NURS 6630 Discussion: Foundational Neuroscience

NURS 6630 Discussion: Foundational Neuroscience

Agonist-to-Antagonist Spectrum of Action

According to Burstein (2019), an agonist is any drug that attaches to a particular receptor in the brain-stimulating an action. A partial agonist is a substance that functions as an agonist but does not fully stimulate the action of receptors. NURS 6630 Discussion: Foundational Neuroscience An inverse agonist is a drug that binds to receptors as an agonist but exerts an opposite pharmacological response to that of the agonist. An antagonist is a drug that blocks the action of receptors, so they cannot attach to the agonist. An example of an agonist is Heroin, the antagonist is Naloxone, and a partial agonist is Buprenorphine (Burstein, 2019). Heroin is an addictive agonistic substance. During a Heroin overdose, Naloxone, an antagonist, can be used to counter the binding and block receptors from binding to heroin receptors. Pharmacological treatment for Heroin addiction includes the partial agonist, Buprenorphine. Buprenorphine allows partial binding to opioid receptors, reducing withdrawal symptoms (Burstein, 2019) NURS 6630 Discussion: Foundational Neuroscience.

Compare and Contrast: Ion Gated Channels and G-couple-proteins

Ion Gated Channels (IGCs) and G-protein-coupled receptors (GPCRs) are two groups of postsynaptic receptors. IGCs, have two territories. One part works to attach to neurotransmitters(extracellular), and the other part forms the ion channel (Moreau et al., 2017). GPCRs are used by cells to convert extracellular signals into intracellular responses by involving protein-dependent signaling pathways and G protein-independent signaling pathways (Moreau et al., 2017). When the neurotransmitter attaches to the receptors, the G-proteins are stimulated, which results in separation from the receptor to directly interact with the ion channels (Moreau et al., 2017).

Epigenetics and Pharmacological Action

Epigenetics is a term coined to describe alterations that result in changes in gene expression without changing the DNA. The difference in the gene can also be inherited. Thus, epigenetics can explain how a medication works and what diseases individuals are prone to be affected by (Ganesan et al., 2019). A drug could work on a particular gene, but if that gene is modified in any way, the medication’s effectiveness could change.

Best Practice

A psychiatric mental health nurse practitioner should perform a thorough medical examination to gather adequate family history before prescribing medications. Medications that have been effective for patients should be considered, and recommendations for genetic testing for patients who have failed multiple trials of drugs. Patients may have inherited some genes that affect the medication effectiveness. Gathering information about medications that have been effective for the patient’s close family may help treat the patients’ symptoms due to Epigenetics. For example, working as a case manager at an inpatient psychiatry hospital, a patient was treated with an initial dose of haloperidol 2.5mg. Genetic testing results showed why the initial amount produced rapid extrapyramidal symptoms.

  

References

 

Burstein, E. S. (2019). Should inverse agonists be defined by pharmacological mechanism or

clinical effect? CNS Spectrums, 24(4), 349–351.

https://doi.org/10.1017/s1092852918001761

Ganesan, A., Arimondo, P. B., Rots, M. G., Jeronimo, C., & Berdasco, M. (2019). The timeline

of epigenetic drug discovery: From reality to dreams. Clinical Epigenetics, 11(1).

https://doi.org/10.1186/s13148-019-0776-0

Moreau, C. J., Revilloud, J., Caro, L. N., Dupuis, J. P., Trouchet, A., Estrada-Mondragón, A.,

Nieścierowicz, K., Sapay, N., Crouzy, S., & Vivaudou, M. (2017). Tuning the allosteric

regulation of artificial muscarinic and dopaminergic ligand-gated potassium channels by

protein engineering of G protein-coupled receptors. Scientific Reports, 7(1).

https://doi.org/10.1038/srep41154

 

 

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20 days ago
NURS 6630 Discussion: Foundational NeuroscienceJeannie Higgin 
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According to research,  Haldol has neurotoxic effects  ( Rucker et al., 2013).  Perhaps using other medications may have been beneficial.  The dopamine receptor is a G protein-coupled receptor-targeted for antipsychotic drugs ( Urs et al., 2017, p. 1).  As a psychiatric mental health nurse practitioner, it is essential to have information on different medications to arrive at the same effect.  For example, if the provider wants to calm a belligerent patient down, perhaps giving a newer antipsychotic medication may help to decrease patient side effects and relax the person.  Dopamine is a neurotransmitter with physiological implications (Urs et al., 2017, p. 1).  When a neurotransmitter is disrupted, it can cause dysregulation in the central nervous system, and signs and symptoms in patient behavior can alert the clinician to change medications to aid in homeostasis.  It is essential to consider as many options to mitigate side effects and help stabilize the patient.

References

A., Rucker, M., Ohl, F. et al. Mechanisms Underlying the Protective Potential of α-Tocopherol  (Vitamin E) against  Haloperidol-associated Neurotoxicity. Neuropsychopharmacol 26, 397-407 (2002). https://doi.org/10.1016/S0893-133X(01)00364-5

Urs, N. M., Peterson, S. M., & Caron, M. G. (2017). New concepts in dopamine D2 receptor biased signaling and implications for schizophrenia therapy. Biological Psychiatry, 81(1),            78-85. https://doi.org/10.1016/j.biopsych.2016.10.011

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20 days ago
NURS 6630 Discussion: Foundational NeuroscienceJeannie Higgin 
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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceSteven St. Onge WALDEN INSTRUCTOR MANAGER 
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Hi Candy,

Great summary here.  Can you share why we would combine a partial agonist such as Buprenorphine with an antagonist such as Naloxone into a single medication such as Suboxone?  As you are probably aware, oral naloxone has nearly 0% bioavailability when given orally.  If none of the drug is absorbed, why use it in the combination?

Thanks!

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceCandy Woods 
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Thank you, Dr St. Onge. As a result of buprenorphine’s opioid effects, it is likely to be misused. Naloxone is added to buprenorphine to decrease the likelihood of misuse of the combination of drugs. When both drugs are taken orally, buprenorphine’s opioid effects lead naloxone and blocks opioid withdrawals. If the combination oral drugs are crushed and injected, however, the naloxone effect leads and can bring on opioid withdrawals (Blazes & Morrow, 2020).

                                               

                                                 Reference

Blazes, C. K., & Morrow, J. D. (2020). Reconsidering the usefulness of

adding naloxone to buprenorphine. Frontiers in

          Psychiatry, 11. https://doi.org/10.3389/fpsyt.2020.549272

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceCorey Miller 
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Hello, Candy

The agonist antagonist relations ship between ions in the synaptic cleft helps patients receive the pharmacological needs they have. Ions that cling to a receptor in the case Opioids a the mu- opioid receptor can be counter acted by naloxone. Naloxone’s competitiveness to the mu opioid receptors allows the quick reversal of opioids at the sites (Chimbar & Moleta, 2018). Naloxone antagonist effect to opioids gives the drug life saving properties. The ion channels having extracellular receptors in the postsynaptic cleft, as well as the direct signaling pathways allow for the rapid transfer of signals in comparison to G couple proteins (Camprodon & Roffman, 2016). The G couple proteins use secondary messengers and travel much slower to the action potential of a neuron. People without hereditary dispositions to depression suicidality, and PTSD can develop these things in their DNA due to epi genetics. Epigenetics are influenced by a person’s environment and the negative effects can be evidenced on abused children. Children who are abused have DNA changes and resulting in PTSD. There are changes in the Methylation of neurotransmitter activity in patients with PSD (Sheerin et al., 2017). The changes in Methylation of the neuropath as a direct response to abuse and stressful life events, The epigenetics and environment is a resulting factor in the development of PTSD. I agree the foundation of finding a patients epigenetic and environmental predisposition to mental illness is a thorough history. The patient may have hereditary links to mental illnesses and may have to be probed in order to understand that there may be an environmental cause resulting in underlying depression suicidality and PTSD. The changes in patients DNA due to the stressors can be addressed when the patient gives providers the information that in not objective from the health history.

