Date of Award

8-29-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Serotonin (5-HT) is a ubiquitous neurotransmitter in the brain that is involved in various physiologic functions including the regulation of hypothalamic hormones and has been implicated in various mood disorders such as depression. Preclinical and clinical data from studies in adults have shown that antidepressant drugs produce time-dependent changes in serotonergic and other systems and can also normalize dysfunction associated with the hypothalamic-pituitary-adrenal (HPA) axis. To date, our understanding of the mechanisms of 5-HT receptor signaling and the actions of drugs on serotonergic function have been derived from extensive preclinical research carried out using cell lines in vitro or in adult animal models in vivo. Fewer studies have investigated serotonergic signaling mechanisms or the effects of antidepressants (i.e., selective serotonin reuptake inhibitors (SSRIs)) in animal models prior to sexual maturation. This is a scientific and clinically relevant issue as (1) SSRIs, the most effective pharmacological option for treating mood disorders in children and adolescents, are being increasingly prescribed and may be associated with suicidal thoughts or behaviors in these age groups and (2) preclinical studies in rodents indicate that SSRI-induced modulation of the serotonergic system prior

to sexual maturation produces effects that are distinct and more long-lasting than those produced in adults. To date, few if any studies have investigated mechanisms of 5-HT receptor signal transduction in peripubertal hypothalamic neurons in vivo and their regulation by SSRIs, despite a wealth of existing comparative data on serotonin 1A (5-HT1A) receptor signaling in adult hypothalamic rat paraventricular nucleus (PVN).

Given the clinical relevance of potential age-dependent differences in serotonergic signaling and regulation of hypothalamic function, the objective of the studies in this dissertation was to identify and characterize the mechanisms of 5-HT1A receptor signaling in the peripubertal hypothalamic PVN.

The data generated by studies in this dissertation project provide the first in vivo evidence that 5-HT1A receptors in the peripubertal PVN can activate multiple responses: (1) oxytocin and adrenocorticotropic hormone (ACTH) plasma hormone responses, (2) activation of extracellular signal-regulated kinase (ERK), and (3) activation of protein kinase B (Akt). The data also demonstrate that these pathways may be differentially responsive to different classes of 5-HT1A receptor agonists. (+)8-OH-DPAT (an aminotetralin), acted as a "full" agonist on each of the respective pathways, while tandospirone (an azapirone) exhibited "partial" agonist activity on activation of Akt but exhibited "full" agonist activity on neuroendocrine responses and activation of ERK. 5-HT1A receptors produce a rapid and prolonged activation of ERK in the peripubertal PVN, unlike the rapid but more transient response in the adult PVN. In addition, the 5-HT1A activation of ERK may be expressed only in certain populations of neuroendocrine cells in the peripubertal PVN. These studies have also revealed some unique aspects that G α proteins in the peripubertal PVN, since: (1) there are age-dependent increases only in Gαo levels, (2) Gαi3 and Gαo are not reduced by intra-PVN injection with pertussis toxin, and (3) Gαz proteins are not reduced by 7 or 14 days of fluoxetine treatment. We also have determined that chronic fluoxetine treatment desensitizes 5-HT1A receptor-mediated phosphorylation of GSK3β in the absence of changes in its canonical upstream kinase, Akt. These data suggest fluoxetine may induce changes in phosphatase activity or that there may be a different upstream kinase mediating the phosphorylation of GSK3β in the peripubertal PVN.

In conclusion, the present studies determined the mechanisms of 5-HT1A receptor-mediated signaling in peripubertal PVN and identified some aspects of 5-HT1A receptor signaling that differ from those previously identified in adults. These findings may be clinically relevant with respect to facilitating a better understanding of mechanisms mediating the therapeutic and/or side effects of SSRIs prescribed to young patients or to identify novel drug targets to treat mood disorders in children and adolescents.

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