Discussion-Respond 1

Foundational Neuroscience
The agonist-to-antagonist spectrum of psychopharmacologic agents
In Psychiatry, medications are generally small molecules and act differently (Berg & Clarke, 2018).  Traditional receptor theory states that ligands activate receptor sites and act as agonists with various degrees of intrinsic efficacy or as antagonists with zero intrinsic efficacy (Berg & Clarke, 2018).  Inverse agonists have the opposite effect of an agonist and reduce the “constitutive” activity of the receptor (Berg & Clarke, 2018).  Psychopharmacologic agents can be agonists, antagonists, and simultaneously agonists, antagonists, and inverse agonists acting at the same receptor (Berg & Clarke, 2018). Agonists act to mimic the action of an endogenous neurotransmitter (Berg & Clarke, 2018).  Antagonists block the effects of endogenous neurotransmitters and oppose normal synaptic transmission (Berg & Clarke, 2018).  Partial agonists act somewhat like agonists in that they directly act on receptors, but if used in the presence of an agonist, they compete for the receptor and have partial blocking properties; hence they are sometimes called agonist–antagonists (Berg & Clarke, 2018).
G Couple Proteins and Ion Gated Channels
A neurotransmitter can affect the activity of a postsynaptic cell via two different types of receptor proteins (Purves et al., 2001).  Ionotropic receptors are linked directly to ion gated channels. These receptors contain two features: an extracellular site that binds neurotransmitters and a “membrane-spanning domain” that forms an ion channel (Purves et al., 2001).  The second family of neurotransmitters receptors does not have ion channels as part of their structure; instead, they affect channels by activating intermediate molecules called G-proteins (Purves et al., 2001).  G protein-coupled receptors (GPCRs) are the largest known class of membrane receptors and are the target of about 30-50% of modern medicinal drugs (Purves et al., 2001).  When signaling molecules, or ligands, bind to GPCRs, G-protein activation triggers the production of second messengers, like hormones (Purves et al., 2001).  Like in GPCRs, ligands also bind to ion gated channels and initiate a chemical response.  Once the ligand binds to the allosteric site of the ligand-gated ion receptor, the channel opens, and the ion permeability of the entire plasma membrane can quickly change (Purves et al., 2001).  When the channel opens, ions like potassium, sodium, or calcium can move through the open channel, and an electrical signal is generated inside the cell (Purves et al., 2001).  Ligand-gated ion channel receptors generally mediate rapid postsynaptic effects, while activating metabotropic receptors (GPCRs) typically produce a much slower response (Purves et al., 2001).
Epigenetics
Epigenetics are chemical modifications that can silence or activate genes without modifying the nucleotide sequence (Stefanska & MacEwan, 2015).  It describes “genetic information that is ‘beyond’ or ‘above’ that information coded solely by our genetic code”  (Stefanska & MacEwan, 2015, p. 2702).  Often epigenetic variations are the cause of an underlying disease (Stefanska & MacEwan, 2015).  Drugs may not be designed to be as exact to a particular ligand or specific to a particular gene or protein subtype; they may indeed have to be able to be broader ‐ acting over a range of epigenetic large-scale events (Stefanska & MacEwan, 2015).  Pharmacological intervention may need to focus on one type of ligand or a particular gene. Still, rather drugs may need to be more “broad” to work more effectively against certain diseases (Stefanska & MacEwan, 2015).   Such knowledge can provide a strong biological foundation for developing better targeted personalized medication strategies (Stefanska & MacEwan, 2015). Epigenetic modification can be influenced by environmental factors such as recreational drugs, diet, and exercise (Stefanska & MacEwan, 2015).  “Transcription and numerous other genomic functions are epigenetically controlled via heritable but potentially reversible changes in DNA modification and histones (acetylation, methylation, phosphorylation)” (Browne et al., 2020, p. 22).  
Impact on patients
Psychiatric nurse practitioners need to consider epigenetics when prescribing medications.  An example would be in the treatment of patients who have opioid use dis .  Susceptibility to opioid addiction is known to be strongly influenced by environmental factors. Thus, epigenetics could be important for understanding individual vulnerability to addiction and response to treatment (Hurd & O’Brien, 2018).  “The epigenetic mechanisms that turn genes on and off to set the state of gene expression patterns and thus cellular function include methylation of DNA and modifications (e.g., methylation, acetylation, and phosphorylation) of histones” (Hurd & O’Brien, 2018, p. 938).  An example of an epigenetic change in chronic heroin users includes increased methylation of the OPRM1 gene, which leads to reduced mu-opioid receptors(Hurd & O’Brien, 2018).  A reduction of mu-opioid receptors translates to a higher dose of opioids needed to satisfy the prior therapeutic effect (Hurd & O’Brien, 2018).  Frontline treatment of opioid addiction with mu OR agonists or partial agonists, such as methadone or buprenorphine, produces epigenetic modifications (Browne et al., 2020).
References
Berg, K. A., & Clarke, W. P. (2018). Making sense of pharmacology: Inverse agonism and functional selectivity. International Journal of Neuropsychopharmacology, 21(10), 962–977. https://doi.org/10.1093/ijnp/pyy071
Browne, C. J., Godino, A., Salery, M., & Nestler, E. J. (2020). Epigenetic mechanisms of opioid addiction. Biological Psychiatry, 87(1), 22–33. https://doi.org/10.1016/j.biopsych.2019.06.027
Hurd, Y. L., & O’Brien, C. P. (2018). Molecular genetics and new medication strategies for opioid addiction. American Journal of Psychiatry, 175(10), 935–942. https://doi.org/10.1176/appi.ajp.2018.18030352
Nutt, D., & Lingford-Hughes, A. (2007). Key concepts in psychopharmacology. Psychiatry, 6(7), 263–267. https://doi.org/10.1016/j.mppsy.2007.05.002
Purves, D., Augustine, G. J., Fitzpatrick, D., Katz, L. C., LaMantia, A.-S., McNamara, J. O., & Williams, S. M. (2001). Neuroscience (2nd ed.). Sinauer Associates.
Stefanska, B., & MacEwan, D. J. (2015). Epigenetics and pharmacology. British Journal of Pharmacology, 172(11), 2701–2704. https://doi.org/10.1111/bph.13136
Stern, T. A., Fava, M., Wilens, T. E., & Rosenbaum, J. F. (2016). Massachusetts general hospital psychopharmacology and neurotherapeutics e-book (1st 

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