Reference

Camprodon, J. A., & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital psychopharmacology and neurotherapeutics (pp. 1–19). Elsevier

Chimbar, L., & Moleta, Y. (2018). Naloxone Effectiveness: A Systematic Review. J Addict Nurs, 29(3), 167-171. https://doi.org/10.1097/jan.0000000000000230

Sheerin, C. M., Lind, M. J., Bountress, K. E., Nugent, N. R., & Amstadter, A. B. (2017, 2017/04/01/). The genetics and epigenetics of PTSD: overview, recent advances, and future directions. Current Opinion in Psychology, 14, 5-11. https://doi.org/https://doi.org/10.1016/j.copsyc.2016.09.003

Foundational Neuroscience

Explain Agonist to Antagonist Action of Psychopharmacologic Agents: Include Partial and Inverse Functionality and How It May Impact the Efficacy of Treatment

To briefly discuss the relationship on the aforementioned, Rosenthal & Burchum (2021), provide information that agonists activate receptors to mimic endogenous actions of regulatory molecules, thereby making these drugs have a high affinity (strength of attraction between drug and receptor) and high intrinsic activity (the ability of a drug to activate receptors once bound) (p.26). Conversely, antagonists prevent receptor activation and do not have any intrinsic activity. The response an antagonist drug has is determined by how much agonist is present. As the number of a cell’s potential receptors can be altered, agonist drugs may become less effective as the cell is sensitized (p. 27). Either way, if a cell becomes desensitized or over sensitized, the patient’s medication treatment regimen is at risk for a subtherapeutic outcome.

Compare/Contrast G Couple Proteins and Ion Gated Channels

Weis & Kobilka, (2018), define G Couple Proteins (GCPRs) as those proteins that intercede many cellular responses to stimuli from exogenous sources such as light and smell.  GCPRs have the capability to activate another type of protein called arrestins, which then ultimately create downstream signaling pathways for agonist binding at a given site (para. 5). Inversely, Ligated Ion Channels (LGICs) as per Thompson & Baenziger, (2020), are crucial to creating fast synapses, which can be involved in many neurological disorders involving memory, learning abilities, and skeletal muscle coordination.  LGICs are both inhibitory and excitatory and they respond to the binding of neurotransmitters with brief openings of ion channels across pre and post-synapses (para 4.) Among other proteins, lipids, and endocannabinoids help in creating signaling for these channels to open (para. 5).

Explain how Epigenetics May Contribute To Pharmacologic Action

As literature continues to evolve on the study of hereditary traits and the causal relationship of psychiatric disorders, we as advancing professionals have the capability of being a part of a myriad of possible strategies to treat psychiatric disturbances.  In study conducted by Barker, et al., (2014) with regard to alcohol-seeking behavior, it was noted that signaling pathways in the amygdala can be altered on an individual basis to help identify stronger addictive properties in certain specimens more so than others (p.1007).  As there are varied definitions for the term epigenetics, it is of good practice to consider gene function may change under hereditary terms, but there is also the point that a gene’s function may differ without any code specifics (Stern, et al., 2016).  Continual progress in making effort to treat the disease process depends on factors that involve the environment and its respective changes among gene expression.

Explain How This May Impact My Prescribing Process; Provide Case Example

Reading all of this information is going to impact my practice by being and remaining hypervigilant about the choice of medication with regard to the mechanism of action, and desired therapeutic result.  Having a thorough knowledge base of receptor agonist or antagonist or both will be exemplary in proper patient outcomes, and it can help identify potential safety hazards. Specifically, the mental health nurse practitioner would want to be aware of such hazards as in treating a patient with schizophrenia who is on a first-generation antipsychotics such as Haldol. As Haldol has a strong, potent dopamine blockade in the CNS (Rosenthal & Burchum, 2021), the practitioner must know that this puts the patient at risk for developing extrapyramidal symptoms. Although first-generation antipsychotics differ in potency, they produce the same results with different side effects (p. 204).

References

Barker, J. M., Zhang, H., Villafane, J., Wang, T. L., Torregrossa, M. M., & Taylor, J. R. (2014). Epigenetic and pharmacological regulation of 5ht3 receptors controls compulsive ethanol seeking in mice. European Journal of Neuroscience, 39(6), 999–1008. https://doi.org/10.1111/ejn.12477

Rosenthal, L., & Burchum, J. (2021). Lehne’s Pharmacotherapeutics (2nd ed.). Elsevier.

Stern MD, Theodore A., Maurizio, F. M., Wilens MD, Timothy E., & Rosenbaum MD, Jerrold F. (2016). Massachusetts general hospital psychopharmacology and neurotherapeutics (1st ed.). Elsevier.

Thompson, M. J., & Baenziger, J. E. (2020). Structural basis for the modulation of pentameric ligand-gated ion channel function by lipids. Biochimica et Biophysica Acta (BBA) – Biomembranes, 1862(9), 183304. https://doi.org/10.1016/j.bbamem.2020.183304

Weis, W. I., & Kobilka, B. K. (2018). The molecular basis of g protein–coupled receptor activation. Annual Review of Biochemistry, 87(1), 897–919. https://doi.org/10.1146/annurev-biochem-060614-033910

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24 days ago
NURS 6630 Discussion: Foundational NeuroscienceJulia nuzzo 
RE: Julia Nuzzo’s Week 2 Initial Post
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Dear Dr. St. Onge,

Kindly accept this addendum to the first part of the discussion to complete the requirement.

I had been curious about the method of antidepressant medication with the ability to both activate and inhibit certain serotonin receptors and the result in alleviating the depression. To date, vortioxetine is one of the medications with this mechanism of action. According to Slifirski, et al., (2021), vortioxetine acts as a partial agonist specifically to 5-HT1B receptors while antagonizing 5HT3, 7, and 1D respectively. Serotonergic dysfunction related to 5HT1A receptors is clinically significant in Major Depressive Disorder and its treatment (para 5.). With research and the emergence of newer medications such as these, the method of treatment is aimed at alleviating the disturbed central 5HT synapses with partial agonist and antagonism to result in a more effective and possibly quicker antidepressant result (para 8.).

Another interesting fact about vortioxetine is that it currently is the only antidepressant available that appears to have pro-cognitive benefits (Sagud et al., 2021). This is the result of the medication also stimulating and increasing Brain Derived Neurotropic Factor (BDNF) which is strongly associated with improvement in cognition (p.1576).

References

Sagud M, Nikolac Perkovic M, Dvojkovic A, Jaksic N, Vuksan-Cusa B, Zivkovic M, Kusevic Z, Mihaljevic-Peles A, & Pivac N. (2021). Distinct association of plasma BDNF concentration and cognitive function in depressed patients treated with vortioxetine or escitalopram. Psychopharmacology, 238(6), 1575–1584. https://doi.org/10.1007/s00213-021-05790-2

Ślifirski, G., Król, M., & Turło, J. (2021). 5-HT Receptors and the Development of New Antidepressants. International journal of molecular sciences, 22(16), 9015. https://doi.org/10.3390/ijms22169015

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22 days ago
NURS 6630 Discussion: Foundational NeuroscienceLynda Boegner 
RE: Julia Nuzzo’s Week 2 Initial Post: Response #1
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WEEK2: RESPONSE #1 TO JULIA

Hi Julia! Thank you for your informative post particularly regarding agonists and antagonists. In addition to the information you presented, it is important to understand the activity of inverse agonists. Inverse agonists can bind to receptors and produce the opposite pharmacological effect that would be produced by an agonist or an endogenous ligand. They may also cause an opposite effect by suppressing signaling at receptor sites (Berg & Clarke, 2018). For example, if the binding agonist produced sedation, an inverse agonist may produce wakefulness. An inverse agonist suppresses basal or constitutive activity of a receptor while an antagonist blocks ligand stimulation of receptors but permits basal or constitutive activity. Pimavanserin is a selective 5-HT2A inverse agonist used for treatment of hallucinations and delusions in Parkinson’s disease. 5-HT2A receptors are serotonin receptor types that influence various physiological and neurological processes such as memory, sleep, nociception, eating, aggression, anxiety, cognition, learning, and memory (Kianirad & Simuni, 2017). Pimavanserin inhibits the action of 5-HT2A receptors and suppresses their basal and constitutive activity (Howland, 2016). Essentially, it decreases the activity of 5-HT2A receptors. An awareness of disease processes coupled with an understanding of these actions help PMHNPs plan and implement appropriate treatment that will ensure better health outcomes.

References

Berg, K. & Clarke, W. (2018). Making sense of pharmacology: Inverse agonism add functional selectivity. International Journal of Neuropsychopharmacology, 21(100), 962-977.

