Neurotransmitter Transporters-Based Psychiatric Treatment Research Paper

Neurotransmitters

Neurotransmitters are small chemical messengers or substances that relay information from one neuron to the other (Bray, 2014). This information is called an impulse, which is initially in the form of an electrical wave in the direction of the neuronal path. When the impulses get to the end of the neuron, an area referred to as the synapses, they are converted to chemical signals (Barz, Schreiber & Barz, 2013). These chemical signals are then referred to as neurotransmitters. Once the biological signals are relayed to the central nervous system, there is a need for quick termination (Aslam, Singh, & Rajbhandari, 2014), which occurs to ensure there is proper homeostasis of neurotransmitter turns within the nerve cessations (Fields, 2015). To terminate these synaptic commutations, the chemicals (neurotransmitters) undergo enzymatic degradation or active transport in neuronal and/or glial cells by neurotransmitter transporters (Gupta, Singh, & Narayan, 2015; Rastogi et al., 2015).

Reuptake of Neurotransmitters by Neurotransporters

The transmission of the biological message must be harnessed because continuous transmission can be detrimental to the cells. Harnessing ensures that the neuronal transmissions are effective in the subsequent impulse. The harnessing process is enhanced by the neurotransmitter transporters (Wang, Penmatsa, & Gouaux, 2015; Penmatsa, Wang, & Gouaux, 2013). Neurotransmitter transporters are proteins that traverse the neurons’ cell membranes. The two major families of neuro transporters are the ATP-binding cassette and the solute carrier family. The ABC transporter is involved in the binding from ATP hydrolysis and works as efflux carriers. Solute carrier transporters, on the other hand, are predominantly for the transport of small molecules into the cell (Januchowski et al., 2013; Lin et al., 2015).

Their prime role is to convey the neurotransmitters through the membrane and to steer them to precise sites within the cell. After the transmission of the impulse, the neurotransmitters also need to be transported into synaptic vesicles for storage and protection from degradation (Hediger et al., 2013). As opposed to neurotransmitter receptors which are diverse, the miscellany of neurotransmitter transporters is limited. For example, serotonin, which has been implicated in a number of neuropsychiatric disorders, has only one gene SERT that codes for its transporter. Similarly, monoamines, dopamine (DAT for dopamine transporter) and the norepinephrine-epinephrine [noradrenaline-adrenaline (NET for norepinephrine transporter) have only a single transporter each. The narrow range of the neurotransmitter transporters has created a great platform for the phraseological drug development (Wang et al., 2013).

Neurotransmitter Transporters and Neurological Disorders

Many neurological or neuropsychiatric disorders involve disturbances of the neuronal transmission and can either be the uncontrolled transmission of the transmitters into the CNS or failure of the neuron to transmit the impulses properly (Rask-Andersen et al., 2013). Many of the current phraseological drugs counteract some of these unordinary functions of the nervous system. A classic example is that of the involvement of serotonin in depression and emotional variation (Arpawong et al., 2016). Studies have revealed that serotonergic neurotransmission affects a range of human behaviours from food intake, reproduction and reproductive activity, cognition, emotion the sensory processing to motor function (Lewis, 2014).

Serotonin Transporters and Depression

Serotonin transporter (SERT or 5-HTT) is one of the classical solute carrier families of transporters. It belongs to the solute carrier family 6 member 4 and is encoded by the gene SLC6A4 (Arpawong et al., 2016). The transporter is tasked with the removal of serotonin released into the synaptic cleft and transports it to the neurons. The transport of serotonin by 5-HTT ends the function of serotonin and recycles it in a proton-dependent manner. The SERT or the 5-HTT is the target of many antidepressant drugs. A number of disorders have been associated with the repeat length polymorphism in the transcription of the SLC6A4 gene (Ho et al., 2013). The defective expression of the gene results in an altered rate of serotonin uptake. Some of the disorders that are associated with serotonin uptake include belligerent behaviour in Alzheimer disease patients, sudden infant death syndrome, post-traumatic stress disorder and depression susceptibility in persons with emotional trauma.

