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If a dopamine is released at T=0 and binds to receptor D2, what determines the time when the concentration of this neurotransmitter bound to the receptor reaches half of the original concentration? In other words, when will the effect of neurotransmitter on the intercell signalling fall in half?

Is there any time estimate of how quickly the brain thinks that neurotransmitter has "fulfilled its purpose" and is to be re-uptaken? Or is this process completely random?

Thank you for your input!

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    $\begingroup$ All processes involving reuptake or metabolism of biological molecules are completely random. However, when you look at a large number of molecules over time, the random events combine into a stable, predictable rate of decay. This rate is usually either exponential decay (a half-life) or, more rarely, a constant amount per second. $\endgroup$ – octern Nov 18 '12 at 19:10
  • $\begingroup$ I don't know what the answer is for dopamine, and individuals probably vary in how zealous their brains are about dopamine reuptake. $\endgroup$ – octern Nov 18 '12 at 19:12
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The half life of dopamine in the extracellular space is of the order of 200 milliseconds.

Yavich,L. (2007) Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum. J. Neurosci. 27:10196-10202

In Figure 1 of this paper the authors present values for the half-life (τ) of dopamine elimination from extracellular space in the caudate nucleus and prefrontal cortex of mice as:

caudate nucleus: 0.2 +/- 0.03 sec

prefrontal cortex: 1.92 +/- 0.22 sec

Apparently this is because dopamine is usually inactivated when the presynaptic cell takes it back up using the dopamine transporter, but in the prefrontal cortex uptake is instead via a lower affinity norepinephrine transporter on neighbouring neurones. Thus the value of 200 milliseconds seen in the caudate nucleus is probably more typical.

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  • $\begingroup$ Interesting. Does this mean that upon release, dopamine has 200ms to either bind to a receptor or be reabsorbed? $\endgroup$ – Alex Stone Nov 18 '12 at 23:28
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    $\begingroup$ If we think of release as instantaneous, we now have a pool of extracellular dopamine. This will begin to bind to receptor, setting up an equilibrium between free and bound. The free dopamine will also be taken up by DAT, and because the binding to receptor is a reversible process, as the external pool shrinks the level of DA-receptor complex will shrink. An individual molecule could be taken up without ever binding to a receptor, or could undergo multiple receptor binding/release cycles before being taken up. The half-life reflects the interaction between these processes. $\endgroup$ – Alan Boyd Nov 19 '12 at 13:08
  • $\begingroup$ If I understand correctly, the DAT cleans up extracellular and bound DA, and deposits it back within the neuron. As less and less extracellular DA is available, there's a higher chance that bound DA will be recovered. Is this correct? $\endgroup$ – Alex Stone Nov 19 '12 at 16:57
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Dopamine (DA) secreted by neurons is selectively reuptaken by the dopamine transporter (DAT), present on nerve terminals.

Monoamine reuptake
(source: inist.fr)

Image source: Plasma membrane monoamine transporters: structure, regulation and function - Torres et al. - Nat Rev Neurosci., 2003

DAT acts as a symporter, using the Na+ and Cl- gradients to generate the energy required to transport DA back in the cytosol.

The mechanism of reuptake has been investigated in vitro allowing the description of a model for DA reuptake by DAT.

In particular, from the abstract of this paper: A multisubstrate mechanism of striatal dopamine uptake and its inhibition by cocaine. - McElvain and Schenk, Biochem Pharmacol., 1992

Dopamine uptake was found to be first order in dopamine with a Vmax of 582 pmol/sec/g wet weight and a Km of 1.2 μM. The results of experiments in which choline and isethionate were substituted for Na+ and Cl−, respectively, suggested that the uptake process is second order in Na+ and first order in Cl−. Multisubstrate analyses of the initial velocities of uptake over the concentration range of 0.025 to 1.5 μM dopamine suggested that the mechanism of binding of dopamine to the uptake carrier is a partially random, sequential mechanism where dopamine or Na+ binds first with the uptake carrier and Cl− binds last.

A transport scheme is reported in: Dopamine Neuronal Transport Kinetics and Effects of Amphetamine

DAT schematics

Scheme 1 is a kinetic scheme for a simple carrier adapted from that of Stein (1986) for the DAT. The subscripts o and i represent the outside and inside, respectively, of a DA neuron. Scheme 2 describes a possible mechanism for the cotransport of another species. All symbols are as in scheme 1 except that A corresponds to amphetamine.

From the text

This scheme describes transport as a series of steps: the competition between binding and dissociation of the substrate to the transporter on the extracellular side, a similar process on the cytoplasmic side, and an equilibrium between the unoccupied transporter facing toward the extracellular or cytoplasmic side. The driving force for inward transport arises from the cotransport of Na1 and Cl2 as well as the membrane potential difference (Stein, 1986; Sonders et al., 1997). Biochemical (Krueger, 1990) and electrophysiological (Sonders et al.,1997) studies have established that DA transport is accompanied by transport of at least two Na1 ions and one Cl2 ion and that DA transport can be bidirectional in isolated preparations.

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  • $\begingroup$ If I'm reading this correctly, then Dopamine is randomly extracted from receptors, right? $\endgroup$ – Alex Stone Nov 18 '12 at 23:31
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    $\begingroup$ Not really "extracted"... dopamine will randomly detach from the receptor, and randomly bind to DAT. The speed of this may depend on the actual concentration of dopamine, dopamine receptor and DAT present in the system. $\endgroup$ – nico Nov 18 '12 at 23:49
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This is an attempt to illustrate how a system like this behaves kinetically, to help Alex visualise it. The model shown below contains external dopamine which can bind reversibly to a receptor. The unbound dopamine is subject to irreversible reuptake.

enter image description here

I built a quick simulation using Copasi. I haven't made any attempt to refine the parameters to fit the information in my previous answer - I'm just trying to illustrate qualitatively how the three different pools of dopamine (free external, bound external, internalised) behave in this kind of system. As @nico says, there is no question of extracting the receptor-bound dopamine - it will dissociate as the free dopamine concentration falls due to reuptake.

enter image description here

enter image description here

enter image description here

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