Exercise as a treatment for drug addiction, pharmacological mechanisms related to dopaminergic and glutamatergic systems of the brain

According to a recent paper which is published in the journal of biomarkers (mentioned at the last of this article), physical exercise reverse damages caused by the addictive substances to the brain. Addictive substances disrupts various neurotransmitter systems in the brain, including the dopaminergic and glutamatergic systems which are the most studied in terms of their roles in addictive behaviors.

    We knows that dopamine is one of brain neurotransmitter which is affected by addictive. Chronic use of addictive substances decrease the basal (tonic) level of dopamine in the brain (although drugs increase dopamine instantly after use for short time which cause drugs associated euphoria). This chronic decrease in the level of dopamine is one of the majors causes which forces the individual of starts the drugs again. Exercise plays the role here. This new studies have collected multiple evidences from previously published papers that exercise increase the level of dopamine, which was affected by the addictive substances in the brain (particularly in the striatum), and prevent relapse. This paper also reported that other aspects of dopaminergic systems such as receptors density and dopamine transporter availability which is disrupted by the additive substances is also recovered by exercise. 

Reference article

1) "Dopaminergic and glutamatergic biomarkers disruption in addiction and regulation by exercise: a mini review"

https://www.tandfonline.com/doi/full/10.1080/1354750X.2022.2049367

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Disease Related with LDL receptor Disfunction

Familial Hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism in which the level of cholesterol rises. The discovery of this disease dates to the 18 hundred BC.  Later, the discovery lead to the homozygous and heterozygous form of FH.  Almost it took a decade, they found a relationship that the hallmark of this disease is the increase level of LDL.  Further on the LDL receptor discovery and the deficits in LDL receptor caused by mutation, leading to lower amount of LDL receptor turnover and decreased activity of LDL receptor, were the culprits responsible for increase level of LDL in the blood.

LDL Receptor Structure domains and their functions

LDL receptor is a bio-membrane mosaic receptor containing 839 amino acids with subdivision of five sub domains.  Included are Ligand binding domain which is extracellular and bind with apoB and apoE of LDL and VLDL respectively. The EGF precursor homology domain attached next to the ligand binding domain is also responsible for the VLDL and LDL attachment and control the release and recycling of the LDL receptor to the cell surface. The O-linked binding domain next is just outside the plasma membrane stretches out the ligand molecule and provide ease in binding to LDL-R.  Membrane spinning domain is the next which anchor the LDL receptor in the plasma membrane and cause its spinning. The last domain of LDL receptor is cytoplasmic domain which function is to direct the LDL-Rs to the coated pits and clustering in these pits. Mutations in LDL-Receptor which is responsible for internalization of LDL can lead to consequences of FH.  Point mutations which cases defects in LDL-Rs are:

1)    Class 1: In this type of mutation the receptor or precursor protein synthesis is absent subsequently increasing the level of LDL causing hypercholesterolemia..

2)    Class 2: In this class of mutation there occur defects like absent or impaired formation of LDL-Rs. The normal routing of LDL-R receptor is very slow or completed blockage of the LDL protein to Leave Endoplasmic Reticulum.

3)    Class 3:  In class three mutation the defects of synthesis and transport of LDL are intact, but the binding domain is mutated and cause impaired LDL binding to the receptor.    

4)    Class 4: In class four mutation the clustering ability of the LDL receptors and further on internalization to the cell vanishes.

5)    Class 5: No receptor recycling and rapid degradation caused by mutation in EGFP-H domain. 

6)    Class 6: Mutation in cytoplasmic domain causing receptors failing to be targeted to membrane.

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Receptor Tyrosine Kinase Dysfunction Related Disease

Receptor Tyrosine Kinase and receptor associated tyrosine kinase are mainly the two-existing type of tyrosine kinase. Three domains are there of receptor tyrosine kinase including are: the outer most extracellular domain, a transmembrane domain and the intracellular domain which has the ability to intrinsically act as a tyrosine kinase.

Receptors tyrosine kinase Receptor and active sites of Phosphorylation 

Structurally 4 similar receptors which come under the family of Epidermal growth factor receptor (EGFR) which is protein kinase. Included are EGFR HER1, HER2, HER3 and HER4 in human beings. Many diseases are linked to EGFR dysregulation.

Cancer is the pathological condition in which the cells are grown abnormally and are undifferentiated with metastatic capabilities. EGFR dysregulation is one the pathophysiological aspect which lead is found in various type of cancers like Lungs cancer, Brain Tumors, esophageal cancer and Intestinal cancer. Dysregulation of EGFR many include overexpression and copy number variation.  

In 40-80 percent Non-small cell lung cancer patient there occur the over expression of EGFR, one of the reasons why this is the potential target for treatment outcomes. EGFR physiologically upon ligand binding go to receptor homo heterodimerization which leads to the activation of cascade of several pathways of downward signaling. These pathways may be Ras-Raf MAP Kinase, STAT and PI3-AKT. The outcomes usually include cell proliferation, apoptosis and cell differentiation.

