This study shows that serotonin in the brain can pass the BBB and elevate the serotonin in the blood. However, an SSRI abolished the elevation as it decreases the serotonin transporter that is necessary for the pass through the BBB. This study doesn't state if serotonin in the blood can elevate brain serotonin.
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"The present study revealed that whole‐blood 5‐HT levels exhibited significant augmentation when brain 5‐HT levels were elevated after 5‐HTP administration in rats that had undergone total removal of their gastrointestinal tracts and kidneys, along with liver inactivation.
This result implies that 5‐HT may cross the brain into the circulating blood via the BBB. However, there are two major reasons that may be cited as evidence as to why 5‐HT cannot possibly cross from the brain into the circulating blood via the BBB.
First, the BBB is formed by tight junctions of the brain capillary endothelial cells. The role of these junctions is to prevent neurotransmitters including 5‐HT from crossing the junction and thus ensuring that all neurotransmitters are retained in the brain. However, recent in vitro studies (Brust et al., 2000; Wakayama et al., 2002) have revealed the presence of 5‐HT transporter mRNA in vascular endothelial cells. This indicates that the BBB may act as an efflux transport system for 5‐HT. Based on this new data, we conducted the present in vivo functional study. As a result, we found that indeed 5‐HT can cross from the brain into the circulating blood via the BBB.
The second reason that is cited as to why 5‐HT cannot cross the BBB is related to the 5‐HT content that is found within the organs. It has been reported that > 90% of the total 5‐HT content in the whole body is distributed within the gastrointestinal tract (West, 1958; Gaginella, 1995), and that only a very small percentage of the total 5‐HT content is found within the brain. Therefore, it has been believed that the augmented ECF 5‐HT in the brain does not contribute to any significant changes in the 5‐HT levels within the circulating blood. Therefore, we administered 5‐HTP intravenously in rats that had undergone the abdominal operation in an attempt to elevate brain 5‐HT alone. As a result, we found that whole‐blood 5‐HT levels significantly increased whenever brain ECF 5‐HT levels were elevated by the 5‐HTP administration in the rats undergoing the abdominal operation. Therefore, it is reasonable to hypothesize that the augmented brain ECF 5‐HT does contribute to a significant change in 5‐HT levels within the circulating blood. In other words, augmented brain ECF 5‐HT can translocate from the brain into the blood via the BBB.
This hypothesis may be further supported by the data concerning regional differences of the 5‐HTP decarboxylase, which is the enzyme responsible for metabolizing 5‐HTP to 5‐HT. A study by West (1958) demonstrated that there was high 5‐HTP decarboxylase activity in the kidneys (188 µg/tissue) and the liver (125 µg/tissue), with only a very low activity noted in the gastrointestinal tract (1–2 µg/tissue). The brain exhibited moderate activity for 5‐HTP decarboxylase (32 µg/tissue). In addition, 5‐HT that is produced by the gastrointestinal tract is thought to be metabolized by monoamine oxidase in the liver, as it circulates through the portal vein (Gillis, 1985). Therefore, it is unlikely that the gastrointestinal tract would make any significant contribution towards increasing blood 5‐HT when 5‐HTP is administered to the intact rat.
With regard to intrarenal formation of 5‐HT by renal decarboxylase, Stier & Itskovitz, 1985) demonstrated that administration of 5‐HTP resulted in an increase in urinary 5‐HT without a concomitant increase in plasma 5‐HT in the rat. Based on this result, it is reasonable to speculate that intrarenal formation of 5‐HT may not contribute to an increase in 5‐HT in whole blood after 5‐HTP administration.
Based on data by West (1958), the whole organs that exhibit 5‐HTP decarboxylase activity include the kidneys, the liver, the gastrointestinal tract, the brain and the skin. After 5‐HTP administration in rats that underwent resection of their gastrointestinal tracts and kidneys along with liver inactivation, the skin in addition to the brain were the two organs found to be capable of augmenting the whole‐blood 5‐HT levels. However, skin has been demonstrated to show the lowest amount of enzyme activity (1 µg/tissue). Thus, it is less likely that 5‐HT in the skin contributes to any significant augmentation of 5‐HT in the whole blood after 5‐HTP administration, even though we can not completely rule out this possibility.
