How do antidepressants influence synaptic transmission?

How do antidepressants influence synaptic transmission?

The research to question that guides this review is: How do antidepressants influence synaptic transmission? The question comes from the book Biopsychology 10th Ed. Chapter 4: Neural Conduction and Synaptic Transmission: How Neurons Send and Receive Signals. The subtopic on How Drugs Influence Synaptic Transmission and the Learning Outcome 4.17: provide a general overview of how drugs influence synaptic transmission.

Introduction

The basis of neuropharmacological research is the concept that centrally acting drugs affect behavior by influencing neurotransmitter function at particular points of controlling synaptic transmission. The synapse is a specialized cellular interface that offers a chemical and physical link which facilitates communication between cells of the central nervous system (CNS) (Knapp, Breese, Mueller& Breese, 2001). Certain endogenous chemicals, including neurotransmitters, ions, and hormones, determine the transmission of information from one cell to the next and allow modification and shaping of neural signals based on the need of the organism. Synaptic junctions are the site where complex electrochemical interactions occur; interactions that influence the neural messages within the brain circuits that lead to cognition, motor and emotional responses. Synaptic links are the epicenter for both the origin of psychiatric and neurological disease states as well as therapeutic interventions for these diseases (Knapp et al., 2001).Knowledge of how various drugs influence synaptic transmission will facilitate the understanding of the neuropathological foundation of psychiatric and neurological disorders. Drugs attach or bind to different synaptic elements to potentially affect neurotransmission. Interruption of neurotransmitter synthesis within the presynaptic neuron leads to a disruption of normal neurotransmission. The focus of this review is how antidepressants influence synaptic transmission.

Therapeutic Effect of Antidepressants

Research shows that therapeutic effects of antidepressants result from correction of dysregulation of serotonin (5-HT) and/or noradrenaline neural pathways (Knapp et al., 2001). Researchers continue to give more attention to the serotonergic system as it is implicated in cognitive impairments in various psychiatric disorders such as depression and anxiety (Komlósi et al., 2010). Serotonin-selective reuptake inhibitors (SSRIs) are a class of antidepressants that selectively inhibit the uptake of serotonin within the synapse in antidepressant therapy. Examples of SSRIs that increase the level of serotonin in the synapse include fluoxetine, zimelidine, citalopram, paroxetine, escitalopram, fluvoxamine, sertraline, and vilazodone (Knapp et al., 2001; Mnie-Filali et al., 2013). SSRIs have proven to be effective in treating depression.

However, like other antidepressants, it takes an extended period before the effect of SSRIs on symptoms can be seen (Knapp et al., 2001). Monoamine oxidase inhibitors (MAOIs) is another class of antidepressants that inhibit the enzyme monoamine oxidase, which is responsible for breaking down monoamines. MAOIs increase the levels of serotonin in the brain, which exceeds the levels of dopamine and noradrenaline.

Synaptic Plasticity

Synaptic plasticity is an important mechanism where synaptic transmission facilitates modification of brain function through neural activity generated by an experience. Plasticity is an essential property of the mammalian brain (Citri & Malenka, 2008). Synaptic plasticity plays an integral role in the capacity of the brain to store transient experiences into memory, and it refers to “the activity-dependent modification of the strength or efficacy of synaptic transmission at preexisting synapses” (p. 41). Research shows that impairments in synaptic plasticity mechanisms contributed to the development of neuropsychiatric disorders.

Antidepressants in Treating Major Depressive Disorder

Antidepressants are recommended as “first-line” medications in the treatment of major depressive disorder (MDD). However, there is a time lag before a clinically significant effect of antidepressants is observed (Mnie-Filali, Abrial, Lambás-Señas & Haddjeri, 2013; Knapp et al., 2001). Also, severe side effects and toxicity of MAOIs and tricyclic antidepressants (TCAs) limit their usefulness. The common aspect in all antidepressants is that they have a similar mode of action, which is enhancing synaptic transmission of the monoamines serotonin (5-HT) and/or norepinephrine.

Furthermore, the monoaminergic theory of depression largely influenced the development of antidepressant medications. The theory associates a deficiency of cerebral 5-HT and/or norepinephrine to the pathophysiology of depression. Synaptic plasticity, particularly activity that induces long-term depression potentially plays a role in the development of MDD (Kullyev et al., 2010; Mnie-Filali et al., 2013). Antidepressants control various forms of synaptic plasticity. Research suggests that antidepressants regulate synaptic plasticity and reorganization by modulating cell adhesion protein and synaptic function/structure genes.