Abnormal EGFR overexpression is possible to be secondary to changes like 1) Ligand overexpression 2) amplification of the receptor 3) Mutation in the receptor 4) or reduction which occur in the intracellular phosphatases.

Targeted outcomes in such types of cancers in which the EGFR is one of the case for cancer include: Monoclonal antibodies (Mabs) and Receptor tyrosine kinase inhibitors (TKIs).  Mabs (drug i.e transtuzumab, cetuximab and bevacizumab) target the circulation Ligands of receptor tyrosine kinases and prevent their receptor activation.  TKIs (i.e imatinib and gefitinib etc) in the other hand cause the inhibition of kinases of the intracellular domain and prevent ATP to bind to the kinase domain. Drug: Anlotinib Phase 2 clinical Trails (2018). Its mechanism of action is that it is a multitargeted Tyrosine Kinase inhibitor and inhibits multiple sub cascading pathways.

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Electroceuticals "Introduction to Non-Invasive Brain Stimulation as a therapeutic Tool"

Electrical Tools for Treatment of Diseases (The future) 

Non-invasive brain stimulation (NIBS) include techniques like Transcranial Direct current stimulation (TDCS) and Transcranial Magnetic stimulation (TMS).  TMS techniques relate with change in the electrical activity of the neurons at the axonal level not at the cell bodies which has higher threshold.

TMS utilize the power of magnetic field which is generated by a coil. This magnetic field penetrate the scalp and cerebrospinal fluid and activate the intended area on which it is fixed. Thus, activate the neurons. The same effect of Faraday,s law of induction of current from a magnetic field (the concept of Higher secondary Schooling ) .  At the other side TDCS cause the activation of neurons by a small amount of current applied through the sponges connected to the specific area of the brain (i.e Dorsolateral Prefrontal Cortex in Depression).

Both techniques have been extensively studied in depression and has approval form therapeutic use in Depression. Methods and protocols needed to be refined for further therapeutic use in the neuropsychiatric disorders like schizophrenia, Autism and related moods disorders.

NIBS Available Techniques

TMS

TMS is one of the techniques as mentioned above induces current and cause cortical excitability through magnetic field.  In rTMS instead of single pulses, repetitive pulses are used, hence the name Repetitive Transcranial magnetic stimulation (r TMS).

As a convention the low frequency (LF) 1 Hz or less cause decrease in cortical excitability and High frequency (HF) 5Hz and above increase the cortical excitability. But it is just a simplistic view as some studies have shown decrease in the cortical excitability with 5HZ and above.

Various protocols are followed for rTMS, may include continues Transcranial brain stimulation (c TBS) decrease cortical excitability while intermittent TBS (i TBS) increase cortical excitability. Quadripulse stimulation (QPS) and thetaburst stimulation are also protocols applied in in the r TMS. Quadripulse (4 pulses) with short interstimulus interval (e.g 5ms) increase Motor Evoked Potential (MEPS) showing higher cortical excitability and vice versa for 50ms.

Transcranial Electrical Stimulation

Electrical Stimulation include techniques like transcranial direct current stimulation (t DCS), transcranial alternative current stimulation (t ACS) and transcranial random noise stimulation (t RNS).

Transcranial direct current stimulation uses a current of 0.5-2 mA to stimulate the brain and cause neuronal polarization. T DCS may be anodal or cathodal. Anodal stimulation causes cortical stimulation and cathodal stimulation cause suppression in the cortical activity.

NIBS Mechanism

The mechanism of NIBS is thought to be Long Term Potentiation and Long-Term depression (LTP/LDP) like effect. In which are considered to the mechanism involved in potentiating the synaptic interactions between neurons and the various brain circuits while weakening others (LTD).   In addition, other mechanism which can is considered to be responsible include Post tetanic Potentiation (which is a short term increase in the neurotransmitters release after a brief short term high frequency actional potentials).

Pharmacological manipulations have show the effect LTP/LDP like effect where the application of some antagonist of glutamate receptors like dextromethorphan and memantine prevented the TMS after-effects.  Like TMS TDCS is also considered to be generating LTP/LDP life effect.

Current NIBS Therapeutic Application

NIBS therapeutic applications have been tried for various diseases ranging from moods disorders like MDD, Anxiety disorder, OCD and other disorder including schizophrenia, drug addiction, eating disorder/food craving and tinnitus etc.

It has been show that the application bring definite efficacy in condition like in Pain (HF r TMS of M1 contralateral to the pain side) and Depression (HF  r TMS of Left DLPFC).  Condition with probable efficacy include Low Frequency (LF) r TMS of the right DLPFC for depression and HF r TMS of DLPFC for negative symptoms of Schizophrenia.

There is possible efficacy in conditions like tinnitus and auditory hallucinations, PD, LF r TMS for epilepsy (remember LF r TMS decrease cortical excitability), hemispatial neglect, PTSD and CRPS etc

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