The transcription of SLC6A4 is modulated by a number of variations, for example, a repetitive sequence and SLC6A4-linked polymorphic region (5-HTTLPR), which has a short and long version and results in differential 5-HTT expression as well as function (Schuch et al., 2016). A study showed that a variation in the expression of SLC6A4 contributes to the differences in individual personality traits. A study in a population and family-based genetic study revealed significant correlation between the low expression of 5-HTTLPR short variant and neuroticism. The trait was linked to individual emotional states such as anxiety, depression and individual stress reactivity (Moya et al., 2014).

Serotonin transporters are transmembrane proteins that span the plasma membrane approximately twelve times. Most psychiatric drugs used to treat depression usually target serotonin transporters (Kovtun et al., 2015). Examples of such medications are the selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitors (SSRIs). Though the mechanism of action of serotonin-specific reuptake inhibitors is still peculiar, they are thought to elevate the amounts of serotonin in the extracellular space by keeping a tight rein on its assimilation into the presynaptic cells. Fluoxetine is one of the selective serotonin reuptake inhibitors, which has been used in mild as well as moderate cases of depression (Cuijpers et al., 2014). One of the most common devastating psychiatric disorders is the major depression disorder. Traumatic life occurrences particularly those connected to the loss or threat to social recognition are linked to the beginning of key depressive ailments. Several studies have associated defects with serotonin transporters with MDD (Gray et al., 2013).

Neurotransmitter Transporters as Drug Targets in Depression Disorder

The neurotransmitter transporters play a vital role in the transmission of neurotransmitters to the central nervous system. The biological principle of psychiatry is the underlying assumption that the human brain is connected with the rest of the body. Therefore, mental disorders are accompanied by biochemical changes (Geddes & Miklowitz, 2013; Barkley, 2014). It is hypothesized that some of the disorders such as mood variation are associated with the alteration of nervous signal transmission in the brain at the level of chemical synapses. On the other hand, molecular-based neurological disorders are caused by compromised neurotransmitters, their receptors, transporters and other intracellular processes involved in the activation of neurotransmitter receptors and growth factors. Since the neurotransmitter transporters are directly involved in the transmission of signals to the central nervous system, they provide a good target for the chemotherapy of psychiatry disorders (Hasenhuetl et al., 2015; Kell, 2016).

Advantages and Disadvantages of Neurotransmitter Transporters as Drug Targets

Depression is one of the most complex psychiatric disorders associated with disability, reduced quality of life, and a substantial societal burden for individuals with this condition. The most common type is major depressive disorder (MDD) (Asherson et al., 2012). The first-line drugs for the management of depression are antidepressants particularly the selective serotonin receptor inhibitors (SSRIs). SSRIs are a class of medications that include fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline and escitalopram (Ishima, Fujita, & Hashimoto, 2014). These drugs inhibit serotonin transporters, block reuptake and increase serotonin/neurotransmitter concentration within the synapses. The pharmacokinetics analyses of SSRIs show that the drugs are quickly absorbed and metabolized by the liver. Their absorption not affected by food intake thereby making the administration of food and SSRIs a good strategy to curb the gastrointestinal side-effects associated with the drugs (Dale, Bang-Andersen, & Sánchez, 2015).

The SSRIs have long-term acting mechanisms that cause them to be administered as single daily doses. The tendency for a certain SSRI to cause withdrawal symptoms on abrupt cessation is related to its half-life. Paroxetine has the highest incidence of adverse effects while fluoxetine has the least side-effects (Katona & Katona, 2013).

However, SSRIs are linked to several adverse effects. The emergence of SSRIs was accompanied by great optimism about their effectiveness and safety. However, their efficacy has encountered scepticism due to data generated from various studies (Khin et al., 2015). Meta-analyses of antidepressants also show that their benefits increase with the severity of the disease. SSRIs have been implicated in complications such as sexual dysfunction, bleeding disorders, pregnancy complications, especially with peroxamine, which is believed to cause congenital heart defects, hyponatraemia and cardiovascular effects (Weinshilboum et al., 2014).

