”Subheading: Ethanol”
”Subheading: Ethanol”
In the VTA, low levels of ethanol increase dopamine release. Ethanol acts as a positive allosteric modulator by binding to α6 nAChRs on the axon terminals of GABAergic neurons outside the VTA, which connect to other GABAergic neurons within the VTA. When ACh binds to these receptors, it allows Ca2+ influx into the upstream GABAergic neurons. Ethanol enhances this influx. This increases GABA release onto the VTA GABAergic neurons, inhibiting them and reducing their suppression of dopaminergic neurons. As a result, the dopaminergic neurons fire more rapidly, increasing dopamine release within the VTA.<ref>{{cite journal
In the VTA, low levels of ethanol increase dopamine release. Ethanol acts as a positive allosteric modulator by binding to α6 nAChRs on the axon terminals of GABAergic neurons outside the VTA, which connect to other GABAergic neurons within the VTA. ACh to these receptors Ca2+ influx into the upstream GABAergic neurons. Ethanol enhances this influx. This increases GABA release onto the VTA GABAergic neurons, inhibiting them and reducing their suppression of dopaminergic neurons. As a result, the dopaminergic neurons fire more rapidly, increasing dopamine release within the VTA.<ref>{{cite journal
|last1=Heydary
|last1=Heydary
|first1=Y. H.
|first1=Y. H.
 |
This is the sandbox page where you will draft your initial Wikipedia contribution.
If you’re starting a new article, you can develop it here until it’s ready to go live. If you’re working on improvements to an existing article, copy only one section at a time of the article to this sandbox to work on, and be sure to use an edit summary linking to the article you copied from. Do not copy over the entire article. You can find additional instructions here. Remember to save your work regularly using the “Publish page” button. (It just means ‘save’; it will still be in the sandbox.) You can add bold formatting to your additions to differentiate them from existing content. |
Tissue Distribution:
α6-containing nicotinic acetylcholine receptors (nAChRs) show a restricted expression pattern in the brain. α6 nAChRs are primarily expressed in three regions: the Ventral Tegmental Area (VTA) and the Substantia Nigra (SN), which are both part of the midbrain dopaminergic system, and the Locus Coeruleus (LC), located in the brainstem.[1]
α6 nAChRs are expressed on dopamine, glutamine, noradrenaline, and GABA-releasing neurons, but their expression patterns vary between different types of neurons.[2]
α6 subunits cannot form homomeric receptors. Instead, they form heteromeric receptors along with other alpha or beta subunits. Different combinations of subunits create receptors with unique pharmacology.[3]
Function:
α6 nACh receptors play a key role in regulating dopaminergic neurotransmission.
==Nicotine==
In the presence of nicotine, α6 nAChRs activate dopamine release in the VTA. This appears to take place through two mechanisms.
First, nicotine binds to α6 nAChRs on the axon terminals of presynaptic GABAergic neurons, which synapse onto postsynaptic dopaminergic neurons. Nicotine quickly desensitizes these receptors, preventing them from allowing Ca2+ to enter the axon terminal. Without Ca2+ to trigger neurotransmitter release, less GABA is released onto dopaminergic neurons. As a result, dopaminergic neurons are less inhibited, leading to more dopamine release.[4][5]
Second, nicotine binds to and activates α6 nAChRs on dopaminergic neurons. In the dendrites, this causes excitatory depolarization, increasing the dopaminergic cells’ firing rate. At the axon terminals, this allows Ca2+ to enter, facilitating neurotransmitter release. Together, these effects cause dopaminergic neurons to release more dopamine.[6][7]
Dopamine release following activation of these neurons is thought to be involved in the addictive properties of nicotine. Studies in mice show that knocking out the α6 subunit causes mice to stop self-administering nicotine, while reintroducing the subunit reverses this result.[8][9]
Subheading: Ethanol
In the VTA, low levels of ethanol increase dopamine release. Ethanol acts as a positive allosteric modulator by binding to α6 nAChRs on the axon terminals of GABAergic neurons outside the VTA, which connect to other GABAergic neurons within the VTA. ACh binding to these receptors causes Ca2+ influx into the upstream GABAergic neurons. Ethanol enhances this influx. This increases GABA release onto the VTA GABAergic neurons, inhibiting them and reducing their suppression of dopaminergic neurons. As a result, the dopaminergic neurons fire more rapidly, increasing dopamine release within the VTA.[10][11]
However, very high levels of ethanol actually reduce dopamine release. The exact mechanism for this is unknown.[12][13]
Research in animals has implicated α6-containing nAChRs in the abusive and addictive properties of ethanol, with mecamylamine demonstrating a potent ability to block these properties.
Minor adjustment to the Clinical Significance section:
Because of their selective distribution and role in dopamine regulation in the Substantia Nigra, α6-containing receptors have been investigated as therapeutic targets. Due to their selective localisation on dopaminergic neurons, α6-containing nACh receptors have also been suggested as a possible therapeutic target for the treatment of Parkinson’s disease.
