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How do drugs enter synapses?

How do drugs enter synapses?


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Many psychopharmaceutical drugs change synapse chemistry or directly agonize neuroreceptors in the brain. For example, cabergoline is a D2 agonist.

How do these compounds enter the physical synapses? Are they simply lipid soluble and diffuse throughout all cells?


The answer is that cabergoline does not need to enter a cell in order to function.

Cabergoline (as well as most (possibly all?) other drugs that target synapses) interact with proteins on the surfaces of the synapses. For example, the D2 receptor that you mention is a dopamine receptor which in its active form is expressed on the surface of neurons near the synaptic cleft.


During period 4 I want us to review these learning objectives:

  • Hypothermia is a condition in which body temperature falls below 35°C.
  • Normal thermoregulatory mechanisms fail.
  • The processes involved in thermoregulation in a mammal. The role of thermoreceptors in the skin and the hypothalamus.
  • The role of positive feedback as temperature continues to fall.

Here’s a powerpoint we will use as a starting point.

We’ll also use this lino that we created last week to help us answer some past paper questions about hypothermia.

Following on from this we will use period 5 to review our learning of the whole topic. I will get you to highlight areas of the syllabus that you feel we need to concentrate on both in remaining lesson that we (may) have available to us, and on the crammer day (Monday 7th Jan).


E4 Neurotransmitters & Synapses

Review Nerves content from the Core before completing this topic.

Fantastic resources available from Utah, including the mouse party, neuron and synapse animations and an interactive involving pedigree charts and the role of genetics in addiction.

Spend some time here to really read around the subject of drugs and addiction – you’ll be glad you did and it really helps answer the ‘discuss the causes of addiction’ question!

Drunken Monkeys! What do alcoholic vervet monkeys have in common with us and the genetic basis for addiction? Read this blog post at punctuated equilibrium, which accompanies this video. Thanks DaveF for the link.

Drugs and The Brain

Jellinek is a Dutch drugs education website that has some great, accessible resources for neurobiology of drugs and the brain. Animations are available in multiple languages.

Neurotransmitters and Drugs:

Inhibitory and excitatory drugs:

    , Cocaine, Nicotine as excitatory psychoactives (McGill ‘The Brain’) , Cannabis (THC), Alcohol as inhibitory psychoactives (McGill ‘The Brain’)

TOK and Biology: The Nutt-Sack Affair

Leader of advisory panel on drug safety sacked for disagreeing with UK government:

Read around the topic, and then answer these questions:

  1. How does this story show the conflict between science and politics?
  2. What do you feel the respective roles of science and politics should be in the government of a country?
  3. Suggest reasons why some drugs which are clearly very harmful, such as tobacco and alcohol, are still legal in many countries.
  4. If you were to form a new country and write a whole new set of drug laws, which would you make illegal or legal and why? Upon which sources of evidence would you rely in order to make your decisions? How would you balance political pressures with scientific evidence?

Find out more about drug laws and the rationale behind them in your own country and the countries you visit or live in.

Remember – regardless of your own opinion on drug laws, if you are caught breaking the law wherever you are, penalties can be very severe.

Here is an interesting half-hour: Russell Brand speaks to a UK Parliamentary Committee on Addiction. What are some of the ideas he proposes? What evidence would you need to see to support those ideas?


What are the ways that drugs can affect synaptic transmission?

Our body produces natural chemicals such as hormones and neurotransmitters, these chemicals assist or prevent synaptic transmissions.

Explanation:

Drugs are made of man-made chemicals, All of these chemical, can imitate how our hormones and neurotransmitters work. These chemicals vary on how they affect a person synaptic transmission, some of them, can speed up synaptic transmissions, some can slow down them down, some can block them from transmitting, while some can even cause chemical reaction, causing our natural chemical to affect us differently.

Three main ways: affect the number of neurotransmitters available, the rate of release of neurotransmitters, and binding affinity of neurotransmitter receptors to the neurotransmitters.

