Nicotine

links: Drugs reference: Pubmed - Beneficial effects of nicotine https://www.reddit.com/r/NooTopics/comments/ryo2sn/exploring_the_mystery_of_nicotine_gts21/ 4-29-2021

Nicotine #

• Out of all the nAChR subtypes, its highest binding affinity is for α4β2 nAChR, representing >90% of its binding in brain tissue, supposedly the primary mediatory of its addictiveness, since they release dopamine.
  • Another mechanism of its addiction is α4 nAChR upregulating inhibitory GABAergic neurons.
  • α4β2 Nicotinic Acetylcholine Receptors on Dopaminergic Neurons Mediate Nicotine Reward and Anxiety Relief
    • Mice lacking α4 nAChRs have elevated levels of basal anxiety.
  • For instance, GTS-21, an α7 agonist, does not activate the ’nicotine cue’ R
• Nicotine reverses hypofrontality in animal models of addiction and schizophrenia
  • The interesting part of the study is how it affects Somatostatin interneurons.
  • α5 nAChR: rs16969968 (Asp398Asn) (A/A (Me: AG)). Associated with nicotine dependence but lower risk of cocaine dependence. Results in loss of function.
    • Reduced resting-state functional connectivity, and circuits involving the PFC are altered: A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction
      • Specifically, α4β2α5 nAChR function, which somehow ‘incorporates’ itself into heteromers like α4β2.
      • Previously: Association of nicotine addiction and nicotine’s actions with separate cingulate cortex functional circuits: Resting-state dACC-striatum functional connectivity may serve as a circuit-level biomarker for nicotine addiction
      • Molecular genetics of successful smoking cessation: convergent genome-wide association study results
        • The supplementary pdf has like a good 100 SNPs. Would like to see this on Nebula… it’s a lot of cool stuff; a lot of actin proteins. Even ADAM12 (one I have is rs7920207 AC)
  • Layer VI is one of only a handfyl of brain regions that express α5.
  • Deletion α5 in mice leads to PFC-linked behavioral deficits, altered cholinergic excitation and aberrant neuronal morphology in the PFC: Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex
    • 
    • More smoking genes in the α3-α5-β4 cluster: Genome-wide meta-analyses identify multiple loci associated with smoking behavior
      • Strongest association was the α3 nAChR rs1051730 (A (Me: AG))
      • rs1329650 (G (Me: –))
      • rs1028936 (A (Me: AC))
      • rs3733829 (G (Me: AG))
        • EGLN2
      • Smoking cessation: rs3025343 (G (Me: AG))
      • BDNF: rs6265 (A (Me: TC (So AG?)))
        • Implcated in introversion, quicker mental decline in Alzheimer’s, impaired motor skills learning. It may be protective against depression though R
  • α5 nAChR is implicated in schizophrenia: ts. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased Somatostatin interneuron inhibitory drive over layer II/III pyramidal neurons - this resembles hypofrontality, and was reversed by chronic nicotine.
• Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis
  • Upregulates striatal Tyrosine Hydroxylase for a few days after administration, probably downstream of GDNF (itself downstream of FGF2)
• Releases Kisspeptin
• Nicotinic modulation of neuronal networks: from receptors to cognition
• Stimulates presynaptic α7 nAChR in glutamatergic neurons, enhancing projections to DA neurons.
• Nicotine Effects and the Endogenous Opioid System
  • The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2.

• Activation and Desensitization of Nicotinic α7-type Acetylcholine Receptors by Benzylidene Anabaseines and Nicotine #

• [Sustained Nicotine Exposure Differentially Affects α3β2 and α4β2 Neuronal Nicotinic Receptors Expressed in Xenopus Oocytes]
  • Nicotine decreases α4β2 responsiveness much faster than α3β2 nAChR.
• Inhibits 3α-HSD, boosting synthesis of DHT. R But this then decreases synthesis allopregnanolone and androsterone.
• 3 mg/kg/day for 6 weeks reduced 43% body weight gain and 65% blood insulin level, but had no effect on blood glucose level,… demonstrated that nicotine enhancement enhanced insulin sensitivity. R
• Chronic use downregulates NCAM
• Increased expression of VMAT2 in dopaminergic neurons during nicotine withdrawal
• Nicotine reduces discrimination between threat and safety in the hippocampus, nucleus accumbens and amygdala
  • Overactivation of the VTA.
• Nicotine effects on default mode network during resting state
• Activates + upregulates Orexin
  • Activation of orexin neurons by acute nicotine
  • Nicotine up-regulates expression of orexin and its receptors in rat brain
  • Hypocretin and Nicotine Excite the Same Thalamocortical Synapses in Prefrontal Cortex: Correlation with Improved Attention in Rat

Tolerance #

• Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path
  • Chronic nicotine does not change α4* receptor levels in dopaminergic neurons of VTA or Pars Compacta. Instead, upregulated, functional α4 receptors localize to the GABAergic neurons* (Medium Spiny Neurons or interneurons??) of the VTA and Pars Reticula.
• Acute Nicotine-Induced Tachyphylaxis Is Differentially Manifest in the Limbic System
  • … whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance.
• Temporal change in human nicotinic acetylcholine receptor after smoking cessation: 5IA SPECT study
  • The binding potential of nAChRs in the brains of smokers decreased by 33.5% +/- 10.5% after 4 h of smoking cessation, increased by 25.7% +/- 9.2% after 10 d of smoking cessation, and decreased to the level of nonsmokers after 21 d of smoking cessation.
• β2-Nicotinic Acetylcholine Receptor Availability during Acute and Prolonged Abstinence from Tobacco Smoking
  • 
    • The acute decrease of availability in the Thalamus is quite weird. Not sure how that happens.
  • Nicotine induced increases in nAChR, termed “upregulation”, are conferred by a specific microdomain that is in the β2-subunit 34 and thus this upregulation is confined to nAChR that contain the β2-subunit

Dosing #

• Per 1mL of e-liquid, 5% - 50mg, and so on. Breeze Plus has 6mL (so 300mg nicotine total) at up to 2000 puffs. Thus, 0.15mg per 0.003mL puff. A Breeze (the little one) has 50mg total over 800 puffs, so ~0.06mg nicotine per hit, so like 16 hits for 1mg. A cigarette has about 1.2mg.

Tobacco #

• Goated Longecity thread: http://www.longecity.org/forum/topic/61248-the-intelligent-smoker-what-should-a-smoker-take-to-nullify-harm/… and that other one
• ENTER: @Travis https://raypeatforum.com/community/threads/guilt-free-smoking-room.25186/post-371950
• https://raypeatforum.com/community/threads/is-it-possible-to-increase-your-intelligence.18445/post-258211
• https://raypeatforum.com/community/threads/androgenic-benefits-of-tobacco.29114/
• https://raypeatforum.com/community/threads/travis-quora-page.37049/post-572670 Pipe smoking requires attention to detail as one packs, lights, tamps and tends to their pipe. Like many forms of meditation, it requires focus on the breath as one must puff gently and slowly in order to avoid over- heating the pipe and scorching the tongue. There is a ritual playing out of elemental opposites- the abstract and the concrete (a Yin-Yang) – as attention shifts between following billows of ephemeral smoke heavenward and admiring the grain and gnarls of the briar bowl resonating warmth in the palm of your hand. This playing out of opposites encourages dialectical thinking as one can clearly see the interplay of polarities in their smoking process. This ability to see opposite poles may lead to a better understanding of nuances or “gray areas” and enhances the power of observation and circumspection.
• Don’t forget about the Hunter S. Thompson TarGuard. Idk if they do anything though.