Editing Dehydroepiandrosterone (section)

===Neurosteroid activity===

====Neurotransmitter receptors====
DHEA has been found to directly act on several [[neurotransmitter receptor]]s, including acting as a [[positive allosteric modulator]] of the [[NMDA receptor]], as a [[negative allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]], and as an [[agonist]] of the [[sigma-1 receptor|σ<sub>1</sub> receptor]].<ref name="King2012" /><ref name="pmid26908835" />

====Neurotrophin receptors====
{{main|Neurotrophic factor receptor}}

In 2011, the surprising discovery was made that DHEA, as well as its sulfate ester, [[dehydroepiandrosterone sulfate|DHEA-S]], directly bind to and activate [[TrkA]] and [[p75NTR|p75<sup>NTR</sup>]], receptors of [[neurotrophin]]s like [[nerve growth factor]] (NGF) and [[brain-derived neurotrophic factor]] (BDNF), with high affinity.<ref name="pmid26908835">{{cite journal | vauthors = Prough RA, Clark BJ, Klinge CM | title = Novel mechanisms for DHEA action | journal = Journal of Molecular Endocrinology | volume = 56 | issue = 3 | pages = R139–55 | date = April 2016 | pmid = 26908835 | doi = 10.1530/JME-16-0013 | doi-access = free }}</ref><ref name="pmid21541365">{{cite journal | vauthors = Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A | title = Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis | journal = PLOS Biology | volume = 9 | issue = 4 | pages = e1001051 | date = April 2011 | pmid = 21541365 | pmc = 3082517 | doi = 10.1371/journal.pbio.1001051 | doi-access = free }}</ref> DHEA was subsequently also found to bind to [[TrkB]] and [[TrkC]] with high affinity, though it only activated TrkC not TrkB.<ref name="pmid26908835" /><ref name="pmid25330101">{{cite journal | vauthors = Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A | title = Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors | journal = Endocrinology | volume = 156 | issue = 1 | pages = 16–23 | date = January 2015 | pmid = 25330101 | doi = 10.1210/en.2014-1596 | url = https://zenodo.org/record/894291 | doi-access = free }}</ref> DHEA and DHEA-S bound to these receptors with affinities in the low [[nanomolar]] range (around 5&nbsp;nM), which were nonetheless approximately two orders of magnitude lower relative to highly potent [[polypeptide]] neurotrophins like NGF (0.01–0.1&nbsp;nM).<ref name="pmid26908835" /><ref name="pmid21541365" /><ref name="pmid25330101" /> In any case, DHEA and DHEA-S both circulate at requisite concentrations to activate these receptors and were thus identified as important endogenous [[neurotrophic factor]]s.<ref name="pmid26908835" /><ref name="pmid21541365" /> They have since been labeled "steroidal microneurotrophins", due to their [[small-molecule]] and steroidal nature relative to their polypeptide neurotrophin counterparts.<ref name="pmid23074265">{{cite journal | vauthors = Gravanis A, Calogeropoulou T, Panoutsakopoulou V, Thermos K, Neophytou C, Charalampopoulos I | title = Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells | journal = Science Signaling | volume = 5 | issue = 246 | pages = pt8 | date = October 2012 | pmid = 23074265 | doi = 10.1126/scisignal.2003387 | s2cid = 26914550 }}</ref> Subsequent research has suggested that DHEA and/or DHEA-S may in fact be phylogenetically ancient "ancestral" ligands of the neurotrophin receptors from early on in the [[evolution]] of the [[nervous system]].<ref name="pmid26908835" /><ref name="pmid25330101" /> The findings that DHEA binds to and potently activates [[neurotrophin receptor]]s may explain the positive association between decreased circulating DHEA levels with age and age-related [[neurodegenerative disease]]s.<ref name="pmid26908835" /><ref name="pmid21541365" />

====Microtubule-associated protein 2====
Similarly to [[pregnenolone]], its synthetic derivative [[3β-methoxypregnenolone]] (MAP-4343), and [[progesterone]], DHEA has been found to bind to [[microtubule-associated protein 2]] (MAP2), specifically the MAP2C subtype (K<sub>d</sub> = 27&nbsp;μM).<ref name="pmid26908835"/> However, it is unclear whether DHEA increases binding of MAP2 to [[tubulin]] like pregnenolone.<ref name="pmid26908835" />

====ADHD====
Some research has shown that DHEA levels are too low in people with ADHD, and treatment with methylphenidate or bupropion (stimulant type of medications) normalizes DHEA levels. <ref>{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/17763937/ | pmid=17763937 | year=2008 | last1=Lee | first1=M. S. | last2=Yang | first2=J. W. | last3=Ko | first3=Y. H. | last4=Han | first4=C. | last5=Kim | first5=S. H. | last6=Lee | first6=M. S. | last7=Joe | first7=S. H. | last8=Jung | first8=I. K. | title=Effects of methylphenidate and bupropion on DHEA-S and cortisol plasma levels in attention-deficit hyperactivity disorder | journal=Child Psychiatry and Human Development | volume=39 | issue=2 | pages=201–209 | doi=10.1007/s10578-007-0081-6 | s2cid=11041447 }}</ref>