User:Seppi333/sandbox
Sortable wikitable gene location test
[edit]List of human protein-coding genes
| Gene symbol | Gene name | Gene location | Gene location (sortable) |
|---|---|---|---|
| A3GALT2 | alpha 1,3-galactosyltransferase 2 | 1p35.1 | 01p35.1 |
| A4GALT | alpha 1,4-galactosyltransferase (P blood group) | 22q13.2 | 22q13.2 |
| A4GNT | alpha-1,4-N-acetylglucosaminyltransferase | 3q22.3 | 03q22.3 |
| AADACL2 | arylacetamide deacetylase like 2 | 3q25.1 | 03q25.1 |
| AADACL3 | arylacetamide deacetylase like 3 | 1p36.21 | 01p36.21 |
| AADACL4 | arylacetamide deacetylase like 4 | 1p36.21 | 01p36.21 |
| AADAT | aminoadipate aminotransferase | 4q33 | 04q33 |
| AADAT_B | aminoadipate aminotransferase B | 4q33.1 | 04q33.1 |
| AADAT_C | aminoadipate aminotransferase C | 4q33.3 | 04q33.3 |
| AAGAB | alpha and gamma adaptin binding protein | 15q23 | 15q23 |
| AAK1 | AP2 associated kinase 1 | 2p13.3 | 02p13.3 |
| AAK1_1 | AP2 associated kinase 1C | 2p13.1 | 02p13.1 |
| AAK1_B | AP2 associated kinase 1B | 2p13.4 | 02p13.4 |
| AAK1_C | AP2 associated kinase 1C | 2p13.6 | 02p13.6 |
| PPP4R3A | protein phosphatase 4 regulatory subunit 3A | 14q32.12 | 14q32.12 |
| PPP4R3B | protein phosphatase 4 regulatory subunit 3B | 2p16.1 | 02p16.1 |
| PPP4R3B_2 | protein phosphatase 4 regulatory subunit 3B2 | 2p16.2 | 02p16.2 |
| PPP4R3C | protein phosphatase 4 regulatory subunit 3C | Xp21.3 | Xp21.3 |
| PPP4R3C_1 | protein phosphatase 4 regulatory subunit 3C1 | Xp21.1 | Xp21.1 |
| PPP4R3C_4 | protein phosphatase 4 regulatory subunit 3C4 | Xp21.4 | Xp21.4 |
| PPP4R4 | protein phosphatase 4 regulatory subunit 4 | 14q32.2 | 14q32.2 |
| PPP6R3 | protein phosphatase 6 regulatory subunit 3 | 11q13 | 11q13 |
| PPP6R3_10q99 | protein phosphatase 6 regulatory subunit 3_10q99 | 10q99 | 10q99 |
| PPP6R3_12q01 | protein phosphatase 6 regulatory subunit 3_12q01 | 12q01 | 12q01 |
| PPP6R3_05 | protein phosphatase 6 regulatory subunit 3_05 | 11q05 | 11q05 |
| PPP6R3_15 | protein phosphatase 6 regulatory subunit 3_15 | 11q15 | 11q15 |
| PPP6R3_26 | protein phosphatase 6 regulatory subunit 3_26 | 11q26 | 11q26 |
| PPP6R3_1 | protein phosphatase 6 regulatory subunit 3_1 | 11q13.1 | 11q13.1 |
| PPP6R3_3 | protein phosphatase 6 regulatory subunit 3_3 | 11q13.3 | 11q13.3 |
| PPP6R3_5 | protein phosphatase 6 regulatory subunit 3_5 | 11q13.5 | 11q13.5 |
| PPWD1 | peptidylprolyl isomerase domain and WD repeat containing 1 | 5q12.3 | 05q12.3 |
| PRAF2 | PRA1 domain family member 2 | Xp11.23 | Xp11.23 |
| PRAF2_06 | PRA1 domain family member 2_06 | Xp11.06 | Xp11.06 |
| PRAF2_1 | PRA1 domain family member 2_1 | Xp11.1 | Xp11.1 |
| PRAF2_17 | PRA1 domain family member 2_17 | Xp11.17 | Xp11.17 |
| PRAF2_15 | PRA1 domain family member 2_15 | Xp11.15 | Xp11.15 |
| PRAF2_21 | PRA1 domain family member 2_21 | Xp11.21 | Xp11.21 |
| PRAF2_24 | PRA1 domain family member 2_24 | Xp11.24 | Xp11.24 |
| PRKX | protein kinase cAMP-dependent X-linked catalytic subunit | Xp22.33 | Xp22.33 |
| PRKX_Xp22 | protein kinase cAMP-dependent X-linked catalytic subunit_Xp22 | Xp22 | Xp22 |
| PRKX_Xp22.13 | protein kinase cAMP-dependent X-linked catalytic subunit_Xp22.13 | Xp22.13 | Xp22.13 |
