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Downregulation question - Corrections

Posted by Scott L. Schofield on April 21, 2000, at 21:53:11

In reply to Re: Amineptine: what does this mean: Scott, CamW, posted by Scott L. Schofield on April 21, 2000, at 17:23:39

Please pardon my unpardonably deficient proofreading.

One "postsynaptic" should have been a "presynaptic".


> This is a quote for m a depression study abstract:
> Chronic treatment with amineptine induces downregulation of dopamine d2, beta- and alpha 2 adrenergic receptors.....
> What does this imply, 'downregulation'?
> AndrewB

"Downregulation" means roughly the same thing as "desensitization". Downregulation is the process by which the neuronal cell membrane becomes less sensitive to stimulation by the neurotransmitter. There are two mechanisms by which this may occur:

1. Reduction in the numbers of receptors along the membrane; decreased receptor density.
- measured as maximum binding sites (Bmax)

2. Decrease in the binding affinity of receptor for the transmitter molecule; decreased receptor "stickiness".
- measured as the dissociative constant (Kd)

Downregulation can be the result of increased levels of neurotransmitter within the synapse or exposure to ligand receptor agonists. Downregulation of receptors can also be brought about through mechanisms other than exposure to substrate. It can be thought of as the neuron's attempt to compensate for changes in its environment or workload.

That amineptine seems to cause a downregulation of noradrenergic receptors indicates that this drug may inhibit the reuptake of norepinephrine, as was initially described in early studies.

Basic results of downregulation at the synapse:

A downregulated POSTSYNAPTIC membrane requires a greater concentration of synaptic neurotransmitter to stimulate that neuron to fire (induce an action potential). The membrane is considered to be subsensitive. Neurotransmission is decreased.

A downregulated PRESYNAPTIC membrane requires a greater concentration of synaptic neurotransmitter to engage the negative feedback loop responsible for inhibiting neurotransmitter synthesis and vesicular release. Neurotransmission is increased.

Upregulation and its consequences can be regarded as the reverse.

Example: Upregulation of postsynaptic striatal D2 receptors is the result of their blockade by chronic administration of neuroleptic antipsychotics such as Haldol. The resulting supersensitivity of these membranes is thought to account for the development of tardive-dyskinesia.

Is depression the result of the abnormal regulation of neural activity brought about by inappropriate adjustments of membrane receptor sensitivities - dysregulation?

Hmmm. :-)

Thing get more interesting when specific receptor subtypes are selectively upregulated or downregulated. For more, see film at eleven.

- Scott

P.S. Andrew, I want a FREE autographed first edition copy of your upcoming book.




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