Fluoxetine Action on Synaptic Transmission

Fluoxetine is an SSRI that acts primarily as an inhibitor of the serotonin reuptake transporter (SERT) in blocking the removal of serotonin from the synaptic cleft resulting in enhancement of serotonin signals. Fluoxetine and other SSRIs are commonly prescribed for many behavioural and neurological disorders (Komlósi, Molnár, Rózsa, Oláh, Barzó & Tamás, 2012; Kullyev et al., 2010). The principal mechanism of terminating 5-HT signalling is blocking SERT, which is localized in the plasma membrane and transports extracellular serotonin (5-HT) into the cytoplasm. Therapeutic effects of SSRIs result from blocking SERT from removing 5-HT in the synaptic cleft, hence increasing the levels of 5-HT signals (Komlósi et al., 2010). 5-HT functions as a neuromodulator to inhibit or facilitate the synaptic transmission of other neurotransmitters.A study by Kullyev et al. (2010) shows that fluoxetine influences discrete steps of synaptic transmission of GABA, Ach, and glutamate. Research suggests that the regulation of 5-HT signaling plays myriad roles in modulating emotion, cognition, and motor function in mammals (Knapp et al., 2001; Kullyev et al., 2010). In humans, increased central cholinergic tone induces depression. 5-HT modulation of synaptic activity underscores the synaptic plasticity involved in learning, adaptation, stress responses, and memory. Researchers recognize that while SSRIs can facilitate early changes in emotional processing, other symptoms of depression can only be treated with chronic medication (Komlósi et al., 2010).

 

Annotated Bibliography

Knapp, D. J., Breese, C. R., Mueller, R. A., & Breese, G. R. (2001). Drugs and the Synapse. e LS.

This article provides an overview of the effects of drugs on neurotransmission by binding or attaching to various synaptic elements. It has a section explaining the action of drugs treating depression through the prevention of neurotransmitter uptake (serotonin) into synaptic endings. Also, the article describes the action of monoamine oxidase inhibitors (MAOIs) in treating depression. Reading the article provided a basic understanding of drug actions at the synapse and how it advances the science of neuropharmacology and how the science applies to patient care. Also, the article serves to introduce ideas that such therapeutic effects of antidepressants whose details are provided by other articles considered in the study.

Citri, A., & Malenka, R. C. (2008). Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology, 33(1), 18-41.

This article is about synaptic plasticity, a mechanism that involves synaptic transmission in the modification of brain activity. An understanding of the mechanisms underlying synaptic plasticity in various regions of the brain will better the knowledge on the neural basis of many elements of normal and pathological brain function.

Mnie-Filali, O., Abrial, E., Lambás-Señas, L., & Haddjeri, N. (2013). Long-term adaptive changes induced by antidepressants: From conventional to novel therapies. Mood Disorders, 145.

This is a chapter of a book that examines long-term changes that antidepressants induce in the treatment of major depressive disorder. The authors begin the chapter by providing statistics in the prevalence of MDD worldwide before it shifts focus to medications given to treat the condition. The article also notes the time lag that exists before the effects of antidepressants are observed. The chapter explores the therapeutic effects of various types of antidepressants, including SSRIs, MAOIs, and TCAs. Notable, the chapter links the effect of antidepressants on synaptic plasticity. The chapter provides details on the effects of various antidepressants, including fluoxetine on synaptic transmission.

Komlósi, G., Molnár, G., Rózsa, M., Oláh, S., Barzó, P., & Tamás, G. (2012). Fluoxetine (prozac) and serotonin act on excitatory synaptic transmission to suppress single layer 2/3 pyramidal neuron-triggered cell assemblies in the human prefrontal cortex. Journal of Neuroscience, 32(46), 16369-16378.

Like the article Kullyev et al. (2010), this article also focuses on the fluoxetine on synaptic transmission. The information in this article validates information contained in other studies contained in this review such as the link between depression and 5-HT signalling, the therapeutic effects of SSRIs, and role of synaptic transmission on cognition, motor and emotional control.

 

Kullyev, A., Dempsey, C. M., Miller, S., Kuan, C. J., Hapiak, V. M., Komuniecki, R. W., … & Sze, J. Y. (2010). A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans. Genetics, 186(3), 929-941.

This article focuses on the effects of SSRI fluoxetine on synaptic transmission. Much of the information in the literature review section of this study correlate with that in other studies considered in this article. Examples include the role played by 5-HT signaling in emotion, cognition, and motor behavior; and the effects of SSRIs on 5-HT signaling. A focus on fluoxetine provides insights into the therapeutic effects of SSRIs in general.