| PRKX_Xp22.53 | protein kinase cAMP-dependent X-linked catalytic subunit_Xp22.53 | Xp22.53 | Xp22.53 |
| PRKX_Xp3 | protein kinase cAMP-dependent X-linked catalytic subunit_Xp3 | Xp3 | Xp3 |
| PRKX_Xp3.03 | protein kinase cAMP-dependent X-linked catalytic subunit_Xp3.03 | Xp3.03 | Xp3.03 |
| PRKX_1 | protein kinase cAMP-dependent X-linked catalytic subunit | Xp22.1 | Xp22.1 |
| PRKX_05 | protein kinase cAMP-dependent X-linked catalytic subunit | Xp22.05 | Xp22.05 |
Human protein-coding gene list WD SPARQL queries
[edit]Python library with utility functions for running SPARQL queries on Wikidata: mkwikidata
SELECT DISTINCT ?gene ?geneLabel ?hgncsym ?gname ?pname
{
?gene wdt:P31 wd:Q7187 .
?gene wdt:P703 wd:Q15978631 .
?gene wdt:P353 ?hgncsym .
?gene wdt:P688 ?protein .
OPTIONAL {
?article schema:about ?gene ;
schema:name ?gname ;
schema:isPartOf <https://en.wikipedia.org/> .
}
OPTIONAL {
?article schema:about ?protein ;
schema:name ?pname ;
schema:isPartOf <https://en.wikipedia.org/> .
}
SERVICE wikibase:label { bd:serviceParam wikibase:language "en" } .
}
Click here to launch the Wikidata query
This gives you 1.gene item, 2.item name, 3.HGNC name, 4.(optional)article name linked from gene item, 5.(optional)article name linked from protein item.
SELECT DISTINCT ?gene ?geneLabel ?HGNC_ID ?HGNCsymbol ?protein ?proteinLabel ?UNIPROT_ID ?wd_gene_item_article_link ?wd_protein_item_article_link
{
?gene wdt:P31 wd:Q7187 .
?gene wdt:P703 wd:Q15978631 .
?gene wdt:P279 wd:Q20747295 .
?gene wdt:P354 ?HGNC_ID .
?gene wdt:P353 ?HGNCsymbol .
?gene wdt:P688 ?protein .
?protein wdt:P352 ?UNIPROT_ID .
OPTIONAL {
?article schema:about ?gene ;
schema:name ?wd_gene_item_article_link ;
schema:isPartOf <https://en.wikipedia.org/> .
}
OPTIONAL {
?article schema:about ?protein ;
schema:name ?wd_protein_item_article_link ;
schema:isPartOf <https://en.wikipedia.org/> .
}
SERVICE wikibase:label { bd:serviceParam wikibase:language "en" } .
}
Click here to launch the Wikidata query
This gives you 1.gene item, 2.item name, 3.HGNC name, 4.(optional)article name linked from gene item, 5.(optional)article name linked from protein item.
When "expressed in (P5572)" is linked to more than one wikidata item about a protein (i.e., gene encodes multiple proteins) and one of these proteins is linked to a Wikipedia article, this query appears to generate a duplicate entry for the gene - one for the WP-article-linked protein and one for the unlinked protein. E.g., RET (Q18253720) has protein links (ret proto-oncogene (Q415976) - RET proto-oncogene 1114 AA isoform; Ret proto-oncogene (Multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease), isoform CRA_d (Q21141355) - unlinked item about a 1114 AA protein isoform; Proto-oncogene tyrosine-protein kinase receptor Ret (Q21139027) unlinked item about a 181 AA protein isoform) & PTHLH (Q14863103) has protein links (parathyroid hormone like hormone (Q2007821) - parathyroid hormone-like hormone; PTHrP(1-36) (Q66584163) - an unlinked item about a protein fragment), and each of genes (and their HGNC IDs) appear twice in the list with and without the protein-linked article.