Camprodon, J. A. & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital Psychopharmacology and Neurotherapeutics (pp. 1-19). Elsevier.

Howland, R. H. (2016). Pimavanserin: An inverse agonist antipsychotic drug. Journal of Psychosocial Nursing Mental Health Services, 54 (6), 21-24.

Kianirad, Y. & Simuni, T. (2017). Pimavanserin, a novel antipsychotic for management of Parkinson’s disease psychosis. Expert Review of Clinical Psychology, 2017 (17), 1161-1168.

Sullivan, L. C., Clarke, W. P., 7 Berg, K. A. (2015). Atypical antipsychotics and inverse agonism at 5-HT2 receptors. Current Pharmaceutical Design, 21 (26), 3732-3738.

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22 days ago
NURS 6630 Discussion: Foundational NeuroscienceJulia nuzzo 
RE: Julia Nuzzo’s Week 2 Initial Post: Response #1
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Hi Lynda!

Thank you for reading and responding to my post. I appreciate and understand the extra information you provided regarding inverse agonists, and you are correct, understanding the different mechanisms of action will allow for focused and acceptable treatment with improved outcomes.  I happen to really enjoy learning about Parkinson’s and am curious to read about pimavanserin, and it’s clinical efficacy, so thank you so much!

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceSteven St. Onge WALDEN INSTRUCTOR MANAGER 
RE: Julia Nuzzo’s Week 2 Initial Post
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Hi Julia

Nice job with your post.  Can you please share with your peers some examples of antagonists and partial agonists?  Thanks!

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceJulia nuzzo 
RE: Julia Nuzzo’s Week 2 Initial Post
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Hi Dr. St. Onge,

Sure! In addition to the information I provided on vortioxetine above, another partial agonist example is the medication cytisine (for smoking cessation).  Antidepressant effects occur as a result of particular partial agonist activity on specific nicotinic acetylcholine receptors (Mineur, et al., 2009).  Also, pentazocine, when administered as a solo form of pain management will act as a partial agonist, but when given in combination with an opioid, it will have an antagonistic and prevent the opioid receptors from activation (Rosenthal & Burchum, 2021).

Additionally, Remeron, (mirtazapine), an atypical antidepressant has significant antagonist action with 5HT2A and 2C receptors specifically (Thorat, et al., 2019). According to their literature review, several studies conclude that agonism of these receptors increases dopaminergic pathway activity in the nigrostriatal region, but antagonism decreases this, thereby decreasing dopamine release (p.30).

Thank you for getting me to think a little bit more about the actions of these drugs. The last article I referenced was very informative and helpful to me.

References

Mineur, Y. S., Eibl, C., Young, G., Kochevar, C., Papke, R. L., Gündisch, D., & Picciotto, M. R. (2009). Cytisine-based nicotinic partial agonists as novel antidepressant compounds. The Journal of pharmacology and experimental therapeutics, 329(1), 377–386. https://doi.org/10.1124/jpet.108.149609

Rosenthal, L., & Burchum, J. (2021). Lehne’s Pharmacotherapeutics (2nd ed.). Elsevier.

Thorat, V. M., Khanwelkar, C. C., Matule, S. M., Salve, P. S., Surle-Patil, S. A., & Sadanandan, S. (2019). Effect of Mirtazapine, a 5-HT2A/2CAntagonist Pre-treatment on Stereotyped Behaviour Induced by Apomorphine and Dexamphetamine in Albino Wistar Rats. Pravara Medical Review, 11(4), 29–36.

week 2 initial post
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An agonist is a substance that initiates a response that is physiological as it binds to a receptor (Colquhoun, 1998, p. 925).  Agonists can imitate neurotransmitters in the body (Mukhtasimova & Sine, 2018, p.713).  Receptors in the cell selectively bind to substances once the receptor becomes excited and can cause a response in the body.  An example of an agonist is methadone (Jordan et al., 2019).  Partial agonists do not execute a maximum retort even when it binds to the receptor fully (Weir, 2020).  When an agonist and a partial agonist arrive at the same site, the partial agonist can act like an antagonist  (Weir, 2020 ).

An antagonist substance binds to a receptor but does not set off a response (Mukhtasimova & Sine, 2018, p. 713).  The antagonist can block a receptor when it binds to a site, and other neurotransmitters cannot cause an action or effect.  One example of an antagonist is Naltrexone (Jordan et al., 2019). When an individual taking opiates overdoses and receives Naltrexone, the effects of the opiate can be blocked, causing a reversal of the original intent to block pain or abuse of the opiate.  Inverse agonist binds to receptors and activates them (Berg & Clarke, 2018, p. 962).  An inverse agonist binds to a receptor, and the opposite effect of the original desired effect is seen.  For example, if a person takes a drug that is supposed to cause sedation and it binds to a receptor, an inverse agonist would cause the effect of wakefulness.

Neurotransmitters in the central nervous system can intervene by ionotropic receptors (Weir, 2020, p. 377).  Ion channels are sorted according to the stimulus needed to open or gate (Weir, 2020, p. 377).  Ligand-gated ion channels are responsible for inhibitory neurotransmitters like Gamma-aminobutyric acid (GABA), a ligand is a hormone (Weir, 2020, p. 377).  For example, Gabapentin is a drug that treats neuropathic pain and is an anti-epileptic (Kukkar et al., 2013, p. 237).  It reduces the effects of pain neurotransmitters by producing an anti-hypersensitivity action to pain (Kukkar et al., 2013, p. 237). Guanine nucleotide (G) proteins couple different receptors to ionic channels (Brown & Birnbaumer, 1988).  G proteins act on potassium and calcium ion channels in the body (Brown & Birnbaumer, 1988).  G receptors are essential for neuronal excitation and have a role in learning and memory Weir, 2020, p. 377).  Epigenetics is an idea that speaks to changes in the expression of genes that do not involve DNA coding (Shukla et al., 2008, p. 1525).

Epigenetics includes information processed by the patient’s environment and what individuals are exposed to.  An example of epigenetics’ role in health includes eating food that supports health and cell function. A healthy diet can help change damage done to cells in the body, thereby influencing epigenetics.  Epigenetics can tell cells in our body to switch on and off.  Epigenetics may be used in pharmacology to change the way a person with schizophrenia may behave by taking medication to help correct signs and symptoms of the disease process.  Alcohol dependence or alcohol-induced dependence can cause changes in the body (Shukla et al., 2008, p. 1532).

As a provider, specific situations have arisen in which patients have requested pharmacologic intervention to decrease alcohol dependence.  Individuals may benefit from medications used to decrease alcohol cravings.  Disulfiram is a medication that can be used within therapeutic parameters to help decrease alcohol use (Gaval-Cruz & Weinshenker, 2009). In this case, pharmacology can change epigenetics related to environmental stimuli and abusing alcohol.  Alcohol can change cell function in the liver (Shukla et al., 2008, p. 1531).  The psychiatric mental health nurse practitioner should be aware that alcohol negatively affects the liver, and providing medication to decrease craving can help to possibly decrease cell damage in the body.

.

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

Brown, A. M., & Birnbaumer, L. (1988). Direct G protein gating of ion channels. American Journal of Physiology-Heart and Circulatory Physiology, 254(3), H401-H410. https://doi.org/10.1152/ajpheart.1988.254.3.h401

Colquhoun, D. (1998). Binding, gating, affinity, and efficacy: The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. British Journal of Pharmacology, 125(5), 923-947. https://doi.org/10.1038/sj.bjp.0702164

Gaval-Cruz, M., & Weinshenker, D. (2009). Mechanisms of disulfiram-induced cocaine abstinence: Antabuse and cocaine relapse. Molecular Interventions, 9(4), 175-187. https://doi.org/10.1124/mi.9.4.6

Jordan, C. J., Cao, J., Newman, A. H., & Xi, Z. (2019). Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine. Neuropharmacology, 158, 107609. https://doi.org/10.1016/j.neuropharm.2019.04.015

Kukkar, A., Bali, A., Singh, N., & Jaggi, A. S. (2013). Implications and mechanism of action of gabapentin in neuropathic pain. Archives of Pharmacal Research, 36(3), 237-251. https://doi.org/10.1007/s12272-013-0057-y

Mukhtasimova, N., & Sine, S. M. (2018). Full and partial agonists evoke distinct structural changes in opening the muscle acetylcholine receptor channel. Journal of General Physiology, 150(5), 713-729. https://doi.org/10.1085/jgp.201711881

Shukla, S. D., Velazquez, J., French, S. W., Lu, S. C., Ticku, M. K., & Zakhari, S. (2008). Emerging role of epigenetics in the actions of alcohol. Alcoholism: Clinical and Experimental Research, 32(9), 1525-1534. https://doi.org/10.1111/j.1530-0277.2008.00729.x

Weir, C. J. (2020). Ion channels, receptors, agonists, and antagonists. Anaesthesia & Intensive Care Medicine, 21(1), 62-68. https://doi.org/10.1016/j.mpaic.2019.10.022

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23 days ago
NURS 6630 Discussion: Foundational NeuroscienceJulia nuzzo 
RE: Higgin, J week 2 initial post
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Hi Jeannie,

Thank you for the insight you provided on this week’s discussion; I think you did a great job relaying your understanding of all the topics at hand. I would like to delve a little bit further into the subject of epigenetics because you piqued my interest when you mentioned just how important nutritional status is in regard to preventing and overcoming mental illness.  I fully agree, and would like to add that stress control is equally important.

