m-CPP) as a 5-HT2c probe in a neuroendocrine challenge paradigm. I used the same approach to assess whether polymorphic variation in the 5-HT2c receptor (serine vs cysteine substitution) was associated with differences in functional response to 5-HT2C receptor challenge. I then studied whether polymorphic variation in the serotonin transporter promotor region (long versus short form) was associated with differing functional responses to acute challenge with clomipramine, a tricyclic antidepressant with a high affinity for the serotonin transporter. Finally, I studied whether either of these polymorphic variants influenced the clinical response of patients with major depression to treatment with SSRI's and clomipramine. SSRI treatment significantly lowered the sensitivity of 5-HT2c receptors as predicted from animal experimental studies. However polymorphic variation in the 5-HTzc receptor did not significantly influence functional responses to m-CPP challenge. In contrast polymorphic variation in the serotonin transporter was associated with differing neuroendocrine responses to acute clomipramine challenge with greater prolactin release being seen in subjects with the long polymorphic variant. Neither the 5-HTzc nor the transporter polymorphisms correlated with clinical response to SSRI and clomipramine treatment in patients with major depression. The ability of SSRI's to produce a functional down-regulation of 5-HTzc receptors may be relevant to certain of their therapeutic effects. Polymorphic variation in the 5-HT2c receptor (serine vs cysteine) seems unlikely to explain functional differences in responses to 5-HTzc receptor challenge or antidepressant responses to SSRI treatment. In contrast variation in the serotonin transporter promotor is associated with differing functional responses to acute serotonin re-uptake blockade. However, this did not correlate with clinical response to longer-term SSRI treatment