Need to include UNIPROT IDs for all encoded proteins linked to each HGNC ID in the query. Then, merge the datasets for entries that have an exact 1:1 match on HGNC ID & UNIPROT ID entry pairs.
x
[edit]Addiction is a disorder of the brain's reward system developing through transcriptional and epigenetic mechanisms as a result of chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of cocaine, engagement in sexual activity, participation in high-thrill cultural activities such as gambling, etc.) over extended time.[1][2][3] DeltaFosB (ΔFosB), a gene transcription factor, is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions.[2][3][4][5] Two decades of research into ΔFosB's role in addiction have demonstrated that addiction arises, and the associated compulsive behavior intensifies or attenuates, along with the overexpression of ΔFosB in the D1-type medium spiny neurons of the nucleus accumbens.[1][2][3][4] Due to the causal relationship between ΔFosB expression and addictions, it is used preclinically as an addiction biomarker.[1][2][4] ΔFosB expression in these neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement, while decreasing sensitivity to aversion.[note 1][1][2]
| Transcription factor glossary | |
|---|---|
| |
 |
Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection.[5][13][14] The most important transcription factors that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[5] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.[5] ΔFosB expression in nucleus accumbens D1-type medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.[note 1][1][2] ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including alcohol, amphetamine and other substituted amphetamines, cannabinoids, cocaine, methylphenidate, nicotine, opiates, phenylcyclidine, and propofol, among others.[2][5][13][15][16] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.[1][5][17] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs (i.e., the alterations mediated by ΔFosB).[4][5]
ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[5][18] Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[3][5][18] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;[5][3][18] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[18] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ΔFosB.[3][19][20] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.[3]
ΔFosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.[21]
The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex.[22][23] Altered dopamine neurotransmission is frequently observed following the development of an addictive state.[3] In humans and lab animals that have developed an addiction, alterations in dopamine or opioid neurotransmission in the nucleus accumbens and other parts of the striatum are evident.[3] Studies have found that use of certain drugs (e.g., cocaine) affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region.[24]
Reward system
[edit]![[icon]](/wiki/File:Wiki_letter_w_cropped.svg){kind=small} | This section needs expansion. You can help by adding to it. (August 2015) |
Mesocorticolimbic pathway
[edit]ΔFosB accumulation from excessive drug use
Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.[11][25] |
Understanding the pathways in which drugs act and how drugs can alter those pathways is key when examining the biological basis of drug addiction. The reward pathway, known as the mesolimbic pathway, or its extension, the mesocorticolimbic pathway, is characterized by the interaction of several areas of the brain.
- The projections from the ventral tegmental area (VTA) are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors (AMPAR and NMDAR). These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases DA into the forebrain.[26] These neurons also project and release DA into the nucleus accumbens,[27] through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,[28] in addition to their specific effects.
- The nucleus accumbens (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of GABAergic medium spiny neurons (MSNs).[29] The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.[26] Overexpression of ΔFosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction;[1] ΔFosB is a strong positive modulator of positively reinforced behaviors.[1]
- The prefrontal cortex, including the anterior cingulate and orbitofrontal cortices,[30] is another VTA output in the mesocorticolimbic pathway; it is important for the integration of information which helps determine whether a behavior will be elicited.[31] It is also critical for forming associations between the rewarding experience of drug use and cues in the environment. Importantly, these cues are strong mediators of drug-seeking behavior and can trigger relapse even after months or years of abstinence.[32]
Other brain structures that are involved in addiction include:
- The basolateral amygdala projects into the NAcc and is thought to also be important for motivation.[31]
- The hippocampus is involved in drug addiction, because of its role in learning and memory. Much of this evidence stems from investigations showing that manipulating cells in the hippocampus alters dopamine levels in NAcc and firing rates of VTA dopaminergic cells.[27]
Role of dopamine and glutamate
[edit]Dopamine is the primary neurotransmitter of the reward system in the brain. It plays a role in regulating movement, emotion, cognition, motivation, and feelings of pleasure.[33] Natural rewards, like eating, as well as recreational drug use cause a release of dopamine, and are associated with the reinforcing nature of these stimuli.[33][34] Nearly all addictive drugs, directly or indirectly, act upon the brain's reward system by heightening dopaminergic activity.[35]