Sexual dysfunction is a serious concern because it persists over time. A study on the pharmacogenetics of SSRIs in association with sexual dysfunction shows that neurotransmitters and hormones influence SSRI-associated sexual dysfunction. Testosterone, oestrogen, serotonin (5HT) and NO influence libido. NO, acetylcholine, and 5HT influence psychological sexual arousal. Norepinephrine and 5HT play a vital role in orgasm (Safa et al., 2013). The study also links sexual dysfunction to variants CYP2D6 and CYP2C19 isoenzymes (products of the CYP450 gene), which are involved in the metabolism of SSRIs. These effects are common with all SSRIs. Other genes that are associated with sexual dysfunction are GRIA3 and GRIK2 (decrease libido), GRIN3A (causes erectile dysfunction), and GRIA1 (delayed or absent orgasm) (Bishop et al., 2012).

References

Arpawong, T. E., Lee, J., Phillips, D. F., Crimmins, E. M., Levine, M. E., & Prescott, C. A. (2016). Effects of recent stress and variation in the serotonin transporter polymorphism (5-HTTLPR) on depressive symptoms: A repeated-measures study of adults age 50 and older. Behavior Genetics, 46(1), 72-88.

Asherson, P., Akehurst, R., Kooij, J. S., Huss, M., Beusterien, K., Sasané, R., & Hodgkins, P. (2012). Under diagnosis of adult ADHD cultural influences and societal burden. Journal of Attention Disorders, 16(5), 20-38.

Aslam, A., Singh, J., & Rajbhandari, S. (2014). Pathogenesis of painful diabetic neuropathy. Pain Research and Treatment, 2014 Article ID 412041, 1-7.

Barkley, R. A. (Ed.). (2014). Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment. New York: Guilford Publications.

Barz, H., Schreiber, A., & Barz, U. (2013). Impulses and pressure waves cause excitement and conduction in the nervous system. Medical Hypotheses, 81(5), 768-772.

Bishop, J. R., Chae, S. S., Patel, S., Moline, J., & Ellingrod, V. L. (2012). Pharmacogenetics of glutamate system genes and SSRI-associated sexual dysfunction. Psychiatry Research, 199(1), 74-76.

Bray, N. (2014). Neurotransmitters: Dopamine tone depends on DAT. Nature Reviews Neuroscience, 15(8), 495-495.

Cuijpers, P., Sijbrandij, M., Koole, S. L., Andersson, G., Beekman, A. T., & Reynolds, C. F. (2014). Adding psychotherapy to antidepressant medication in depression and anxiety disorders: A meta‐analysis. World Psychiatry, 13(1), 56-67.

Dale, E., Bang-Andersen, B., & Sánchez, C. (2015). Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochemical Pharmacology, 95(2), 81-97.

Geddes, J. R., & Miklowitz, D. J. (2013). Treatment of bipolar disorder. The Lancet, 381(9878), 1672-1682.

Gray, N. A., Milak, M. S., DeLorenzo, C., Ogden, R. T., Huang, Y. Y., Mann, J. J., & Parsey, R. V. (2013). Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder. Biological Psychiatry, 74(1), 26-31.

Gupta, V., Singh, R., & Narayan, S. (2015). Motion analysis of fluidyne engines. Tehnički Glasnik, 9(3), 242-244.

Hediger, M. A., Clémençon, B., Burrier, R. E., & Bruford, E. A. (2013). The ABCs of membrane transporters in health and disease (SLC series): Introduction. Molecular Aspects of Medicine, 34(2), 95-107.

Ho, P. S., Ho, K. K. J., Huang, W. S., Yen, C. H., Shih, M. C., Shen, L. H., & Huang, S. Y. (2013). Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression. Psychiatry Research: Neuroimaging, 212(3), 216-222.

Ishima, T., Fujita, Y., & Hashimoto, K. (2014). Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. European Journal of Pharmacology, 727, 167-173.

