Editing Amphetamine (section)

====Other neurotransmitters, peptides, hormones, and enzymes====
{| class="wikitable sortable" style="margin-left: 8px; float:right; text-align:center"
|+ Human [[carbonic anhydrase]]<br />activation potency
! [[Enzyme]]
! K<sub>A</sub> ({{abbrlink|nM|nanomolar}})
! class="unsortable" | <small>Sources</small>
|-
| [[Carbonic anhydrase 4|hCA4]] || 94 ||<ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 5A, mitochondrial|hCA5A]] || 810 ||<ref name="Amphetamine-induced activation of 7 hCA isoforms">{{cite journal | vauthors = Angeli A, Vaiano F, Mari F, Bertol E, Supuran CT | title = Psychoactive substances belonging to the amphetamine class potently activate brain carbonic anhydrase isoforms VA, VB, VII, and XII | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 32 | issue = 1 | pages = 1253–1259 | date = December 2017 | pmid = 28936885 | pmc = 6009978 | doi = 10.1080/14756366.2017.1375485 | quote = Here, we report the first such study, showing that amphetamine, methamphetamine, phentermine, mephentermine, and chlorphenteramine, potently activate several CA isoforms, some of which are highly abundant in the brain, where they play important functions connected to cognition and memory, among others26,27.&nbsp;... We investigated psychotropic amines based on the phenethylamine scaffold, such as amphetamine 5, methamphetamine 6, phentermine 7, mephentermine 8, and the structurally diverse chlorphenteramine 9, for their activating effects on 11 CA isoforms of human origin&nbsp;... The widespread hCA I and II, the secreted hCA VI, as well as the cytosolic hCA XIII and membrane-bound hCA IX and XIV were poorly activated by these amines, whereas the extracellular hCA IV, the mitochondrial enzymes hCA VA/VB, the cytosolic hCA VII, and the transmembrane isoform hCA XII were potently activated. Some of these enzymes (hCA VII, VA, VB, XII) are abundant in the brain, raising the possibility that some of the cognitive effects of such psychoactive substances might be related to the activation of these enzymes.&nbsp;... CAAs started to be considered only recently for possible pharmacologic applications in memory/cognition therapy27. This work may bring new lights on the intricate relationship between CA activation by this type of compounds and the multitude of pharmacologic actions that they can elicit.<br /> —Table 1: CA activation of isoforms hCA I, II, IV, VII, and XIII [5: amphetamine]<br /> —Table 2: CA activation of isoforms hCA VA, VB, VI, IX, XII, and XIV [5: amphetamine]}}</ref><ref name="IUPHAR Amphetamine">{{cite web | title=Amphetamine: Biological activity | url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=4804 | website=IUPHAR/BPS Guide to Pharmacology | publisher=International Union of Basic and Clinical Pharmacology | access-date=31 December 2019}}</ref>
|-
| [[Carbonic anhydrase 5B, mitochondrial|hCA5B]] || 2560 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 7|hCA7]] || 910 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" /><ref name="IUPHAR Amphetamine" />
|-
| [[Carbonic anhydrase 12|hCA12]] || 640 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 13|hCA13]] || 24100 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 14|hCA14]] || 9150 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
|}
Acute amphetamine administration in humans increases [[endogenous opioid]] release in several brain structures in the [[reward system]].<ref name="Amphetamine-induced endogenous opioid release review" /><ref name="Opioids" /><ref name="Opioids cited primary source" /> Extracellular levels of [[Glutamate (neurotransmitter)|glutamate]], the primary [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] in the brain, have been shown to increase in the striatum following exposure to amphetamine.<ref name="EAAT3" /> This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of [[EAAT3]], a glutamate reuptake transporter, in dopamine neurons.<ref name="EAAT3" /><ref name="SLC1A1" /> This internalization is mediated by [[RhoA]] activation and its downstream effector [[Rho-associated coiled-coil kinase|ROCK]].<ref name="handbook2022_DAT" /><ref name="EAAT3 review">{{cite journal | vauthors = Bjørn-Yoshimoto WE, Underhill SM | title = The importance of the excitatory amino acid transporter 3 (EAAT3) | journal = Neurochem. Int. | volume = 98 | issue = | pages = 4–18 | date = September 2016 | pmid = 27233497 | pmc = 4969196 | doi = 10.1016/j.neuint.2016.05.007 | quote = Recently, it was reported that amphetamine decreases the surface expression of EAAT3 (Underhill et al., 2014).&nbsp;...<br />RhoA is a downstream target of intracellular amphetamine. Both mechanisms of RhoA activation lead to a rapid decrease the surface expression of EAAT3. }}</ref> Amphetamine also induces the selective release of [[histamine]] from [[mast cell]]s and efflux from [[Tuberomammillary nucleus|histaminergic neurons]] through {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="E Weihe" /> Acute amphetamine administration can also increase [[adrenocorticotropic hormone]] and [[corticosteroid]] levels in [[blood plasma]] by stimulating the [[hypothalamic–pituitary–adrenal axis]].<ref name="Evekeo" /><ref name="Human amph effects">{{cite book | vauthors = Gunne LM | title=Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence | date=2013 | publisher=Springer | location=Berlin, Germany; Heidelberg, Germany | isbn=9783642667091 | pages=247–260 | access-date=4 December 2015 | chapter=Effects of Amphetamines in Humans | chapter-url=https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA247}}</ref><ref name="Primary: Human HPA axis">{{cite journal | vauthors = Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS | title = Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine | journal =Neuropsychopharmacology| volume = 30 | issue = 4 | pages = 821–832 | date = April 2005 | pmid = 15702139 | doi = 10.1038/sj.npp.1300667 | s2cid = 12302237 | quote = Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans| doi-access = free | title-link = doi }}</ref><!--
Amphetamine has no direct effect on [[acetylcholine]] neurotransmission, but several studies have noted that acetylcholine release increases after its use.<ref name="Acetylcholine">{{cite journal |vauthors=Hutson PH, Tarazi FI, Madhoo M, Slawecki C, Patkar AA | title = Preclinical pharmacology of amphetamine: implications for the treatment of neuropsychiatric disorders | journal =Pharmacol Ther| volume = 143 | issue = 3 | pages = 253–264 | date = September 2014 | pmid = 24657455 | doi = 10.1016/j.pharmthera.2014.03.005}}</ref> In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.<ref name="Acetylcholine" /> -->

In December 2017, the first study assessing the interaction between amphetamine and human [[carbonic anhydrase]] enzymes was published;<ref name="Amphetamine-induced activation of 7 hCA isoforms" /> of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the [[human brain]], with low nanomolar through low micromolar activating effects.<ref name="Amphetamine-induced activation of 7 hCA isoforms" /> Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects;<ref name="Carbonic anhydrase modulators 2019 Review" /> but, based upon the clinical use of [[carbonic anhydrase inhibitor]]s, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as [[ocular]] activation exacerbating [[glaucoma]].<ref name="Carbonic anhydrase modulators 2019 Review">{{cite journal | vauthors = Bozdag M, Altamimi AA, Vullo D, Supuran CT, Carta F | title = State of the Art on Carbonic Anhydrase Modulators for Biomedical Purposes | journal = Current Medicinal Chemistry | volume = 26 | issue = 15 | pages = 2558–2573 | date = 2019 | pmid = 29932025 | doi = 10.2174/0929867325666180622120625 | s2cid = 49345601 | quote = CARBONIC ANHYDRASE INHIBITORS (CAIs). The design and development of CAIs represent the most prolific area within the CA research field. Since the introduction of CAIs in the clinical use in the 40', they still are the first choice for the treatment of edema [9], altitude sickness [9], glaucoma [7] and epilepsy [31].&nbsp;... CARBONIC ANHYDRASE ACTIVATORS (CAAs)&nbsp;... The emerging class of CAAs has recently gained attraction as the enhancement of the kinetic properties in hCAs expressed in the CNS were proved in animal models to be beneficial for the treatment of both cognitive and memory impairments. Thus, CAAs have enormous potentiality in medicinal chemistry to be developed for the treatment of symptoms associated to aging, trauma or deterioration of the CNS tissues.}}</ref>