In literature supporting how stress can affect epigenetic outcomes, DeSocio (2018), outlines the predisposition of the occurrence of mental illness from the moment of conception. Genetic variability of different mental illnesses ranges from forty to an astounding 70 percent (p. 901).  In the past twenty years, scientists have discovered epigenetic actions that can last the course of a person’s lifetime, particularly how detrimental stress is in the perinatal period (p. 902).

As far as the nutrition component to epigenetics, a mother’s nutritional status at the time of conception can highly impact gene formation leading to untoward health risks (Stevens, Rucklidge, Kennedy, 2018). As continued research is necessary to further understand connections, strong ties are apparent in DNA changes when a fetus is exposed to dietary pollutants, cigarettes, and of course, alcohol (p.3).  Potentiating future complications, it is also hypothesized that these DNA changes in utero will have the ability to be passed on to offspring for many years to come (p. 4).

References

DeSocio, J. E. (2019). Reprint of “Epigenetics, maternal prenatal psychosocial stress, and infant mental health”…DeSocio JE. Epigenetics, maternal prenatal psychosocial stress, and infant mental health. Archives of Psychiatric Nursing. 2018. 32(6): 901-906. Archives of Psychiatric Nursing, 33(3), 232–237. https://doi.org/10.1016/j.apnu.2019.05.001

Stevens, A. J., Rucklidge, J. J., & Kennedy, M. A. (2018). Epigenetics, nutrition and mental health. Is there a relationship? Nutritional Neuroscience, 21(9), 602–613. https://doi.org/10.1080/1028415X.2017.1331524

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceMelissa Asbal 
melissa asbal, 1st response
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Hello Jeannie, thanks for your post.  It was very organized, clear, and to the point.  I also would like to add something about epigenetics.  As stated, epigenetics is the study of how your behaviors and environment can alter the way your gene’s function (“Epigenetics”, n.d.).   There is so much literature on the benefits of epigenetics and how it can be used in cancer treatments, drug development, etc.  But many drugs can produce an epigenetic effect that is negative.  I came across a couple different studies elaborating on that that I found interesting.  Drug classes such as antidepressants, antiepileptics, and illegal drugs can change the functioning of the brain and one’s personality and behavior by the epigenome (Toth, 2021).  These changes in the brain can cause adverse effects, medication resistance and issues with abuse and addiction (Epigenetic side-effects”, n.d.).  Valproic acid is an example of a medication with epigenomic effects (Epigenetic side-effects”, n.d.).  This drug can lead to replication-independent demethylation of DNA and certain genes.  As a result, abnormalities of glial cell function occur which can lead to psychiatric illnesses and changes in cognition (Epigenetic side-effects”, n.d.).

References

Epigenetics. Genome.gov. (n.d.). Retrieved March 9, 2022, from

https://www.genome.gov/genetics-glossary/Epigenetics

Epigenetic side-effects of common pharmaceuticals: A … (n.d.). Retrieved March 11, 2022, from

http://www.medicinacomplementar.com.br/biblioteca/pdfs/Nutrigenomica

/nutrig-0043.pdf

Toth M. , Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain.

Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:181-201. doi: 10.1146/annurev-pharmtox-

030220-022920. Epub 2020 Sep 30. PMID: 32997604.

Week Two Initial Post
COLLAPSE

Psychopharmacological agents can perform as agonists or antagonists. Agonists refer to drugs that have an affinity to bind to target receptors, and intrinsic efficacy to change the activity of the receptor to yield a response (Berg & Clarke, 2018). Antagonist agents possess affinity but do not have intrinsic efficacy which allows them to bind to the targeted receptors, but they do not produce a response (Berg & Clarke, 2018). Antagonist agents diminish receptor occupancy by agonists, simply by occupying receptors, which leads to a reduced response (Berg & Clarke, 2018). During this phenomenon, the agonist concentration is drastically increased which increases the chance that agonists will occupy receptors, and the inhibitory actions of the antagonist may be overcome (Berg & Clarke, 2018). It is known that a full agonist will yield the maximum response within a system, while a partial agonist will yield a submaximal reaction (Berg & Clarke, 2018). Receptor theory hypothesized that receptors are inactive unless they are activated by a ligand (Berg & Clarke, 2018). In other words, ligands can serve as agonists with variable levels of intrinsic efficacy, or as antagonists with no intrinsic efficacy (Berg & Clarke, 2018). Additionally, receptors can also be stimulated without being triggered by an activating ligand and possess integral activity (Berg & Clarke, 2018). Inverse agonists yield the opposite result of agonists by reducing the standard activity of receptors (Berg & Clarke, 2018).

G-protein coupled receptors directly pair with G proteins across cell membranes and generate assorted cellular responses by aiding in the regulation activity of enzymes and ion channels (Inanobe & Kurachi, 2014). Protein interactions with ion channel receptors can increase the capacity for neuronal signaling cascades and serve as a beneficial target for therapeutic intervention in the presence of neuropsychiatric disease processes (Inanobe & Kurachi, 2014). Ion gated channels are cells composed of transmembrane proteins that permit the flow of ions to pass through the membrane based on their electrochemical gradient and can be voltage-gated, mechanically gated, or ligand-gated (Li et al., 2014). Furthermore, ligand-gated ion channels serve as pivotal players in intracellular communication in the nervous system (Inanobe & Kurachi, 2014).

Epigenetics seeks to explain the relationship between genes and the environment during the critical time of development (Kular & Kular, 2018). More specifically, epigenetics speaks to heritable changes that occur in gene expression that do not include variation in the actual DNA sequence (Kular & Kular, 2018). The processes of epigenetics are mainly derived from non-genetic starting points, with the environment heavily impacting the variance of cell division (Kular & Kular, 2018) NURS 6630 Discussion: Foundational Neuroscience. Due to the malleable characteristics of epigenetic marks, the ability to temper and repair epigenetic changes exists through the use of pharmacology (Kumar & Kumar, 2018).

Drugs possess an added level of discrimination that extends beyond the usual receptor selectivity (Kular & Kular, 2018). It is imperative that both inverse agonism and functional selectivity be well understood and involved in the decision-making process when selecting drugs for use in patients (Kular & Kular, 2018). Additionally, the prudent provider must also consider family history, patient history, environmental factors, and known genetic information when considering medication therapy for a patient. One example that comes to mind is a patient who had a long-standing history of major depressive disorder and alcohol abuse and was diagnosed with MDD in early adolescence. She had a pertinent family history that was significant for multiple suicides and attempts, depression, and anxiety. She’d reported taking several medications previously, but they only increased her suicidal ideation, which caused her to increase her drinking to self-medicate. This history requires the provider to consider the mechanism of action in certain classes of antidepressants, to determine which medication would cause the patient the least amount of negative side effects, and the most benefit NURS 6630 Discussion: Foundational Neuroscience.