Jakó, T., Szabó, E., Tábi, T., Zachar, G., Csillag, A., & Szökő, É. (2014). Chiral analysis of amino acid neurotransmitters and neuromodulators in mouse brain by CE‐LIF. Electrophoresis, 35(19), 2870-2876.

Januchowski, R., Zawierucha, P., Andrzejewska, M., Ruciński, M., & Zabel, M. (2013). Microarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines. Biomedicine & Pharmacotherapy, 67(3), 240-245.

Kell, D. B. (2016). Implications of endogenous roles of transporters for drug discovery: hitchhiking and metabolite-likeness. Nature Reviews Drug Discovery, 15(2), 143-143.

Khin, N. A., Kronstein, P. D., Yang, P., Ishida, E., Hung, H. J., Mathis, M. V., & Temple, R. J. (2015). Regulatory and scientific issues in studies to evaluate sexual dysfunction in antidepressant drug trials. The Journal of Clinical Psychiatry, 76(8), 1-478.

Kovtun, O., Sakrikar, D., Tomlinson, I. D., Chang, J. C., Arzeta-Ferrer, X., Blakely, R. D., & Rosenthal, S. J. (2015). Single-quantum-dot tracking reveals altered membrane dynamics of an attention-deficit/hyperactivity-disorder-derived dopamine transporter coding variant. ACS Chemical Neuroscience, 6(4), 526-534.

Lewis, S. (2014). Neurological disorders: MicroRNA gets motoring. Nature Reviews Neuroscience, 15(2), 67-67.

Lin, L., Yee, S. W., Kim, R. B., & Giacomini, K. M. (2015). SLC transporters as therapeutic targets: Emerging opportunities. Nature Reviews Drug Discovery, 14(8), 543-560.

Moya, J., Ibáñez, M. I., Villa, H., Arias, B., Mezquita, L., Camacho, L., & Ortet, G. (2014). The 5-HTTLPR polymorphism of the SLC6A4 gene and working memory. Personality and Individual Differences, 60(2014), 71-79.

Penmatsa, A., Wang, K. H., & Gouaux, E. (2013). X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature, 503(7474), 85-90.

Rask-Andersen, M., Masuram, S., Fredriksson, R., & Schiöth, H. B. (2013). Solute carriers as drug targets: current use, clinical trials and prospective. Molecular Aspects of Medicine, 34(2), 702-710.

Rastogi, V., Patel, A., Lunagariya, A. D., & Hedna, V. S. (2015). Symptomatic improvement of traumatic dysgeusia from an occipital nerve block. Neurology India, 63(2), 259.

Safa, M., Sadr, S., Talischi, F., & Boroujerdi, F. G. (2013). Study of effects of selective serotonin reuptake inhibitors on stages of sexual function in Iranian patients with major depressive disorder. Therapeutic Advances in Psychopharmacology, 2045125313488906.

Schuch, J. B., Müller, D., Endres, R. G., Bosa, C. A., Longo, D., Schuler-Faccini, L.,& Roman, T. (2016). Psychomotor agitation and mood instability in patients with autism spectrum disorders: A possible effect of SLC6A4 gene? Research in Autism Spectrum Disorders, 26(4), 48-56.

Wang, H., Goehring, A., Wang, K. H., Penmatsa, A., Ressler, R., & Gouaux, E. (2013). Structural basis for action by diverse antidepressants on biogenic amine transporters. Nature, 503(7474), 141-145.

Wang, K. H., Penmatsa, A., & Gouaux, E. (2015). Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature, 521(7552), 322-327.

Weinshilboum, R., Gupta, M., Zhu, H., Ji, Y., Chai, Y., Biernacka, J., & Matson, W. (2014). Selective Serotonin Reuptake Inhibitor (SSRI) Response in Patients with Major Depressive Disorder (MDD): Pharmacometabolomics-informed Pharmacogenomics. Biological Psychiatry 75(9), 165-167.