The other new finding of the present study is that SSRI pretreatment in rats lacking functional kidneys, gastrointestinal tract and liver abolished elevation of whole‐blood 5‐HT levels that was induced by 5‐HTP administration, even though the brain 5‐HT levels remained increased. These results suggest that the 5‐HT transporters that are located on the brain endothelial cells play the inevitable role associated with crossing from the brain via the BBB into the circulating blood. As discussed earlier, the in vitro study by Brust et al. (2000) revealed the presence of a 5‐HT transporter mRNA in the brain endothelium, indicating that cerebral endothelial cells are able to actively participate in the removal of the released 5‐HT within the brain. This possibility was functionally proven in the present in vivophysiological study that used the SSRI. Thus, we hypothesized that the 5‐HT transporters located on the brain endothelial cells may act as the efflux transport system for the 5‐HT that crosses from the brain into the circulating blood.
What physiological role does the 5‐HT transporter located on the brain endothelium actually play? It has been established that the 5‐HT transporter is present not only in the synaptic terminals of 5‐HT neurons but also in the brain endothelial cells (Brust et al., 2000; Wakayama et al., 2002). Therefore, we can hypothesize that both 5‐HT transporters play a significant role in 5‐HT homeostasis within the brain. There is no doubt that 5‐HT transporters located on the terminals of 5‐HT neurons play an inevitable role in 5‐HT homeostasis within the synaptic cleft. On the other hand, it has been reported that 5‐HT's role is more in line with volume transmission than classical neurotransmission (Fuxe & Agnati, 1991; Hornung, 2003; Fuxe et al., 2007). 5‐HT released from the axonal terminals and varicosities diffuses over a long distance to act on other neurons. In this particular case, the released 5‐HT could be detected as a change in ECF 5‐HT in the brain. Augmented ECF 5‐HT within the brain may be drained away via the endothelial 5‐HT transporter that is located in the nearby endothelial cells, thereby maintaining 5‐HT homeostasis in the brain. In other words, the physiological role of the BBB is not only to act as a barrier but also to play a role as a regulatory interface for brain ECF 5‐HT.
In summary, increased brain ECF 5‐HT is removed from the brain into the circulating blood via the 5‐HT transporter system located on the brain endothelial cells."
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"The present study revealed that whole‐blood 5‐HT levels exhibited significant augmentation when brain 5‐HT levels were elevated after 5‐HTP administration in rats that had undergone total removal of their gastrointestinal tracts and kidneys, along with liver inactivation.
This result implies that 5‐HT may cross the brain into the circulating blood via the BBB. However, there are two major reasons that may be cited as evidence as to why 5‐HT cannot possibly cross from the brain into the circulating blood via the BBB.
First, the BBB is formed by tight junctions of the brain capillary endothelial cells. The role of these junctions is to prevent neurotransmitters including 5‐HT from crossing the junction and thus ensuring that all neurotransmitters are retained in the brain. However, recent in vitro studies (Brust et al., 2000; Wakayama et al., 2002) have revealed the presence of 5‐HT transporter mRNA in vascular endothelial cells. This indicates that the BBB may act as an efflux transport system for 5‐HT. Based on this new data, we conducted the present in vivo functional study. As a result, we found that indeed 5‐HT can cross from the brain into the circulating blood via the BBB.
The second reason that is cited as to why 5‐HT cannot cross the BBB is related to the 5‐HT content that is found within the organs. It has been reported that > 90% of the total 5‐HT content in the whole body is distributed within the gastrointestinal tract (West, 1958; Gaginella, 1995), and that only a very small percentage of the total 5‐HT content is found within the brain. Therefore, it has been believed that the augmented ECF 5‐HT in the brain does not contribute to any significant changes in the 5‐HT levels within the circulating blood. Therefore, we administered 5‐HTP intravenously in rats that had undergone the abdominal operation in an attempt to elevate brain 5‐HT alone. As a result, we found that whole‐blood 5‐HT levels significantly increased whenever brain ECF 5‐HT levels were elevated by the 5‐HTP administration in the rats undergoing the abdominal operation. Therefore, it is reasonable to hypothesize that the augmented brain ECF 5‐HT does contribute to a significant change in 5‐HT levels within the circulating blood. In other words, augmented brain ECF 5‐HT can translocate from the brain into the blood via the BBB.