 

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. doi: 10.1093/ijnp/pyy071

Inanobe, A., & Kurachi, Y. (2014). Membrane channels as integrators of G-protein-mediated signaling. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1838(2), 521-531. https://doi.org/10.1016/j.bbamem.2013.08.018

Kular, L., & Kular, S. (2018). Epigenetics applied to psychiatry: Clinical opportunities and future challenges. Psychiatry and Clinical Neurosciences, 72(4), 195-211. https://doi.org/10.1111/pcn.12634

Li, S., Wong, A.H.C., & Liu, F. (2014). Ligand-gated ion channel interacting proteins and their role in neuroprotection. Frontiers in Cellular Neuroscience, 8(125). doi: 10.3389/fncel.2014.00125

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22 days ago
NURS 6630 Discussion: Foundational NeuroscienceJulia nuzzo 
RE: Lindsay Allen Week Two Initial Post
COLLAPSE

Hi Lindsey,

Thank you for the insight and information you provided, especially with respect to G coupled protein receptors (GCPRs) and their role in cellular responses. I found these discussion topics helpful, as I needed to further my understanding of their roles, and functions in psychotropics. NURS 6630 Discussion: Foundational Neuroscience What I found interesting was that they mediate responses to external stimuli such as light, odors, and growth factors and that they are capable of activating downstream signaling pathways (Weis, Kobilka, 2018).

Of particular interest is the role of a specific GCPR related to leading an individual to be predisposed to developing opioid tolerance.  In a study conducted by Lamberts, et al., (2018),  with regard to chronic morphine use, it was discovered that a loss in pain signaling pathways ( μ receptors ) may possibly be due to a lack of expression of a G alpha receptor.  In other words, μ receptors for some reason not fully understood, become uncoupled from this specific G alpha receptor and cause the resulting tolerance (p. 72). This leads me to wonder if this could happen with another type of substance other than opioids.

References

Lamberts, J. T., Rosenthal, L. D., Jutkiewicz, E. M., & Traynor, J. R. (2018). Role of the guanine nucleotide binding protein, Gα in the development of morphine tolerance and dPsychopharmacology, 235(1), 71–82. https://doi.org/10.1007/s00213-017-4742-2

Weis, W. I., & Kobilka, B. K. (2018). The molecular basis of g protein–coupled receptor activation. Annual Review of Biochemistry, 87(1), 897–919. https://doi.org/10.1146/annurev-biochem-060614-033910

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22 days ago
NURS 6630 Discussion: Foundational NeuroscienceLindsay Allen 
RE: Lindsay Allen Week Two Initial Post
COLLAPSE

Julia,

I found the information you provided about G-coupled protein receptors and opioid tolerance intriguing. This information prompted me to think about how G-coupled protein receptors are impacted by certain medications. In fact, G-coupled protein receptors are the biggest collection of approved targets for FDA-approved medications (Sriram & Insel, 2018). The principal agenda of rational drug discovery is the identification of selective ligands, who in turn act on multiple or single drug targets to manifest a desired clinical outcome (Basith et al., 2018). Furthermore, rational drug design works under the premise of identifying pharmaceutically relevant drug candidates gathered from information within biological targets (Basith et al., 2018). G-coupled protein receptors have become increasingly appealing drug targets because of their contributions to the treatment of various diseases and their stance as one of the most important integral membrane protein families (Basith et al., 2018).

References

Basith, S., Cui, M., Macalino, S.J., Park, J., Clavio, N.B., Kang, S., & Choi, S. (2018). Exploring g protein-coupled receptors (GPCRs) ligand space via cheminformatics approaches: Impact on rational drug design. Frontiers in Pharmacology, 9(128). https://doi.org/10.3389/fphar.2018.00128

Sriram K. & Insel, P.A. (2018). G protein-coupled receptors as targets for approved drugs: How many targets and how many drugs? NURS 6630 Discussion: Foundational Neuroscience Molecular Pharmacology, 93(4), 251-258. DOI: https://doi.org/10.1124/mol.117.111062

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21 days ago
NURS 6630 Discussion: Foundational NeuroscienceJulia nuzzo 
RE: Lindsay Allen Week Two Initial Post
COLLAPSE

Thank you LIndsey!  I thought so too, and nice work delving deeper into the research on them!

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceSteven St. Onge WALDEN INSTRUCTOR MANAGER 
RE: Lindsay Allen Week Two Initial Post
COLLAPSE

Hi Lindsay,

Great summary here.  Can you share why we would combine a partial agonist such as Buprenorphine with an antagonist such as Naloxone into a single medication such as Suboxone?  As you are probably aware, oral naloxone has nearly 0% bioavailability when given orally. NURS 6630 Discussion: Foundational Neuroscience  If none of the drug is absorbed, why use it in the combination?

Thanks!

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17 days ago
NURS 6630 Discussion: Foundational NeuroscienceLindsay Allen 
RE: Lindsay Allen Week Two Initial Post
COLLAPSE

Dr. St. Onge,

Originally, Buprenorphine was combined with Naloxone and released as a combination drug for opioid use disorder treatment in the United States in 2002 (Blazes & Morrow, 2020). The two drugs were combined together and advertised under the premise that it was less likely to be abused and injected as a combination drug (Blazes & Morrow, 2020). This assumption was based on the fact that Buprenorphine has a relatively high bioavailability with sublingual absorption at 35-55%, compared to Naloxone which has less than 10% (Blazes & Morrow, 2020). During parenteral administration, Naloxone, a strong opioid antagonist, would be expected to prohibit the partial agonist effects of Buprenorphine (Blazes & Morrow, 2020) NURS 6630 Discussion: Foundational Neuroscience. This was thought to decrease the potential for abuse and misuse of the drug (Blazes & Morrow, 2020).

References

Blazes, C.K., & Morrow, J.D. (2020). Reconsidering the usefulness of adding naloxone to buprenorphine. Frontiers in    Psychiatry, 11. doi: 10.3389/fpsyt.2020.54927

Discussion: Foundational Neuroscience

As a psychiatric nurse practitioner, it is essential for you to have a strong background in foundational neuroscience. In order to diagnose and treat patients, you must not only understand the pathophysiology of psychiatric disorders but also how medications for these disorders impact the central nervous system. These concepts of foundational neuroscience can be challenging to understand. Therefore, this Discussion is designed to encourage you to think through these concepts, develop a rationale for your thinking, and deepen your understanding by interacting with your colleagues.

NURS 6630 Discussion: Foundational Neuroscience

Photo Credit: Getty Images/Cultura RF

For this Discussion, review the Learning Resources and reflect on the concepts of foundational neuroscience as they might apply to your role as the psychiatric mental health nurse practitioner in prescribing medications for patients.

By Day 3 of Week 2

Post a response to each of the following:

  1. Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents, including how partial and inverse agonist functionality may impact the efficacy of psychopharmacologic treatments.
  2. Compare and contrast the actions of g couple proteins and ion gated channels.
  3. NURS 6630 Discussion: Foundational Neuroscience
  4. Explain how the role of epigenetics may contribute to pharmacologic action.
  5. Explain how this information may impact the way you prescribe medications to patients. Include a specific example of a situation or case with a patient in which the psychiatric mental health nurse practitioner must be aware of the medication’s action.

Read a selection of your colleagues’ responses.

By Day 6 of Week 2

Respond to at least two of your colleagues on two different days in one of the following ways:

  • If your colleagues’ posts influenced your understanding of these concepts, be sure to share how and why. Include additional insights you gained.
  • If you think your colleagues might have misunderstood these concepts, offer your alternative perspective and be sure to provide an explanation for them. Include resources to support your perspective.

Note: For this Discussion, you are required to complete your initial post before you will be able to view and respond to your colleagues’ postings. Begin by clicking on the “Post to Discussion Question” link and then select “Create Thread” to complete your initial post. Remember, once you click on Submit, you cannot delete or edit your own posts, and you cannot post anonymously. Please check your post carefully before clicking on Submit!

NURS 6630 Discussion: Foundational Neuroscience

Understanding pharmacology and neuroscience are essential tools for providers as they explore behaviors, uncover pathology, and treat disease. Medicines impact physiological and cellular systems in a variety of ways. Awareness of these concepts will allow for improved treatment of psychiatric disorders with better health outcomes (Camprodon & Roffman, 2016).

