Serotonin-binding site

HT2 serotonin binding sites in rat frontal cortical homogenates. Data from Shannon et al. 1984. 

Savage, D. D., Mendels, J., and Frazer, A. (1980) Monoamine oxidase inhibitors and serotonin uptake inhibitors Differential effects on [3H]serotonin binding sites in rat brain. J. Pharmacol. Exp. Ther., 212 259-263. 

Odagaki Y, Koyama T, Matsubara S, et al Effects of chronic lithium treatment on serotonin binding sites in rat brain. J Psychiatr Res 24 271-277, 1990 O Dwyer AM, Lightman SL, Marks MN, et al Treatment of major depression with metyrapone and hydrocortisone. J Affect Disord 33 123-128, 1995 Oehrberg S, Christiansen PE, Behnke K, et al Paroxetine in the treatment of panic disorder a randomised, double-blind, placebo-controlled study. Br J Psychiatry 167(3)374-379, 1995... 

Manivet P, Schneider B, Smith JC, Choi DS, Maroteaux L, Kellermann O. The serotonin binding site of human and murine 5-HT2B receptors molecular modeling and site-directed mutagenesis. J Biol Chem 2002 277 17,170-17,178. 

Glennon RA, Naiman NA, Pierson ME, et al. Ar-(Phthalimidoalkyl) derivatives of serotonergic agents a common interaction at 5-HT1A serotonin binding sites J Med Chem 1989 32 1921-1926. 

Serotonin, also known as 5-hydroxytryptamine (5-HT) is biosynthesized from tryptophan and is a neurotransmitter. Serotonin plays an important role in many behaviors including sleep, appetite, memory, and mood [52]. People with depressive disorders exhibit low levels of serotonin in the synapses. Protonated serotonin binds to a serotonin reuptake transporter protein, sometimes referred to as the serotonin transporter (SERT) and is then moved to an inward position on the neuron and subsequently released into the cjdoplasm. Selective serotonin reuptake inhibitors (SSRI) bind with high affinity to the serotonin binding site of the transporter. This leads to antidepressant effects by increasing extracellular serotonin levels which in turn enhances serotonin neurotransmission [53]. The SSRI class of antidepressants has fewer side effects than the monoamine oxidase inhibitors. 

Ochoa EL, Bangham AD. N-Acetylneuraminic acid molecules as possible serotonin binding sites. / Neurochem. 1976 26(6) 1193-1198. 

McQueen, JK, Wilson, H, Sumner, BEH and Fink, G (1999) Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids. Molec. Brain Res. 63 241-247. 

Dr. Gibb s hypothesis regarding dopamine involvement, we thought that perhaps MBDB would not be neurotoxic because of a lack of effect on dopamine. But, in fact, it is neurotoxic as well, measured by whole-brain serotonin 5-HIAA and tritiated paroxetine binding sites. It is perhaps two-thirds the toxicity, on a molecular weight basis, of MDMA, but it is toxic. 

ANSWER We used it in the 20 mg/kg twice a day for a 4-day regimen with MDMA, and then corrected for molecular weight and used an equimolar dose of MBDB, sacrificed the animals 2 weeks later, and then measured. We used basically HPLC and used serotonin and 5-HIAA from one hemisphere and then measured tritiated pyroxetine from the other hemisphere. And we got something like 60 percent depletion of serotonin, and the pyroxetine binding site decreased by about 60 percent. With MBDB it was decreased by about 40 percent. It was a clear and significant decrease, but not quite to the extent that we had. But we have not looked at tryptophan hydroxylase. 

H]MDMA interacted with multiple sites in rat brain. A low affinity pH]MDA binding site (apparent Kd>1.0 mM) was found to be resistant to boiling of the synaptosomal preparation for 15 minutes. This site was saturable, as indicated by a 30 pereent inhibition of [ H]MDA binding to boiled synaptosomes by 1.0 mM MDA and a 56 pereent inhibition of the binding by 0.1 mM of the serotonin uptake bloeker paroxetine. The indication of a saturable, nonspecific binding site for [ H]MDA in boiled membranes necessitated that we use boiled tissue to assess nonspecific binding in all subsequent experiments. 

The affinity (Kj values) observed for [ H]MDA and [ HJMDMA binding were similar to the effective doses (i.e., ED50 or K] values) of MDA and MDMA reported for various pre- and postsynaptic monoamine markers, such as serotonin and dopamine release (Johnson et al. 1986), monoamine transport (Steele et al. 1987), and multiple brain, ligand binding sites (Battaglia et al. 1988). 

In addition to its relatively high affinity at postsynaptic 5-HT receptors, MDMA exhibited high affinity for 5-HT uptake sites and has been shown to increase the release of [ H]5-HT and block [ H]5-HT uptake in vitro. These data suggest that some of the actions of MDMA may be mediated at presynaptic binding sites. With respect to [ H]5-HT release, MDMA has been reported to increase the release of [ H]5-HT from brain synaptosomes (Nichols et al. 1982) and hippocampal slices (Johnson et al. 1986). With respect to uptake blockade, MDMA has been reported to competitively inhibit H-5-HT uptake in vitro (Shulgin 1986). Furthermore, the neurotoxic effects of in vivo administration of MDMA on serotonin terminals can be blocked by concomitant administration of the 5-HT uptake blocker citalo-pram (Battaglia et al. 1988b Schmidt and Taylor 1987). Additional evidence in support of the hypothesis that MDMA produces some of its... 

Bruinink A., Lichtensteiger W., Schlumpf M. (1983). Ontogeny of diurnal rhythms of central dopamine, serotonin and spirodecanone binding sites and of motor activity in the rat. Life Sci. 33(1), 31-8. 

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. 

---