This hypothesis may be further supported by the data concerning regional differences of the 5‐HTP decarboxylase, which is the enzyme responsible for metabolizing 5‐HTP to 5‐HT. A study by West (1958) demonstrated that there was high 5‐HTP decarboxylase activity in the kidneys (188 µg/tissue) and the liver (125 µg/tissue), with only a very low activity noted in the gastrointestinal tract (1–2 µg/tissue). The brain exhibited moderate activity for 5‐HTP decarboxylase (32 µg/tissue). In addition, 5‐HT that is produced by the gastrointestinal tract is thought to be metabolized by monoamine oxidase in the liver, as it circulates through the portal vein (Gillis, 1985). Therefore, it is unlikely that the gastrointestinal tract would make any significant contribution towards increasing blood 5‐HT when 5‐HTP is administered to the intact rat.
With regard to intrarenal formation of 5‐HT by renal decarboxylase, Stier & Itskovitz, 1985) demonstrated that administration of 5‐HTP resulted in an increase in urinary 5‐HT without a concomitant increase in plasma 5‐HT in the rat. Based on this result, it is reasonable to speculate that intrarenal formation of 5‐HT may not contribute to an increase in 5‐HT in whole blood after 5‐HTP administration.
Based on data by West (1958), the whole organs that exhibit 5‐HTP decarboxylase activity include the kidneys, the liver, the gastrointestinal tract, the brain and the skin. After 5‐HTP administration in rats that underwent resection of their gastrointestinal tracts and kidneys along with liver inactivation, the skin in addition to the brain were the two organs found to be capable of augmenting the whole‐blood 5‐HT levels. However, skin has been demonstrated to show the lowest amount of enzyme activity (1 µg/tissue). Thus, it is less likely that 5‐HT in the skin contributes to any significant augmentation of 5‐HT in the whole blood after 5‐HTP administration, even though we can not completely rule out this possibility.
The other new finding of the present study is that SSRI pretreatment in rats lacking functional kidneys, gastrointestinal tract and liver abolished elevation of whole‐blood 5‐HT levels that was induced by 5‐HTP administration, even though the brain 5‐HT levels remained increased. These results suggest that the 5‐HT transporters that are located on the brain endothelial cells play the inevitable role associated with crossing from the brain via the BBB into the circulating blood. As discussed earlier, the in vitro study by Brust et al. (2000) revealed the presence of a 5‐HT transporter mRNA in the brain endothelium, indicating that cerebral endothelial cells are able to actively participate in the removal of the released 5‐HT within the brain. This possibility was functionally proven in the present in vivophysiological study that used the SSRI. Thus, we hypothesized that the 5‐HT transporters located on the brain endothelial cells may act as the efflux transport system for the 5‐HT that crosses from the brain into the circulating blood.
What physiological role does the 5‐HT transporter located on the brain endothelium actually play? It has been established that the 5‐HT transporter is present not only in the synaptic terminals of 5‐HT neurons but also in the brain endothelial cells (Brust et al., 2000; Wakayama et al., 2002). Therefore, we can hypothesize that both 5‐HT transporters play a significant role in 5‐HT homeostasis within the brain. There is no doubt that 5‐HT transporters located on the terminals of 5‐HT neurons play an inevitable role in 5‐HT homeostasis within the synaptic cleft. On the other hand, it has been reported that 5‐HT's role is more in line with volume transmission than classical neurotransmission (Fuxe & Agnati, 1991; Hornung, 2003; Fuxe et al., 2007). 5‐HT released from the axonal terminals and varicosities diffuses over a long distance to act on other neurons. In this particular case, the released 5‐HT could be detected as a change in ECF 5‐HT in the brain. Augmented ECF 5‐HT within the brain may be drained away via the endothelial 5‐HT transporter that is located in the nearby endothelial cells, thereby maintaining 5‐HT homeostasis in the brain. In other words, the physiological role of the BBB is not only to act as a barrier but also to play a role as a regulatory interface for brain ECF 5‐HT.
In summary, increased brain ECF 5‐HT is removed from the brain into the circulating blood via the 5‐HT transporter system located on the brain endothelial cells."