Agonist to Antagonist Spectrum of Action

Various substances such as drugs or medicines can interact with living processes through a spectrum of chemical reactions by binding to regularity molecules (proteins) and activating or inhibiting body processes (Camprodon & Roffman, 2016). Simply, agonists activate receptors. Full agonists produce maximal response that mimics the response to the endogenous ligand, such as methadone in the treatment of substance use disorder. Partial agonists produce submaximal response, such as buprenorphine also used in the treatment of substance use. An inverse agonist binds to the same receptor as the agonist and antagonizes the agonist action. It may also cause an opposite effect by suppressing spontaneous receptor signaling.  Pimavanserin (5-HT2A) is an inverse agonist that is used to treat psychosis associated with Parkinson’s disease without extrapyramidal side effects. Antagonists prevent receptor activation or decrease or oppose another drug or endogenous ligand activity. Antagonists can be reversible and competitive meaning that they bind reversibly to the same agonist binding site, irreversible and competitive meaning they bind irreversibly to the same agonist binding site, noncompetitive or allosteric meaning they bind at a different site, preventing the action of the agonist, physiological or functional antagonists where they act on a different receptor producing a response that opposes the agonist, chemical where the antagonist forms a chemical complex with the agonist and reduces the agonist concentration, and finally pharmacokinetic meaning the antagonist influences the absorption, distribution, metabolism, or excretion of the agonist (Berg & Clarke, 2018). NURS 6630 Discussion: Foundational Neuroscience Naltrexone is an antagonist that blocks (reversibly) the subjective effects of exogenous opioids.

Comparison of G Couple Proteins and Ion Gated Channels

Receptors are specific molecules that can interact with specific drugs causing a change in the receptors which then produce a change in regulatory function. The receptors translate the extracellular stimulation into intracellular signals. Two of the major membrane receptors are ion channel linked receptors and G protein couple receptors.

Ion gated channels open and close in response to a chemical signal like the binding of a ligand. The ligand typically binds to an allosteric site, away from the ion channel. The ion permeability of the plasma membrane then changes. Ions such as potassium, sodium, chlorine, and calcium will begin moving in and out causing a change in the electrical properties of the cell (Alexander, et. al., 2017). The duration of the effect of the receptor is short and the extent of the effect is typically short spread. Ionotropic receptors have a fast response time compared to G protein coupled receptors (Wacker, Stevens, & Roth, 2017).

G protein coupled receptors (GPCRs) comprise the largest known class of membrane receptors and respond to many different external signals on cellular outer surfaces (Wacker, Stevens, & Roth, 2017). Structurally, GPCRs have seven transmembrane alpha helices. As the name implies, these receptors work with G proteins NURS 6630 Discussion: Foundational Neuroscience. G proteins can bind guanosine triphosphate and guanosine diphosphate. G proteins that are associated with GPCRs are heterotrimeric (three subunits). Signaling molecules or ligands bind to the GPCR, causing the GPCR shape to change, and initiates a complex cascade of events leading to different cell function. Specifically, after conformational change of the cell, the alpha subunit exchanges GDP for GTP. This causes the alpha subunit to dissociate from the beta and gamma subunits and it begins to regulate target proteins, triggering the production of secondary messages that relay a signal to other cells. As long as the ligand is bound to the GPCR, this process will repeat itself. Eventually, the GTP can be hydrolyzed to GDP causing the ligand to leave and everything will return to its previous state, until a new ligand comes along (Wacker, Stevens, & Roth, 2017). In contrast to the ion gated channels, the duration of the effect of the receptor is long lasting and the extent of the effect is widespread (Alexander, et. al., 2017).

Epigenetics

Epigenetics is the study of inherited, reversible changes in gene expression without specific alteration of the DNA genetic code. Although actual casual relationships have not been identified, researchers have linked several epigenetic mechanisms to various disease states such as diabetes, cancer, and substance use disorder with differential expressions of certain genes leading to differential risks of disease (Schuebel, Gitik, Domschk, & Goldman, 2016). Identifying medication treatments such as DNA methylation inhibitors, bromodomain inhibitors, or histone acetyl transferase inhibitors that potentially reverse the epigenetic changes has very interesting clinical management possibilities (Ganesan, et. al., 2019). Broadly, epigenetic changes may be used to diagnose disease, determine therapeutic response, and monitor disease progression. Pharmacological modification of epigenetic processes such as small changes in specific regions like a single histone octamer or a single CpG dinucleotide may be used to target psychiatric disease (Gilardi, Augsburger, & Thomas, 2018) NURS 6630 Discussion: Foundational Neuroscience.

Application to Clinical Practice

Understanding the principles of foundational neuroscience is essential as PMHNPs strive to uncover mechanisms of neurological disorders and to develop and implement pharmacologic treatment plans with the least amount of side effects and maximum positive outcomes (safety and efficacy).  Knowing the specific actions of medications and what effects they produce will help the provider choose a drug that is safe, choose the appropriate dosing, and identify which clients are most likely to respond to treatment.

For example, consider the use of buprenorphine as treatment of opioid dependence. Buprenorphine is a partial agonist at the mu receptor which means it only partially activates opioid receptors.  Interestingly, its analgesic effects plateau at higher doses, and then the effects become antagonistic. Buprenorphine has a high ceiling effect regarding respiratory depression which gives it a somewhat safer profile than methadone for agonist substitution treatment in addiction (Kumar, Viswanath, & Saadabadi, 2021) NURS 6630 Discussion: Foundational Neuroscience. Buprenorphine is also a weak kappa receptor antagonist and a delta receptor agonist. Like mu, delta and kappa opioid receptors are G protein coupled receptors. Kappa receptor activation in humans can produce anxiety, dysphoria, and drug-seeking behavior. Buprenorphine as a kappa opioid receptor antagonists blocks these receptors and can reduce these stress responses and thus lessen depressive and addictive tendencies (Kumar, Viswanath, & Saadabadi, 2021). It tends to bind strongly to the mu opioid receptors with a slow tendency to dissociate. This will keep morphine, methadone, or other full agonist opioids from binding. The oral version of buprenorphine has poor bioavailability due to the first pass effect, meaning the liver and intestines breakdown most of the drug with little absorption, unlike sublingual administration (Oakley, Wilson, Hayes, & Lintzeris, 2021). Buprenorphine is metabolized by N-dealkylation and by the cytochrome CYP34A enzyme and broken down to norbuprenorphine and finally excreted in feces and urine. The half-life is about 38 hours. Medications that inhibit 34A enzymes such as ketoconazole or protease inhibitors may cause increased levels of buprenorphine, causing its effects to last longer. Medications that induce 34A such as carbamazepine, topiramate, phenytoin, or barbiturates may cause lower levels of buprenorphine. Stopping a CYP34A inducer medication while still taking the buprenorphine may cause an adverse reaction without a dosage adjustment due to possible increases in buprenorphine effects (Kumar, Viswanath, & Saadabadi, 2021).

Because of all these intricate properties and actions of buprenorphine, PMHNPs must ensure that they have up to date information, review psychosocial factors and other psychological treatment options with the client, clearly document why buprenorphine is being prescribed, discuss risks and benefits with the client, review other medications that may interact, and monitor the client closely NURS 6630 Discussion: Foundational Neuroscience.

References

Alexander, S.P., Peters, J.A., Kelly, E., Marrion, N.V., Facenda, E., Harding, S. D… & CGTP Collaborators. (2017). The concise guide to pharmacology 2017/2018: Ligand-gated ion channels. British Journal of Pharmacology, 174(Suppl 1), 130-159.

Berg, K. & Clarke, W. (2018). Making sense of pharmacology: Inverse agonism add functional selectivity. International Journal of Neuropsychopharmacology, 21(100), 962-977.

Camprodon, J. A. & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital Psychopharmacology and Neurotherapeutics (pp. 1-19). Elsevier.

Ganesan, A., Arimondo, P. B., Rots, M. G., Jeronimo, C., & Berdasco, M. (2019). A timeline of epigenetic drug discovery: From reality to dreams. Clinical Epigenetics, 11(174), 1-17.

Gerra, M. C., Dallabona, C., & Arendt-Nielsen, L. (2021). Epigenetic alterations in prescription opioid misuse: New strategies for precision pain management. Genes 12(1226), 1-21 NURS 6630 Discussion: Foundational Neuroscience.

Gilardi, F, Augsburger, M., & Thomas, A. (2018). Will widespread synthetic opioid consumption induce epigenetic consequences in future generations. Frontiers in Pharmacology 9(702), 1-9.

Kumar, R., Viswanath, O., & Saadabadi, A. (2021). Buprenorphine. Retrieved from https://www.ncbi.nim.nih.gov/books/nBK459126/?report=printable on March 4, 2022.

