In vivo Hippocampal Serotonin Dynamics in Male and Female Mice: Determining Effects of Acute Escitalopram Using Fast Scan Cyclic Voltammetry

Abstract

Depression is a highly prevalent psychiatric disorder, impacting females at a rate roughly twice that of males. This disparity has become the focus of many studies which are working to determine if there are environmental or biological underpinnings to depression pathology. The biology of depression is not well understood, but experts agree that a key neurotransmitter of interest is serotonin. Most research on basic serotonin neurochemistry, by us and others, has predominantly focused on male models. Thus, it is now critical to include female models to decipher possible fundamental differences between the sexes that may underlie this disorder. In this paper, we seek to determine any such differences using fast-scan cyclic voltammetry (FSCV) and fast-scan controlled adsorption voltammetry. These techniques allow us to probe the serotonergic system via measurement of evoked and ambient serotonin at carbon fiber microelectrodes (CFMs). Our data reveal no statistical differences, in the hippocampus, in female serotonin chemistry during the different stages of the estrous cycle compared to the mean female response. Furthermore, no difference was observed in evoked serotonin release and reuptake, nor ambient extracellular serotonin levels between male and female mice. We applied a previously developed mathematical model that fits our serotonin signals as a function of several synaptic processes that control the extracellular levels of this transmitter. We used the model to study potential system differences between males and females. One hypothesis brought fourth, that female mice exhibit tighter autoreceptor control of serotonin, is validated via literature and methiothepin challenge. We postulate that this tight regulation may act as a control mechanism against changes in the serotonin signal mediated by estrogen spikes. Importantly, this safety mechanism has no consequence for acutely administered escitalopram’s (ESCIT’s) ability to increase extracellular serotonin between the sexes. This work demonstrates little fundamental differences in in vivo hippocampal serotonin between the sexes, bar control mechanisms in female mice that can be observed under extraneous circumstances. We thus highlight the importance of considering sex as a biological factor in determining pharmacodynamics for personalized medical treatments that involve targeting serotonin receptors.

Dopamine and serotonin interplay for valence-based spatial learning

“…Temporal discrimination of neural activity leading up to the reinforcement signal was achieved through an eligibility trace (Gerstner et al, 2018), also known as proto-weight, for which there is evidence for DA (Brzosko et al, 2017) and 5-HT (He et al, 2015; Figure 1C ). The eligibility trace of 5-HT, adapted from the neocortex, presents slower dynamics than that of DA, in the hippocampus, for an equal Hebbian response (He et al, 2015;Saylor et al, 2019), which implies that distal predictive neural activity is less persistent under the modulation of the latter ( Figure 1C ). For the navigational task we employed a Morris water maze (MWM) where the agent has to find a hidden platform in a water arena (Vorhees and Williams, 2006; Figure 1D).…”

Autoreceptor control of serotonin dynamics

“…A major change from our 2010 model is that the steady state eht concentration is now 60 nM instead of 0.7 nM. The Hashemi Lab has repeatedly verified that the extracellular serotonin concentration in mice is in the range 40–80 nM [ 60 – 62 ], although it varies considerably between the different regions to which the dorsal raphe and medial raphe project. The steady state concentration of histamine in the extracellular space is taken from [ 54 ].…”

“…The Hashemi lab uses Fast Scan Cyclic Voltammetry (FSCV) to measure the time course of eht in vivo in different brain regions (see “ Methods ” section). In this section we examine data recently collected in vivo of responses of male and female mice in the CA2 region of the hippocampus [ 62 ]. The medial forebrain bundle was stimulated and the antidromic spikes stimulate the DRN that projects to the hippocampus and releases serotonin into the extracellular space.…”

Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage

“…Saylor et al, (2019) examined the effects of acute 1 escitalopram administration using fast-scan cyclic voltammetry (FSCV). Following an acute 1 6 dosage of escitalopram, a significant (50%) increase in serotonin response was observed 1 (Saylor et al, 2019). In the current study chronic dosing of escitalopram was used, as long-term use of SSRI more fully characterizes typical SSRI treatment in the context of HIV-1 infection.…”