Title

The serotonin 5-HT$\sb7$ receptor: Circadian rhythm regulation and mechanism of antidepressant action

Date of Completion

January 1997

Keywords

Biology, Neuroscience|Psychology, Psychobiology|Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Circadian rhythm disturbances are often associated with affective disorders and it has been suggested that rhythm dysregulation may play a role in the pathophysiology of depression. Furthermore, it has been demonstrated that serotonergics, including antidepressants, shift rhythmic circadian functions in-vitro and in-vivo. The specific serotonergic receptor mechanisms invoked in the modulation of circadian rhythms, however, are not clear.^ A novel serotonin receptor, 5-HT$\sb7,$ has recently been cloned and localized to the hypothalamus, site of the biological pacemaker--the suprachiasmatic nucleus. This receptor also has a high distribution within other areas of the limbic system, particularly the hippocampus, possibly implicating the 5-HT$\sb7$ receptor in the pathology of depression. In the absence of subtype selective ligands, action at the 5-HT$\sb7$ receptor is currently defined as activation by the endogenous ligand serotonin in the presence of the 5-HT$\rm\sb{1A}$ antagonist ($-$)pindolol and the 5-HT$\rm\sb{1D}$ agonist sumatriptan.^ This work hypothesizes that the 5-HT$\sb7$ receptor is involved in serotonergic regulation of circadian rhythmicity and is mechanistically implicated in post-synaptic actions of antidepressant treatment. Circadian hypothalamic and limbic hippocampal in-vitro responses to agents or antidepressants consistent with 5-HT$\sb7$ receptor pharmacology were investigated using: Fos immunohistochemistry as a marker of neuronal activation and 5-HT$\sb7$ receptor binding as a measure of receptor regulation changes. In addition, the excretion response curve of 6-sulfatoxymelatonin, a measure reflective of in-vivo circadian rhythmicity, was also used to monitor drug effects.^ The results obtained in these investigations suggest that Fos expression in the hypothalamus and hippocampus is acutely induced in response to serotonergic agents, including antidepressants, in a profile consistent with the 5-HT$\sb7$ receptor and that these responses are desensitized after chronic administration. These functional results correlated with a neuroadaptive reduction in the number of 5-HT$\sb7$ receptors in the hypothalamus and hippocampus of chronically treated animals. Furthermore, chronic treatments pharmacologically consistent with 5-HT$\sb7$ receptor activation produced alterations in aMT6s excretion profiles suggestive of a delayed shift in circadian phase.^ Taken together, the results from the present studies accordingly support the hypotheses that the 5-HT$\sb7$ receptor is involved in the modulation of circadian rhythms and is implicated in the mechanism of action of antidepressants. ^