Lerch, J. P., Van Der Kouwee, A. J., Raznahan, A., Paus, T. Johansen-Berg, H…& Sotiropoulos, S. (2017). Studying neuroanatomy using MRI. Natural Neuroscience, 20(3), 314-326. doi: 10.1038/nn.4501.

Oakley, B. Wilson, H., Hayes, V., & Lintzeris, N. (2021). Managing opioid withdrawal precipitated by buprenorphine with buprenorphine. Drug and Alcohol, 2021(40), 567-571.

Schuebel, K., Gitik, M., Domschk, K., & Goldman, D. (2016). Making sense of epigenetics. International Journal of Neuropsychopharmacology, 19(11), 1-10.

Wacker, D., Stevens, R. C., & Roth, B. (2017). How ligands illuminate GPCR molecular pharmacology. Cell 170 (2017), 414-427.

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21 days ago
NURS 6630 Discussion: Foundational NeuroscienceJeannie Higgin 
RE: WK2 Discussion Post: Foundational Neuroscience
COLLAPSE

The insight on Suboxone is appreciated.  The psychiatric mental health nurse practitioner should be aware of the partial agonistic properties of Buprenorphine while treating patients with opioid use disorder.  Suboxone treatment can be implemented and helps to decrease opioid dependence (Finch et al., 2007).  This population should be treated with a holistic approach.  When a person abuses opioids, it can influence the processing and function of the brain. NURS 6630 Discussion: Foundational Neuroscience  Offering an alternative like Suboxone to clients can change lifestyle and behaviors that influence signals in the brain related to opioid use.

Opioid replacement therapy is one of the most effective treatments for opioid dependence (Katt et al., 2013, p. 52).  People can get caught up in a culture of addiction (Furst, 2013, p. 53).  Epigenetics looks at how human behavior and the person’s environment impact changes in the way genes work.  Substance abuse disorder can affect psycho-physical health (Hasanović et al., 2013, p. 374).  When considering epigenetics concerning opioid dependence, helping individuals decrease substance use disorder can help individuals change the effects of chemical dependence in the brain.

References

Finch, J. W., Kamien, J. B., & Amass, L. (2007). Two-year experience with buprenorphine-naloxone (Suboxone) for maintenance treatment of opioid dependence within a private practice setting. Journal of Addiction Medicine, 1(2), 104-110. https://doi.org/10.1097/adm.0b013e31809b5df2

Furst, R. T. (2013). Suboxone misuse along the opiate maintenance treatment pathway. Journal of Addictive Diseases, 32(1), 53-67. https://doi.org/10.1080/10550887.2012.759860

Hasanović, M., Kuldija, A., Pajević, I., Delić, A., Sutović, A., Avdibegović, E., & Stanišić, D. (2013). Medical assisted treatment of opiate dependence with buprenorphine/Naloxon (Suboxone®) of heroin addicts in prison who are aging penalties. Issues in Social Science, 1(1), 21. https://doi.org/10.5296/iss.v1i1.4177

Katt, M., Chase, C., Samokhvalov, A. V., Argento, E., Rehm, J., & Fischer, B. (2013). Feasibility and outcomes of a community-based taper-to-Low- dose-maintenance Suboxone treatment program for prescription opioid dependence in a remote First Nations community in northern Ontario. International Journal of Indigenous Health, 9(1), 52. https://doi.org/10.18357/ijih91201212394

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17 days ago
NURS 6630 Discussion: Foundational NeuroscienceStephanie Schrag 
Schrag.Response2.RE: WK2 Discussion Post: Foundational Neuroscience
COLLAPSE

Lynda,

Thank you for your post this week.  I particularly enjoyed reading about the use of buprenorphine for opioid dependency and it spurred my interest into this area of research.  I was interested to read that the incidence of buprenorphine prescribing for patients with opioid use disorder has been exponentially growing in recent years (Rhee & Rosenheck, 2019).  NURS 6630 Discussion: Foundational Neuroscience The more I looked the more research articles I found on this treatment type.  As I work in a hospital setting most often I was interested to read a study investigating if transdermal buprenorphine would be helpful in a hospital setting to bridge patients to the sublingual therapy.  Of the patients studied 65% were able to transition without symptoms and 96% were able to complete their planned hospitalizations (Tang, et al., 2020).  I plan to keep an eye on this area of study and research and ensure I learn as much as I can about this treatment for opioid use disorder for my future prescribing information.

References

Rhee, T. G., & Rosenheck, R. A. (2019). Buprenorphine prescribing for opioid use disorder in medical practices: can office-based out-patient care address the opiate crisis in the United States? Addiction , 1992-1999.

Tang, V., Lam-Shang-Leen, J., Brothers, T. D., Hansen, K., Caudarella, A., Lamba, W., . . . Lam-Shang-Leen, J. (2020). Case Series: Limmited Opioid Withdrawal with use of Transdermal Buprenorphine to Bridge to Sublingual Buprenorphine in Hospitalized Patients. American Journal of Addictions, 73-76. NURS 6630 Discussion: Foundational Neuroscience

Agonist to Antagonist Spectrum of Action

Agonists and antagonists work in opposition to each other.  When one produces a result the other opposes that same result.  If a drug is a full agonist, it binds fully to receptors and is considered to have high efficacy and creates a full response.  If a drug is a partial agonist, it partially binds to receptors and has a lower efficacy and therefore creates a lower response than a full agonist.  If a drug is an inverse agonist that means it binds to the same receptor as an agonist but creates the opposite result as that agonist and results in a negative efficacy.  A commonly known inverse agonist would be naloxone or Narcan.  Understanding how medications we prescribe function and if they are an agonist or antagonist and what type is key to helping us understand the way different medications will react and can be especially important for patients on more than one medication.

G couple Proteins and Ion Gated Channels

G couple proteins and ion gated channels both allow certain things to pass through a cell membrane, however what they allow to pass is different. NURS 6630 Discussion: Foundational Neuroscience  G protein coupled protein receptors or GPCRs allow many different things to pass through the cell membrane: molecules, photons, proteins, etc…   Ion gated channels are pores in the cell membrane that only allow ions to pass through the cell membrane (Stern, Fava, Wilens, & Rosenbaum, 2016).

 

Epigenetics

                Epigenetics is the study of how a person’s environment and behavior change the way their genes work.  The changes can be reversible if the behavior and/or environment changes.  Rather than the genes themselves changing, the persons behaviors and/or environment can change how their body interprets DNA segments (Chadwick, 2015).

               

Impacts to Prescribing

As practitioners we must always keep in mind all the different interactions going on within the body including agonists, antagonists, ion gated channels, GPCRs, epigenetics and even a patients medication adherence or recreational drug use.  All of these factors impact how a prescribed medication will react in a patient’s body and therefore must be considered when prescribing medications.  A good example of this was a patient who had been in and out of treatment facilities his entire adult life for cocaine addiction.  The provider asked him why he used cocaine and the patient said it calmed him down and helped him focus.  Understanding the mechanism of how cocaine worked in the CNS, the provider felt there was a significant chance the patient had undiagnosed ADHD and started him on appropriate treatment.  The patient was able to successfully get off cocaine and was still attending day groups a year later still sober from cocaine.  A recent study I found showed that for many patients diagnosed with ADHD and also have cocaine abuse disorder, prescribing ADHD medication significantly reduces cocaine addiction behaviors in these patients (Manni, et al., 2019)

References

Chadwick, B. P. (2015). Epigenetics: current research and emerging trends. Norfolk: Caister Academic Press.

Manni, C., Cipollone, G., Pallucchini, A., Maremmani, A., Perugi, G., & Maremmani, I. (2019). Remarkable Reduction of Cocaine Use in Dual Disorder (Adult Attention Deficit Hyperactive Disorder/Cocaine Use Disorder) Patients Treated with Medications for ADHD. International Journal of Enviromental Research and Public Health.