Excessive intake of many types of addictive drugs results in repeated release of high amounts of dopamine, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of dopamine in the synaptic cleft can induce receptor downregulation in the neural pathway. Downregulation of mesolimbic dopamine receptors can result in a decrease in the sensitivity to natural reinforcers.[33]
Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens. This idea is supported with data from experiments showing that drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the nucleus accumbens.[30]
Reward sensitization
[edit]| Target gene |
Target expression |
Neural effects | Behavioral effects |
|---|---|---|---|
| c-Fos | ↓ | Molecular switch enabling the chronic induction of ΔFosB[note 2] |
– |
| dynorphin | ↓ [note 3] |
• Downregulation of κ-opioid feedback loop | • Increased drug reward |
| NF-κB | ↑ | • Expansion of NAcc dendritic processes • NF-κB inflammatory response in the NAcc • NF-κB inflammatory response in the CP |
• Increased drug reward • Increased drug reward • Locomotor sensitization |
| GluR2 | ↑ | • Decreased sensitivity to glutamate | • Increased drug reward |
| Cdk5 | ↑ | • GluR1 synaptic protein phosphorylation • Expansion of NAcc dendritic processes |
Decreased drug reward (net effect) |
Reward sensitization is a process that causes an increase in the amount of reward (specifically, incentive salience[note 4]) that is assigned by the brain to a rewarding stimulus (e.g., a drug). In simple terms, when reward sensitization to a specific stimulus (e.g., a drug) occurs, an individual's "wanting" or desire for the stimulus itself and its associated cues increases.[38][37][39] Reward sensitization normally occurs following chronically high levels of exposure to the stimulus. ΔFosB (DeltaFosB) expression in D1-type medium spiny neurons in the nucleus accumbens has been shown to directly and positively regulate reward sensitization involving drugs and natural rewards.[1][2][4]
"Cue-induced wanting" or "cue-triggered wanting", a form of craving that occurs in addiction, is responsible for most of the compulsive behavior that people with addictions exhibit.[37][39] During the development of an addiction, the repeated association of otherwise neutral and even non-rewarding stimuli with drug consumption triggers an associative learning process that causes these previously neutral stimuli to act as conditioned positive reinforcers of addictive drug use (i.e., these stimuli start to function as drug cues).[37][40][39] As conditioned positive reinforcers of drug use, these previously neutral stimuli are assigned incentive salience (which manifests as a craving) – sometimes at pathologically high levels due to reward sensitization – which can transfer to the primary reinforcer (e.g., the use of an addictive drug) with which it was originally paired.[37][40][39]
Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess a bidirectional reward cross-sensitization effect[note 5] that is mediated through ΔFosB.[3][19][20] In contrast to ΔFosB's reward-sensitizing effect, CREB transcriptional activity decreases user's sensitivity to the rewarding effects of the substance. CREB transcription in the nucleus accumbens is implicated in psychological dependence and symptoms involving a lack of pleasure or motivation during drug withdrawal.[1][25][36]
The set of proteins known as "regulators of G protein signaling" (RGS), particularly RGS4 and RGS9-2, have been implicated in modulating some forms of opioid sensitization, including reward sensitization.[41]
| Form of neuroplasticity or behavioral plasticity |
Type of reinforcer | Sources | |||||
|---|---|---|---|---|---|---|---|
| Opiates | Psychostimulants | High fat or sugar food | Sexual intercourse | Physical exercise (aerobic) |
Environmental enrichment | ||
| ΔFosB expression in nucleus accumbens D1-type MSNs |
↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [3] |
| Behavioral plasticity | |||||||
| Escalation of intake | Yes | Yes | Yes | [3] | |||
| Psychostimulant cross-sensitization |
Yes | Not applicable | Yes | Yes | Attenuated | Attenuated | [3] |
| Psychostimulant self-administration |
↑ | ↑ | ↓ | ↓ | ↓ | [3] | |
| Psychostimulant conditioned place preference |
↑ | ↑ | ↓ | ↑ | ↓ | ↑ | [3] |
| Reinstatement of drug-seeking behavior | ↑ | ↑ | ↓ | ↓ | [3] | ||
| Neurochemical plasticity | |||||||
| CREB phosphorylation in the nucleus accumbens |
↓ | ↓ | ↓ | ↓ | ↓ | [3] | |
| Sensitized dopamine response in the nucleus accumbens |
No | Yes | No | Yes | [3] | ||
| Altered striatal dopamine signaling | ↓DRD2, ↑DRD3 | ↑DRD1, ↓DRD2, ↑DRD3 | ↑DRD1, ↓DRD2, ↑DRD3 | ↑DRD2 | ↑DRD2 | [3] | |
| Altered striatal opioid signaling | No change or ↑μ-opioid receptors |
↑μ-opioid receptors ↑κ-opioid receptors |
↑μ-opioid receptors | ↑μ-opioid receptors | No change | No change | [3] |
| Changes in striatal opioid peptides | ↑dynorphin No change: enkephalin |
↑dynorphin | ↓enkephalin | ↑dynorphin | ↑dynorphin | [3] | |
| Mesocorticolimbic synaptic plasticity | |||||||
| Number of dendrites in the nucleus accumbens | ↓ | ↑ | ↑ | [3] | |||
| Dendritic spine density in the nucleus accumbens |
↓ | ↑ | ↑ | [3] | |||
Neuroepigenetic mechanisms
