Talk:Dopamine receptor D2

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Ketamine[edit]

Why is ketamine not included in the list of agonists? It's a pretty important example IMO. —Preceding unsigned comment added by 65.185.67.95 (talk) 01:20, 14 May 2011 (UTC)

Description of partial agonist LSD misleading[edit]

I edited the text describing LSD's partial agonism for D2, which was reverted.

@Boghog:

The text in question (which I replaced) is: "LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs".

  • In your revision edit summary, you say, "by defintion, partial agonist increase, inverse agonists decrease response". Yet, according to Partial agonist, "[partial agonists] may also be considered ligands which display both agonistic and antagonistic effects".
  • According to the referenced paper's abstract, "LSD produced a dose-dependent inhibition of prolactin secretion", and, "LSD ... potentiated the dopamine-mediated prolactin secretion by pituitary cells".[1] Response increased or decreased depending on the concentration of LSD. This agrees with Wikipedia's definition of a partial agonist.
  • The text in question is confusing. When LSD is agonizing the receptors, prolactin secretion is reduced, not potentiated. It is the antagonistic activity of LSD that potentiates/increases prolactin secretion. You have to know that partial agonists can act both as agonists and competitive antagonists.

References

  1. ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B (1998). "Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro". Life Sciences. 63 (3): 215–22. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051. 

I honestly think the title of the paper is confusing, but I am not a neuroscientist. I think "modulates" would be a better word than "potentiates". The abstract itself says, "[LSD] has a unique capacity for modulating dopaminergic transmission", which I think is a much more accurate statement.

And, why do we need this description added to the bullet point for LSD in the first place? The heading of the list already confers that LSD is a partial agonist. Is the effect of LSD on lactotrophs really that important?

I hope I'm not wrong about this!

Themckinlay (talk) 18:34, 9 July 2016 (UTC)

@Themckinlay: Thank for your thoughtful reply. I am not a neuropharmacologist either and I agree that the source is somewhat confusing. I also agree If an agonist and partial agonist act at the same site, a partial agonist will decrease the functional effect of high concentrations of the full agonist through competitive binding. To say that LSD can either increase or decrease receptor activity or is a receptor modulator is a little vague. These phrases could also be interpreted as meaning that LSD is a mixed agonist/antagonist which the source does not support. LSD only decreases DR activity in the presence of high concentration of dopamine which is not the usual situation. It would be more precise to state that (1) LSD is a partial agonist in the absence of dopamine, (2) potentiates the activity of dopamine at low dopamine concentrations and (3) reduces the activity of dopamine at high dopamine concentrations. Finally I think that is important to mention lactotrophs since the activity of LSD on DR2 may be cell-type/tissue specific. Boghog (talk) 12:22, 10 July 2016 (UTC)
@Boghog: Thanks for the attentive response! This is my first time being a Wikipedian!
If reduction of D2 activity at high concentrations of dopamine is not "the usual situation", then the Wiki article should not state that LSD "potentiates dopamine-mediated prolactin secretion". Instead, the the article should state that LSD "inhibits dopamine-mediated prolactin secretion". D2 agonism inhibits prolactin secretion in lactotrophs. According to Prolactin, "neurons of the arcuate nucleus that secrete dopamine (aka Prolactin Inhibitory Hormone) ... act on the D2 receptors of lactotrophs, causing inhibition of prolactin secretion". Maybe my definition of "potentiation" is confused. I am assuming that potentiation means "eliciting a strictly positive response" (an increase in prolactin secretion in this case).
Also, you say, "LSD is a partial agonist in the absence of dopamine". The term, "partial agonist", applies to situations in which a compound acts as an agonist and to situations in which a compound acts as an antagonist. Yes, the concentration of another compound may influence whether a partial agonist acts as an agonist or an antagonist, but it does not change the fact that the partial agonist remains a partial agonist. Otherwise, why wouldn't LSD be listed under the "agonists" and "antagonists" subsections of the Wiki article as well?
Regarding saliency, where does the paper state that activity may be cell-type/tissue specific? I presume that all of the ligands listed in the Wiki article would have similar effects on lactotrophs. I don't think LSD's effect on lactotrophs is unique enough to mention. Also, your reasoning against using the term modulates states that there is no evidence to support that LSD is a mixed agonist/antagonist.
Themckinlay (talk) 17:14, 10 July 2016 (UTC); edited 19:07, 10 July 2016 (UTC)
I agree that the nomenclature is a bit confusing. According to the source, the effect of dopamine agonism is to decrease prolactin secretion. The agonist/antagonist definition is not based on whether the down stream effect is increased or decreased, but rather based on the effect that the endogenous neurotransmitter has. Dopamine is by definition an agonist, regardless of the direction of the downstream effect. LSD like dopamine also decreases prolactin secretion and hence LSD is considered a dopamine receptor agonist at least in lactotrophs. Potentiation synonymous with synergy (the sum of the activity is greater than its parts). LSD does not potentiate the activity of dopamine at high dopamine concentrations because the activity is already at a maximum. LSD does potentiate the activity of dopamine at physiologically relevant (low to moderate) concentrations of dopamine. The list of agonists and antagonists may be an oversimplification since the same ligand may behave as an agonist in some tissues and while an antagonist other tissues (one definition of a mixed agonist/antagonist). Unfortunately not all ligands have been tested in all tissues. The source in question only states that LSD is an agonist in lactotrophs. Hence based on this source, we cannot say if LSD is a pure D2 partial agonist or a mixed agonist/antagonist. Boghog (talk) 20:15, 10 July 2016 (UTC)
@Boghog: What does "potentiate dopamine-mediated prolactin secretion" mean, then? I understand it as increase dopamine-mediated prolactin secretion. Themckinlay (talk) 21:07, 10 July 2016 (UTC)
  • The definition of "mediate" is "to bring about a result such as a physiological effect". The physiological effect of dopamine in lactotrophs as shown in figure 1 of the source is to reduce prolactin secretion. In the caption of figure 3 of the source, it states "This potentiating effect of LSD on dopamine-mediated prolactin InhIbition vanished when dopamine was present at concentrations 5x10-9 M (D)." Boghog (talk) 04:39, 11 July 2016 (UTC)
  • The title of the source would have been much clearer if it were modified to read: "... LSD ... potentiates dopamine-mediated inhIbition of prolactin secretion in lactotrophs in vitro." Boghog (talk) 08:14, 11 July 2016 (UTC)