Somatodendritic 5-HT1A Autoreceptor Desensitization due to Selective Serotonin Reuptake Inhibitor (SSRI) Therapy for Depression
Introduction: Depression is a mood disorder and is highly prevalent in the United States. Mood disorders affect about 20% of the population while major depressive disorder (MDD) specifically affects almost 7% of the US population.2 Common symptoms of depression include insomnia, lethargy, unexplained pain, GI symptoms, and headaches.3 The 5-HT1A receptor (5-HT1AR) is the target for many anxiolytic, antidepressant, and antipsychotic medications and activation is known to alter levels of various monoamines and other neurotransmitters (NTs).11 However, a delayed action of the pharmacotherapies used for treating depression results in the desensitization of 5-HT1A and 5-HT2A receptors.11 As such, research is needed to determine if new therapies can circumvent this outcome. Objective: In this review, the mechanism and downstream effects of various serotonin receptors were explored as it relates to desensitization and activation of said receptors. Methods: In several experiments, animal models were used to determine the varying effects of neurotransmitter and hormone treatment on the 5-HT1AR. In one such experiment, serotonin (5-HT) was administered to the animals during the postnatal period. Once the animals matured, the control group’s 5-HT1AR expression and behavior were examined. In a similar experiment by the same group, the postnatal animal was treated with a selective serotonin reuptake inhibitor (SSRI) as well as a 5-HT1AR agonist. Similar methodology was used where a control group was compared to an experimental group.8 In a third experiment by a separate group, testosterone was administered to animals expressing subordinate and depressive behavior. These animals were not treated during the postnatal period and were chronically exposed to stressful stimuli (cortisol levels were measured). But similarly, they were compared to a control group and their receptor levels and behavior were assessed.7 Results: In the experiments where 5-HT1AR targeting treatments were given to postnatal animal models, there was increased expression of the 5-HT1AR and a reduced observation of anxiety or depressive behavior when compared to the adult animal control. There was also a decrease in mRNA coding for the GABAA receptor α3 subunit in the experimental groups of the adult animals.8 In the experiment where testosterone was administered to animals expressing subordinate or depressive behavior, there was observed renormalization of their behavior as well as 5-HT1AR expression. Conclusions: From these experiments and the information gathered in researching this topic, it can be concluded that there are possible alternative methods of stimulating the 5-HT1AR that may reduce the desensitization seen with current pharmacotherapies. If possible, one explorable avenue could be the exposure to 5-HT during a high risk individual’s youth.
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