Serotonin Transporters

As is the case for many classical neurotransmitters, termination of the effects of 5-HT in the synaptic cleft is brought about in large part by an active reuptake process mediated by the 5-HT transporter (5-HTT). 5-HT is taken up into the presynaptic terminals, where it is metabolized by the enzyme monoamine oxidase (MAO) or sequestered into secretory vesicles by the vesicle monoamine transporter (see Figure 1-3B). This presumably underlies the mechanism by which MAO inhibitors initiate their therapeutic effects; that is, the blockade of monoamine breakdown results in increasing the available pool for release when an action potential invades the nerve terminal. It is now well established that many tricyclic antidepressants and SSRIs exert their initial primary pharmacological effects by binding to the 5-HTT and blocking 5-HT reuptake, thereby increasing the intrasynaptic levels of 5-HT, which initiates a cascade of downstream effects (see Figure 1-3B for details). It has been hypothesized that the first step in 5-HT transport involves the binding of 5-HT to the 5-HTT and then a cotransport with Na+, while the second step involves the translocation of K+ across the membrane to the outside of the cell. SSRIs bind to the same site on the transporter as 5-HT itself. Recently, elegant biochemical and mutagenesis experiments have elucidated a leucine transporter from bacterial species, providing information that may aid in unraveling the complex process by which mammalian transporters couple ions and substrates to mediate neurotransmitter clearance (Henry et al. 2006).

In the brain, 5-HTTs have been radiolabeled with [3H]-imipramine (Hrdina et al. 1985; Langer et al. 1980) and with SSRIs such as [3H]cyanoimipramine (Wolf and Bobik 1988), [3H]paroxetine (Habert et al. 1985), and [3H]citalopram (D'Amato et al. 1987). The regional distribution of 5-HTT corresponds to discrete regions of rat brain known to contain cell bodies of 5-HT neurons and synaptic axon terminals, most notably the cerebral cortex, neostriatum, thalamus, and limbic areas (Cooper et al. 2001; Hrdina et al. 1990; Madden 2002). The specific cellular localization of 5-HTT in the CNS has also been accomplished by using site-specific antibodies (Lawrence et al. 1995a). Immunohistochemical studies utilizing antibodies against the 5-HT carrier have revealed both neuronal and glial staining in areas of the rat brain containing 5-HT somata and terminals (i.e., DR and hippocampus) (Lawrence et al. 1995b). Experimental alterations of 5-HTT in young mice for a brief period during early development indicate abnormal emotional behavior in the same mice later in life, similar to the phenotype in mice where 5-HTT is deficient throughout life (Ansorge et al. 2004). This suggests the necessity of 5-HT early in emotional development and provides a possible mechanism by which genetic changes in the 5-HTT system may lead to susceptibility to developing psychiatric diseases such as depression (Caspi et al. 2003). Furthermore, 5-HT uptake ability has been documented in primary astrocyte cultures (Kimelberg and Katz 1985) and has been postulated to account for considerable 5-HT uptake in the frontal cortex and periventricular region (Ravid et al. 1992). Since 5-HTT is transcribed from a single copy gene, abnormalities in platelet 5-HTT have been postulated to reflect CNS abnormalities (Owens and Nemeroff 1998). A number of studies on platelet 5-HTT density have been undertaken using [3H]imipramine binding or [3H]paroxetine binding in mood disorders. Although the results of these studies are not entirely consistent, in toto the results suggest that the Bmax value for platelet 5-HT density is significantly lower in depressed subjects compared with healthy control subjects (Owens and Nemeroff 1998).

Beat Depression Today

Beat Depression Today

I know this is hard for you to believe. I mean, to be able to be totally free of depression in such little time... and without any effort... not to mention the freedom to live your life, appear hard to fulfill at first glance... That is until you know the facts On a subconscious level, you will experience an incredible and exclusive Tri- Enhanced trance state of hypnosis to reprogram your mind to free you from negatize emotions.

Get My Free Ebook


Post a comment