Stern, T. A., Fava, M., Wilens, T. E., & Rosenbaum, J. F. (2016). Psychopharmacology and Neurotherapeutics. London: Elsevier. NURS 6630 Discussion: Foundational Neuroscience

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20 days ago
NURS 6630 Discussion: Foundational NeuroscienceAbigail Okyere-Boateng 
RE: Schrag.WK2.main post
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Week 2 Discussion, First Response

Hello Stephanie,

Thank you for enlightening me with your discussion post this week. You did a great job addressing all topics. However, I will like to contribute to your insight on the agonist-antagonist spectrum by providing an example of agonists, antagonists, and partial agonist drugs. Agonists allow the opening of ion channels fully, generating an action potential to elicit optimum effect, whiles antagonistic drugs blocks desired effect (Berg & Clarke, 2018). An example of an agonist is Morphine, a partial agonist is Buprenorphine, and an antagonist is Abilify. Abilify blocks brain receptors with increased dopamine (Michel, Michel-Reher, & Hein, 2020).

Additionally, epigenetics design extended phenotypes, using DNA methylations to differentiate between continuous exposures and consequences of diseases. For example, epigenetics DNA methylation models of smoking can differentiate patients who never smoked from those who smoked heavily. Additionally, epigenetics can be used to indicate the extent to which heavy smokers smoke (Langdon et al., 2021). Psychiatric mental health nurse practitioners need to be cautious and aware concerning the epigenetic properties of drugs because, depending on the gene expression, the drug disposition can change.

References

Langdon, R. J., Yousefi, P., Relton, C. L., & Suderman, M. J. (2021). Epigenetic modelling of former, current and never smokers. Clinical Epigenetics, 13(1), 206. https://doi.org/10.1186/s13148-021-01191-6

Michel, M. C., Michel-Reher, M. B., & Hein, P. (2020). A systematic review of inverse agonism at adrenoceptor subtypes. Cells, 9(9). https://doi.org/10.3390/cells9091923

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceLynda Boegner 
RE: Schrag.WK2.main post (Response #2)
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WEEK 2: RESPONSE #2 TO STEPHANIE

Hi Stephanie! Thank for your very informative post. I particularly enjoyed reading your explanation regarding the use of ADHD medication in treating cocaine use disorder. Cocaine use disorder remains a challenging disorder as there is no FDA approved pharmacologic treatment (National Institute on Drug Abuse, 2020). Stimulants may reduce ADHD and cocaine use among ADHD individuals with cocaine use disorder by improving executive functioning resulting in better control and less impulsivity. Alternatively, stimulants may directly reduce cocaine use in a similar mechanism of action as an agonist would in treating substance use disorder (Levin, et. al., 2018). NURS 6630 Discussion: Foundational Neuroscience Medication treatment facilities have successfully used the agonist approach to treat other substance uses disorders, as in the use of the full agonist Methadone or the partial agonist buprenorphine to treat opioid use disorder.

I am excited to see that research continues to explore a variety of neurological targets in the treatment of cocaine use disorder. Scientists have found that cocaine uses induces changes in the brain related to such neurotransmitters as dopamine, serotonin, gamma aminobutyric acid (GABA), norepinephrine, and glutamate (National Institute on Drug Abuse, 2016). Additional research has focused on testing compounds such as N-acetylcysteine that restores the balance between glutamate and GABA neurotransmission which can be disrupted after long term cocaine use (Levin, et. al., 2018). Interestingly, work is also being done to develop a cocaine vaccine using pharmacogenetics to identify a particular genotype that will respond to the cocaine vaccine allowing the body to create antibodies to enhance the metabolism of cocaine. Substance use disorder is a complex disease involving changes in the brain as well as a range of social, familial, and environmental factors (Havlicek, et. al., 2020). Successful treatment may require both pharmacological and behavioral interventions.

References

Camprodon, J. A. & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital Psychopharmacology and Neurotherapeutics (pp. 1-19). Elsevier.

Havlicek, D. F., Rosenberg, J. B., De, B. P., Hicks, M. J. Sondhi, D., Kaminsky, S. M., Crystal, R. G. (2020). Cocaine vaccine dAd5GNE protects against moderate daily and high-dose “binge” cocaine use. PLoS One, 15 (11), 1-14.

Levin, F. R., Choi, C. J., Pavlicova, M., Mariani, J. J., Mahony, A., Brooks, D. J…Grabowski, J. (2018). How treatment improvement in ADHD and cocaine dependence are related to one another: A secondary analysis. Drug Alcohol Depend, 2018 (188), 135-140.

National Institute on Drug Abuse. (2020). How is cocaine addiction treated? Retrieved from https://nida.nih.gov.publications/research-reports/cocaine/what-treatments-are-effective-cocaine-abusers on March 9, 2022.

National Institute on Drug Abuse. (2016). Slow-release amphetamine medication benefits patients with comorbid cocaine addiction and ADHD. Retrieved from https://archives.drugabuse.gov/news-events/nida-notes/2016/08/slow-release-amphetamine-medication-benefits-patients-comorbid-cocaine-addiction-adhd on March 10, 2022. NURS 6630 Discussion: Foundational Neuroscience

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19 days ago
NURS 6630 Discussion: Foundational NeuroscienceCorey Miller 
RE: Schrag.WK2.main post
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Response 1

Hello, Stephanie

The Antagonist agonist relationship between drugs is a very important relation ship especially when it comes down to drugs like opioids and Narcan. When a person has overused the opioids administration of Narcan is a great reversal agent. Narcan has a high affinity for the mu-opioid receptors in the brain and allows for reversal of opioids at these receptors (Jordan & Morrisonpace, 2022). The G couple proteins are a slower pathway to have an action potential fire in the nervous system. The G couple proteins linked to cytoplasmic enzymes in the cell membrane that signal the slower second messenger cascade (Camprodon & Roffman, 2016).  The ion gated channels have a faster reaction time to action potential. The ion gated channels are able to flux a lot faster through transmitters and control neuronal firing making them faster transporters (Camprodon & Roffman, 2016). Epigenetics role in the development and alteration of a person’s brain is quite interesting. A person doesn’t have to be born with a disposition the mental illness and depression, although may develop them due to life circumstances.  Children been abused as children have been shown to have changes in the chromatin around a gene altering the gene expression (Camprodon & Roffman, 2016). Children’s DNA is being altered to environmental Epigenetics, becoming susceptible to mental illnesses that are no birth related. As a provider taking into consideration a patients’ history can lead to the need for psychopharmacological intervention even if there is no family history. NURS 6630 Discussion: Foundational Neuroscience Patients Who have undergone stressful life events and child abuse may need to be further pressed for depression screenings and PTSD evaluations. The role of epigenetics and health history can uncover the fact that a patient who has been depressed their whole lives may need an SSRI, it’s hard to explain that to a mental heath patient who only knows depression as a baseline.

Reference

Camprodon, J. A., & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital psychopharmacology and neurotherapeutics (pp. 1–19). Elsevier

Jordan, M. R., & Morrisonponce, D. (2022). Naloxone. In StatPearls. StatPearls Publishing

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17 days ago
NURS 6630 Discussion: Foundational NeuroscienceMelissa Asbal 
week 2-second response
COLLAPSE

Hello Stephanie, I enjoyed reading your informative post.  I especially liked the story about the patient with the cocaine addiction and how his body reacted to using and the impacts it had on his brain function.  Genetic and environmental factors lead to epigenetic modifications (Nielsen et al., 2012).  This plays a part in a person’s vulnerability to substance abuse or relapses in recovery.  The changes in epigenetics alter drug responses, continued response, and tolerance which as a result causes addiction (Nielsen et al., 2012).  In cocaine use, it alters the DNA which increases protein production that is prevalent in addiction (“Genetics”, 2019).  Drug seeking behaviors occur because of the higher levels of abnormal proteins (“Genetics”, 2019).  These gene alterations associated with addiction make the traits to pass drug addiction susceptibility to these patients’ offspring (“Genetics”, 2019) NURS 6630 Discussion: Foundational Neuroscience.  It is because of this that addiction can be seen across several generations in some families.

References

NIDA. 2019, August 5. Genetics and Epigenetics of Addiction DrugFacts. Retrieved from

 

       https://nida.nih.gov/publications/drugfacts/genetics-epigenetics-addiction on 2022,

 

       March 12

 

Nielsen, D. A., Utrankar, A., Reyes, J. A., Simons, D. D., & Kosten, T. R. (2012). Epigenetics of

 

       drug abuse: predisposition or response. Pharmacogenomics, 13(10), 1149–1160.

           

       https://doi.org/10.2217/pgs.12.94 NURS 6630 Discussion: Foundational Neuroscience