Synaptic serotonin transporters

Selective serotonine reuptake inhibitor (SSRI) is an abbreviation for the class of antidepressants known as the Selective Serotonin Reuptake Inhibitors. Examples of SSRIs include fluoxetine, paroxetine, citalopram, and sertraline. These drugs selectively inhibit the serotonin transporter thus prolonging the synaptic lifespan of the neurotransmitter serotonin. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

The activity of 5-HT in the synapse is terminated primarily by its re-uptake into serotonergic terminals 234 Acute and chronic regulation of serotonin transporter function provides means for altering synaptic 5-HT concentrations and neurotransmission 236... 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

Fluoxetine Highly selective blockade of serotonin transporter (SERT) little effect on norepinephrine transporter (NET) Acute increase of serotonergic synaptic activity slower changes in several signaling pathways and neurotrophic activity Major depression, anxiety disorders panic disorder obsessive-compulsive disorder post-traumatic stress disorder perimenopausal vasomotor symptoms eating disorder (bulimia) Half-lives from 15-75 h oral activity Toxicity Well tolerated but cause sexual dysfunction Interactions Some CYP inhibition (fluoxetine 2D6, 3A4 fluvoxamine 1A2 paroxetine 2D6)... 

Synaptic serotonin (5-hydroxytryptamine) transporters are inhibited by amphetamines, the tropane alkaloids cocaine and ecgonine [194] and by the indole alkaloid ibogaine (12-methoxyibogamine) and its demethylation product ibogamine [191, 195]. Hyperforin is a major antidepressant constituent of St. John s Wort (Hypericum perforatum) and inhibits serotonin uptake by elevating cytosolic Na+ [196]. The additional... 

FIGURE 5—34. Serotonin (5-hydroxytryptamine [5HT ) is produced from enzymes after the amino acid precursor tryptophan is transported into the serotonin neuron. The tryptophan transport pump is distinct from the serotonin transporter (see Fig. 5—35). Once transported into the serotonin neuron, tryptophan is converted into 5-hydroxytryptophan (5HTP) by the enzyme tryptophan hydroxylase (TryOH) which is then converted into 5HT by the enzyme aromatic amino acid decarboxylase (AAADC). Serotonin is then stored in synaptic vesicles, where it stays until released by a neuronal impulse. 

Mlinar B, Corradetti R. Endogenous 5-HT, released by MDMA through serotonin transporter- and secretory vesicle-dependent mechanisms, reduces hippocampal excitatory synaptic transmission by preferential activation of 5-HT1B receptors located on CA1 pyramidal neurons. Eur J Neurosci 2003 18 1559-1571. 

Synaptic transmission requires the release of neurotransmitters into the extracellular space to bind pre-or postsynaptic receptors, conveying a chemical message to nerve cells (Torres et al 2003a). Termination of this signaling occurs rapidly by uptake of the released neurotransmitter into the presynaptic cell by high-affinity neurotrans-mitter transporters. The clearance of the monoamines dopamine, norepinephrine, and serotonin occurs via the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), respectively (Torres et al., 2003a)... 

Serotonin reuptake transporter (reduces synaptic serotonin levels)... 

Stress is also involved in the modulation of the immune responses through mechanisms involving the neurotransmitter serotonin. This is a biologically active amine that plays a prominent role in the regulation of processes such as mood, appetite and sleep. During neurotransmission, serotonin is released from neurons into the synaptic cleft between cells. The amount of serotonin available for neurotransmission in the synaptic cleft is regulated largely by the serotonin transporter involved in the reuptake of serotonin after it has been released.23... 

The cause or causes and the meaning of the elevation of platelet 5-HT observed in some autistic patients is unknown, but the serotonin transporter (5-HTT) is thought to be involved as it controls the rate of reuptake of serotonin from the synaptic cleft. The fact that selective serotonin reuptake inhibitors ameliorate obsessive compulsive symptoms, stereotypies, affective liability and social relatedness in some subjects with autism [16, 17], lends further support for this hypothesis. After... 

Aldridge, J., Seidler, E, and Slotkin. T. (2004). Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood Critical periods and regional selectivity for effects on the serotonin transporter, receptor. subtypes, and cell signaling. Environ. Health Perspect. 112, 148-155. 

HT and other monoamines affect emotions, whereas ACh and DA affect movement and emotions. Blocking serotonin transporters on presynaptic neurons with drugs increases synaptic concentrations of 5-HT, which makes depressed patients feel better. Other neurotransmitters, such as endogenous opiates, increase pleasure and decrease paia... 

Patients may include psychopaths who express habitual aggression and are responsible for much crime, some of which is violent. Impulsivity, aggression and lack of empathy are often observed in some patients following head trauma or encephalitis, which supports an organic cause. Drugs that block serotonin transporters and increase synaptic serotonin levels help these people. Hormonal effects also are involved, because of gender-related differences in the incidence of violence and aggressiveness. More than... 

Serotonin also affects the emotions of love and romance. Androgens, estrogens, oxytocin, and vasopressin increase the sex drive, whereas increased levels of synaptic serotonin, such as result from the taking of reuptake transporter inhibitors, suppress the sex drive and inhibit feelings of attraction by the opposite sex. Dopamine and norepinephrine increase the sex drive. 

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