Serotonin (5-hydroxytryptamine, 5-HT) has been heavily implicated in the pathophysiology of depression and although its changes in the brain has been well studied using microdialysis, the analysis of its time data is often insufficient as pharmacokinetic (PK) and pharmacodynamic (PD) concepts are often neglected. The works in this dissertation attempt to further explore 5-HT time data via mechanism-based PK/PD modeling. The first work explored the dorsal raphe nucleus (DRN) in which the desensitization of 5-HTIA autoreceptors has been implicated in the several-week delay in onset of therapeutic response to antidepressants. An extension of a standard indirect-response pharmacodynamic modeling approach was used to account for the stimulation of locally administered citalopram on the production of 5-HT in the DRN and the nucleus accumbens. The overall model reasonably captured the time courses of 5-HT in both regions of the brain and predicted 5-HT concentrations in the DRN under a different (subcutaneous) dosing scheme. This model is the first to quantitatively explore an important control mechanism of central 5-HT output as perturbed by an antidepressant administration. The second work explored the combination treatment of citalopram, a serotonin selective reuptake inhibitor (SSRI), and WAY-100635, a 5-HT 1A receptor antagonist. Citalopram plasma kinetics was designated as fixed functions driving the dynamics of 5-hydroxytryptamine (5-HT) output in rat ventral hippocampus assumed in a standard indirect-response PD model which was then extended to fit the PD data for the combination treatment to account for two drugs acting synergistically on separate processes to modulate the same PD endpoint. Contrary to previous conclusions drawn based on peak 5-HT level, simulations from this modeling work showed that the potentiation of WAY-100635 in terms of AUEC (area under the effect curve) is minimally significant. Mechanism based PK/PD modeling as a way to explore pharmacological mechanism is further demonstrated in the third work which explored the mechanism of cancer cell kill in the presence of P-glycoprotein induction. Results from this modeling work suggest the need for reducing therapy-induced P-glycoprotein induction via optimizing dosing schedules to achieve maximal cancer cell reduction.

Naked mole-rats are eusocial rodents that live in subterranean colonies with a strict reproductive and social hierarchy. Breeders are socially dominant and other colony members are non-reproductive subordinates. The effects of manipulating the serotonergic system on aggression are well studied in many species, but not in eusocial rodents like the naked mole-rat. For the current study, the effects of fluoxetine hydrochloride (FLX) on status-specific behaviours of subordinates (Experiment 1) and queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm to investigate how the serotonergic system influences aggression in this species. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status-specific behaviours of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy.

Naked mole-rats are eusocial rodents that live in subterranean colonies with a strict reproductive and social hierarchy. Breeders are socially dominant and other colony members are non-reproductive subordinates. The effects of manipulating the serotonergic system on aggression are well studied in many species, but not in eusocial rodents like the naked mole-rat. For the current study, the effects of fluoxetine hydrochloride (FLX) on status-specific behaviours of subordinates (Experiment 1) and queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm to investigate how the serotonergic system influences aggression in this species. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status-specific behaviours of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy.