View source for Template:Amphetamine pharmacodynamics

{{Annotated image 4
| caption = {{{caption|Amphetamine enters the presynaptic neuron across the neuronal membrane or through {{abbr|DAT|dopamine transporter}}.{{if pagename
|Amphetamine=<ref name="Miller" />
|Phenethylamine=<ref name="Miller" />
|Dextroamphetamine=<ref name="Miller" />
|Adderall=<ref name="Miller" />
|Dopamine transporter=<ref name="Miller" />
|Lisdexamfetamine=<ref name="Miller" />
|TAAR1=<ref name="Miller" />
|other=<ref name="Miller">{{cite journal | author = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = J. Neurochem. | volume = 116 | issue = 2 | pages = 164–176 |date=January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref>
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--> Once inside, it binds to {{abbr|TAAR1|trace amine-associated receptor 1}} or enters synaptic vesicles through {{abbr|VMAT2|vesicular monoamine transporter 2}}.{{if pagename
|Amphetamine=<ref name="Miller" /><ref name="E Weihe" />
|Dextroamphetamine=<ref name="Miller" /><ref name="E Weihe" />
|Adderall=<ref name="Miller" /><ref name="E Weihe" />
|Lisdexamfetamine=<ref name="Miller" /><ref name="E Weihe" />
|Dopamine transporter=<ref name="Miller" /><ref name="E Weihe" />
|other=<ref name="Miller" /><ref name="E Weihe">{{cite journal |vauthors=Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Ann. N. Y. Acad. Sci. | volume = 1216 | pages = 86–98 | date=January 2011 | pmid = 21272013 | pmc=4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | quote = VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)&nbsp;... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).&nbsp;... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.}}</ref>
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--> When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the [[Biology:Cytosol|cytosol]] (light tan-colored area) through VMAT2.{{if pagename
|Amphetamine=<ref name="E Weihe" /><ref name="Amphetamine VMAT2 pH gradient" />
|other=<ref name="E Weihe" /><ref name="Amphetamine VMAT2 pH gradient">{{cite journal | vauthors = Sulzer D, Cragg SJ, Rice ME | title = Striatal dopamine neurotransmission: regulation of release and uptake | journal = Basal Ganglia | volume = 6 | issue = 3 | pages = 123–148 | date = August 2016 | pmid = 27141430 | pmc = 4850498 | doi = 10.1016/j.baga.2016.02.001 | quote = Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle.&nbsp;... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.}}</ref>
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--> When amphetamine binds to TAAR1, it reduces the [[firing rate]] of the dopamine neuron via [[Biology:G protein-coupled inwardly-rectifying potassium channel|potassium channels]] and activates [[Biology:Protein kinase A|protein kinase A]] (PKA) and [[Biology:Protein kinase C|protein kinase C]] (PKC), which subsequently phosphorylate DAT.{{if pagename
|Amphetamine=<ref name="Miller" /><ref name="GIRK" /><ref name="Genatlas TAAR1" />
|TAAR1=<ref name="Miller" /><ref name="GIRK" /><ref name="Genatlas TAAR1" />
|other=<ref name="Miller" /><ref name="GIRK">{{cite journal |vauthors=Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB | title = Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons | journal = Front. Syst. Neurosci. | volume = 5 | pages = 56 | date = July 2011 | pmid = 21772817 | pmc = 3131148 | doi = 10.3389/fnsys.2011.00056 | quote = Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. }}</ref><ref name="Genatlas TAAR1">{{cite web | url = http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1 | title = TAAR1 | date = 28 January 2012 | work = GenAtlas | publisher = University of Paris | accessdate = 29 May 2014 | quote= {{•}} tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA) }}</ref>
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--> {{nowrap|PKA-phosphorylation}} causes DAT to withdraw into the presynaptic neuron ([[Biology:Endocytosis|internalize]]) and cease transport.{{if pagename
|Amphetamine=<ref name="Miller" />
|other=<ref name="Miller" />
}}<!--

--> {{nowrap|PKC-phosphorylated}} DAT may either operate in reverse or, like {{nowrap|PKA-phosphorylated}} DAT, internalize and cease transport.{{if pagename
|Amphetamine=<ref name="Miller" />
|other=<ref name="Miller" />
}}<!--

--> Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a [[CAMKIIα]]-dependent pathway, in turn producing dopamine efflux.{{if pagename
|Amphetamine=<ref name="EAAT3" /><ref name="DAT regulation review" />
|Dopamine transporter=<ref name="EAAT3" /><ref name="DAT regulation review" />
|other=<ref name="EAAT3">{{cite journal |vauthors=Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG | title = Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons | journal = Neuron | volume = 83 | issue = 2 | pages = 404–416 | date = July 2014 | pmid = 25033183 | pmc = 4159050 | doi = 10.1016/j.neuron.2014.05.043 | quote = AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).&nbsp;... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate.&nbsp;... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH}}</ref><ref name="DAT regulation review">{{cite journal |vauthors=Vaughan RA, Foster JD | title = Mechanisms of dopamine transporter regulation in normal and disease states | journal = Trends Pharmacol. Sci. | volume = 34 | issue = 9 | pages = 489–496 | date = September 2013 | pmid = 23968642 | pmc = 3831354 | doi = 10.1016/j.tips.2013.07.005 | quote = AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].}}</ref>}}<!-- 
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| header = {{{header|Pharmacodynamics of amphetamine in a dopamine neuron}}}<br />{{navbar|Amphetamine pharmacodynamics|mini = yes}}
| header_align = center
| header_background = {{{headerbg|#F0F8FF}}}
| alt = A pharmacodynamic model of amphetamine and TAAR1
| image = TAAR1 Dopamine.svg
| align = {{{align|right}}}
| image-width = 540
| image-left = 0
| image-top = 0
| width = 540
| height = 685
| annot-font-size = 14
| annot-text-align = center
| annotations = {{Annotation|190|45|via '''[[Biology:Aromatic L-amino acid decarboxylase|AADC]]'''}}
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