This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamateco-release by such psychostimulants,[1][2]postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[1][3][4] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[1][5][6]c-Fosrepression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[7] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[5][6] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[5][6]
References
^ abcRenthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC2834246. PMID19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. Figure 2: Psychostimulant-induced signaling events
^Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC3250102. PMID22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
^Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
^ abcRobison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression. Figure 4: Epigenetic basis of drug regulation of gene expression
^ abcNestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC3569166. PMID23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
^Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC2607320. PMID18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
Original – See the transcluded wikilink-annotated image insertion template. This image is annotated on commons and in template:psychostimulant addiction.
Reason
It's an interactive image that illustrates the fairly technical process/mechanisms through which addiction to stimulants occurs. It's been linked on the talkpages of three relevant wikiprojects (WP:MCB, WP:MED, WP:PHARM) for feedback prior to this nomination.
Hmm. I'm inclined to Support, but this is one of the most unusual noms I've seen in a while. I'm mainly worried about the technical problems, e.g. how do we put it into a gallery; how do we put it on PotD, etc. Crisco 1492, Armbrust, can we have some commentary on this aspect? Either way, though, I think we should promote it, but we might want to make its own section at FP, for such interactive images. Adam Cuerden(talk) 11:02, 22 August 2014 (UTC)[reply]
The image will be added to the gallery as every other image, the links in the template are not part of the image. There is no need for a separate section. ArmbrustTheHomunculus 13:01, 22 August 2014 (UTC)[reply]
Small technical comment. (Win 7 / IE11) In the actual SVG image at http://upload.wikimedia.org/wikipedia/commons/4/47/%CE%94FosB.svg, the black arrow heads, which apparently should be solid black, appear white with a black border, with the coloured line visibly protruding into the arrow head. In the rendering on this page, and in media viewer, they appear solid black. I'm not sure whether this is a bug in IE rendering or a bug in the SVG. 217.44.214.6 (talk) 14:05, 22 August 2014 (UTC)[reply]
It's a bug in SVG, though I didn't bother correcting it since the image renders correctly once converted to PNG. It appears that way regardless of the browser used. Seppi333 (Insert 2¢ | Maintained) 06:02, 26 August 2014 (UTC)[reply]
Oppose No idea about the accuracy of what is depicted, but definitely needs polishing. It really looks like the kind of diagram one would find in secondary/high school report on a first sight. Even though it's correct, I think it takes more than just accuracy to get FP tag. - Blieusong (talk) 10:09, 23 August 2014 (UTC)[reply]
This image would be featured for its encyclopedic value, not primarily its artistic value. You are on extremely loose footing calling this "high-school" quality, even if you only mean the artistic choices. -- CFCF🍌 (email) 11:03, 23 August 2014 (UTC)[reply]
I do realize that EV gets the priority over here. But it's still featured picture candidate and so we can't do anything artistically wise, which was the point of my comment. I don't ask for Picasso grade diagrams, but at the very least, this candidate should use sans serif fonts, and be less cluttered. - Blieusong (talk) 16:28, 23 August 2014 (UTC)[reply]
I agree with you that this diagram is nothing special in terms of execution. It is easy to find lots of small niggles. I could not comment on other aspects. I do not wish to denigrate the picture overall, as it may be excellent in terms of information content. 86.130.67.100 (talk) 19:59, 23 August 2014 (UTC)[reply]
The diagram uses sans, though I'll point out that font style isn't a criteria for FP. My apologies if it's too complicated for you though; the diagram is geared towards individuals with more than a secondary/high school education. Seppi333 (Insert 2¢ | Maintained) 04:32, 26 August 2014 (UTC)[reply]
OH! What font are you using? It isn't showing up properly on my computer... Are you using Inkscape or illustrator to edit this? Illustrator has an option to convert all text to outline - which will get rid of all the issues. If you don't use it everyone will need the correct font installed (including the MediaWiki software, which has a very limited number of fonts). -- CFCF🍌 (email) 05:33, 26 August 2014 (UTC)[reply]
P.S.It will make the image harder to edit, but the trick here is to save an image for editing with the text as normal as well, and upload it for reference. -- CFCF🍌 (email) 05:35, 26 August 2014 (UTC) [reply]
I used Inkscape to write it; I can change the text to Inkscape's "Microsoft sans serif" font if you think it'll look better. Seppi333 (Insert 2¢ | Maintained) 05:56, 26 August 2014 (UTC)[reply]
comment What are those green rectangles? They should be labelled. I'm assuming they are Adenylate cyclase, in which case they should be bound to the membrane right? Mattximus (talk) 14:02, 24 August 2014 (UTC)[reply]
The issue is that they are labeled in the template, but not in the svg itself. Check the template link.-- CFCF🍌 (email) 21:29, 24 August 2014 (UTC)[reply]
They're G proteins. I omitted AC to reduce the number of nodes in the cascade. Seppi333 (Insert 2¢ | Maintained) 04:51, 26 August 2014 (UTC)[reply]
Comment: Not sure if it's relevant for this FPC, but the template's using red text to represent transcription factors is confusing. I initially thought they were red links. --Paul_012 (talk) 08:16, 25 August 2014 (UTC)[reply]
I don't mind changing it; what color do you suggest as a substitute? Seppi333 (Insert 2¢ | Maintained) 04:32, 26 August 2014 (UTC)[reply]
Actually, I've given it some further thought and think it might be a better idea to have the text in the image itself and using an image map to provide the links. This would help avoid the problem of the stand-alone image being unusable. --Paul_012 (talk) 09:52, 26 August 2014 (UTC)[reply]