[edit]Altered epigenetic regulation of gene expression within the brain's reward system plays a significant and complex role in the development of drug addiction.[17][42] Addictive drugs are associated with three types of epigenetic modifications within neurons.[17] These are (1) histone modifications, (2) epigenetic methylation of DNA at CpG sites at (or adjacent to) particular genes, and (3) epigenetic downregulation or upregulation of microRNAs which have particular target genes.[17][5][42] As an example, while hundreds of genes in the cells of the nucleus accumbens (NAc) exhibit histone modifications following drug exposure – particularly, altered acetylation and methylation states of histone residues[42] – most other genes in the NAc cells do not show such changes.[17]
- ^ a b c d e f g h i j k l Cite error: The named reference
Cellular basiswas invoked but never defined (see the help page). - ^ a b c d e f g h i j Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[…]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.
- ^ a b c d e f g h i j k l m n o p q r s t u v w Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.
Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."
Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" - ^ a b c d e Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045.
[…]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence.
- ^ a b c d e f g h i j k Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
- ^ a b c Renthal 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. PMC 2834246. PMID 19877494.
[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. PMC 3250102. PMID 22200950.
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.
- ^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
- ^ a b c Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
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 - ^ a b c d Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970.
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. PMC 2607320. PMID 18640924.
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
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It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
- ^ a b Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.
Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
- ^ a b Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–64. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065. S2CID 25317397.
- ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–85. ISBN 978-0-07-148127-4.
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- ^ a b Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11042–46. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.
Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in [the] brain after 1–2 months of drug withdrawal ... Indeed, ΔFosB is the longest-lived adaptation known to occur in [the] adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well.
- ^ a b Jones S, Bonci A (2005). "Synaptic plasticity and drug addiction". Current Opinion in Pharmacology. 5 (1): 20–25. doi:10.1016/j.coph.2004.08.011. PMID 15661621.
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- ^ a b c Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924.
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 – cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3 - ^ a b c d e f Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–43. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042.
Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in individuals with addictions.
Cue-triggered 'wanting' for the UCS
A brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.
Cue as attractive motivational magnets
When a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting' for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting' – CS-triggered pulses of intensified 'wanting' for the UCS reward; and (ii) CS-directed 'wanting' – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet. - ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–48, 366–67, 375–76. ISBN 978-0-07-148127-4.
VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards. ...
The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner. ...
The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc. ... If motivational drive is described in terms of wanting, and hedonic evaluation in terms of liking, it appears that wanting can be dissociated from liking and that dopamine may influence these phenomena differently. Differences between wanting and liking are confirmed in reports by humans with addictions, who state that their desire for drugs (wanting) increases with continued use even when pleasure (liking) decreases because of tolerance. - ^ a b c d Edwards S (2016). "Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder". Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs. Progress in Brain Research. Vol. 223. pp. 63–76. doi:10.1016/bs.pbr.2015.07.005. ISBN 978-0-444-63545-7. PMID 26806771.
An important dimension of reinforcement highly relevant to the addiction process (and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary reinforcers (in many cases also considered conditioned reinforcers) likely drive the majority of reinforcement processes in humans. In the specific case of drug addiction, cues and contexts that are intimately and repeatedly associated with drug use will often themselves become reinforcing ... A fundamental piece of Robinson and Berridge's incentive-sensitization theory of addiction posits that the incentive value or attractive nature of such secondary reinforcement processes, in addition to the primary reinforcers themselves, may persist and even become sensitized over time in league with the development of drug addiction (Robinson and Berridge, 1993).
- ^ a b Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633.
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- ^ a b c Cite error: The named reference
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