- ^ Hajy Heydary, Yasamin; Castro, Emily M.; Lotfipour, Shahrdad; Leslie, Frances M. (2025-01-14). “Unraveling the Role of CHRNA6, the Neuronal α6 Nicotinic Acetylcholine Receptor Subunit”. Receptors. 4 (1): 1. doi:10.3390/receptors4010001. ISSN 2813-2564. PMC 12051391. PMID 40331132.
- ^ Hajy Heydary, Yasamin; Castro, Emily M.; Lotfipour, Shahrdad; Leslie, Frances M. (2025-01-14). “Unraveling the Role of CHRNA6, the Neuronal α6 Nicotinic Acetylcholine Receptor Subunit”. Receptors. 4 (1): 1. doi:10.3390/receptors4010001. ISSN 2813-2564. PMC 12051391. PMID 40331132.
- ^ Papke, R. L.; Dwoskin, L. P.; Crooks, P. A.; Zheng, G.; Zhang, Z.; McIntosh, J. M.; Stokes, C. (2008). “Extending the analysis of nicotinic receptor antagonists with the study of α6 nicotinic receptor subunit chimeras”. Neuropharmacology. 54 (8): 1189–1200. doi:10.1016/j.neuropharm.2008.03.010. PMC 2494738. PMID 18448138.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Yang, K. C.; Jin, G. Z.; Wu, J. (2009). “Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology”. Acta Pharmacologica Sinica. 30 (6): 740–751. doi:10.1038/aps.2009.63. PMID 19417766.
- ^ Yang, K.; Buhlman, L.; Khan, G. M.; Nichols, R. A.; Jin, G.; McIntosh, J. M.; Whiteaker, P.; Lukas, R. J.; Wu, J. (2011). “Functional nicotinic acetylcholine receptors containing α6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons”. The Journal of Neuroscience. 31 (7): 2537–2548. doi:10.1523/JNEUROSCI.3003-10.2011. PMID 21325520.
- ^ Heydary, Y. H.; Castro, E. M.; Lotfipour, S.; Leslie, F. M. (2025). “Unraveling the role of CHRNA6, the neuronal α6 nicotinic acetylcholine receptor subunit”. Receptors. 4 (1): 1. doi:10.3390/receptors4010001. ISSN 2813-2564. PMC 12051391. PMID 40331132.
- ^ Drenan, R. M.; Grady, S. R.; Whiteaker, P.; McClure-Begley, T.; McKinney, S.; Miwa, J. M.; Bupp, S.; Heintz, N.; McIntosh, J. M.; Bencherif, M.; Marks, M. J.; Lester, H. A. (2008). “In vivo activation of midbrain dopamine neurons via sensitized, high-affinity alpha 6 nicotinic acetylcholine receptors”. Neuron. 60 (1): 123–136. doi:10.1016/j.neuron.2008.09.009. PMID 18940592.
- ^ Quik, M.; Perez, X. A.; Grady, S. R. (2011). “Role of α6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders”. Biochemical Pharmacology. 82 (8): 873–882. doi:10.1016/j.bcp.2011.06.001. PMID 21664286.
- ^ Pons, S.; Fattore, L.; Cossu, G.; Tolu, S.; Porcu, E.; McIntosh, J. M.; Changeux, J. P.; Maskos, U.; Fratta, W. (2008). “Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration”. The Journal of Neuroscience. 28 (47): 12318–12327. doi:10.1523/JNEUROSCI.3918-08.2008. PMID 19020022.
- ^ Heydary, Y. H.; Castro, E. M.; Lotfipour, S.; Leslie, F. M. (2025). “Unraveling the role of CHRNA6, the neuronal α6 nicotinic acetylcholine receptor subunit”. Receptors. 4 (1): 1. doi:10.3390/receptors4010001. ISSN 2813-2564. PMC 12051391. PMID 40331132.
- ^ Steffensen, S. C.; Shin, S. I.; Nelson, A. C.; Pistorius, S. S.; Williams, S. B.; Woodward, T. J.; Park, H. J.; Friend, L.; Gao, M.; Gao, F.; Taylor, D. H.; Foster Olive, M.; Edwards, J. G.; Sudweeks, S. N.; Buhlman, L. M.; McIntosh, J. M.; Wu, J. (2018). “α6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward”. Addiction Biology. 23 (5): 1079–1093. doi:10.1111/adb.12559. PMID 29167686.
- ^ Heydary, Y. H.; Castro, E. M.; Lotfipour, S.; Leslie, F. M. (2025). “Unraveling the role of CHRNA6, the neuronal α6 nicotinic acetylcholine receptor subunit”. Receptors. 4 (1): 1. doi:10.3390/receptors4010001. ISSN 2813-2564. PMC 12051391. PMID 40331132.
- ^ Steffensen, S. C.; Shin, S. I.; Nelson, A. C.; Pistorius, S. S.; Williams, S. B.; Woodward, T. J.; Park, H. J.; Friend, L.; Gao, M.; Gao, F.; Taylor, D. H.; Foster Olive, M.; Edwards, J. G.; Sudweeks, S. N.; Buhlman, L. M.; McIntosh, J. M.; Wu, J. (2018). “α6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward”. Addiction Biology. 23 (5): 1079–1093. doi:10.1111/adb.12559. PMID 29167686.