Explanation:

I am not too familiar with specific drugs. The following article will describe how they can be affected, and what enzymes/chemicals are available to cause changes. These are not necessarily pharmaceutical drugs.

So I said there are three main ways of drugs affecting synaptic transmission.

Let's go into detail for each one:

Availability of neurotransmitters
Drugs can affect the production of neurotransmitters, movement of neurotransmitters into vesicles, or movement of vesicles to a synapse.

Rate of release of neurotransmitters
Neurotransmitters are released into the synapse via exocytosis. Exocytosis is a complicated process requiring many structural proteins such as SNARE proteins. Selectiveness of exocytosis is also a contributive factor.

  • TAT-NSF polypeptide inhibits SNARE proteins, disabling exocytosis.
  • Tetanus toxin is a specific inhibitor of VAMP3/cellubrevin (one of
    SNARE proteins).

Affinity of neurotransmitter receptors
Drugs that affect the receptors' affinities is probably the most well-known type because they are even mentioned in usual college textbooks. They are also the most common type of recreational drugs.


Opioids

  • morphine
  • codeine
  • heroin
  • fentanyl (a synthetic that is

Opioids also inhibit brain centers controlling coughing, breathing, and intestinal motility. Both morphine and codeine are used as pain killers, and codeine is also used in cough medicine.

Opioids are exceedingly addictive, quickly producing tolerance and dependence. Although heroin is even more effective as a painkiller than morphine and codeine, it is so highly addictive that its use is illegal. Methadone is a synthetic opioid that is used to break addiction to heroin (and replace it with addiction to methadone).

Release of enkephalins suppresses the transmission of pain signals. (Little is to be gained by having the perception of pain increase indefinitely in proportion to the amount of damage done to the body. Beyond a certain point, it makes sense to have a system that decreases its own sensitivity in the face of massive, intractable pain.)

By binding to mu (µ) receptors, opioids like morphine enhance the pain-killing effects of enkephalin neurons. Opioid tolerance can be explained, at least in part, as a homeostatic response that reduces the sensitivity of the system to compensate for continued exposure to high levels of morphine or heroin. When the drug is stopped, the system is no longer as sensitive to the soothing effects of the enkephalin neurons and the pain of withdrawal is produced.

Mu (µ) receptors are also found on the cells in the medulla oblongata that regulate breathing. This accounts for the suppressive effect opioids have on breathing.

Opioid antagonists


How is a nervous impulse transmitted across a synapse?

A nervous impulse is transmitted across the synapse from a pre-synaptic neurone to a post-synaptic neurone through the use of neurotransmitter diffusion. To explain this in more detail let’s take the example of a cholinergic synapse a synapse that uses the neurotransmitter Acetylcholine. The transmission across a cholinergic synapse can be summarised in 10 steps: 1. Firstly, an action potential (change in electrical potential) arrives at the pre-synaptic neurone. 2. This changes the voltage in the neurone causing the voltage-gated calcium channels on the pre-synaptic neurone to open. 3. Calcium ions then diffuse into the pre-synaptic neurone. 4. The increased concentration of Calcium in the neurone then causes synaptic vesicles, containing the neurotransmitter acetylcholine, to move towards the membrane on the pre-synaptic neurone. 5. The vesicles fuse to the membrane and the neurotransmitter is released into the gap between the two neurones (known as the synaptic cleft). 6. The acetylcholine neurotransmitter then diffuses across the synaptic cleft towards the post-synaptic neurones membrane. 7. Here, the acetylcholine neurotransmitter then binds to the complimentary receptors on the post-synaptic neurone’s membrane. 8. The increase in concentration of the neurotransmitter causes ligand (chemical) gated sodium channels in the post-synaptic neurone membrane to open, allowing sodium to diffuse into the post-synaptic neurone. 9. The increased concentration of sodium ions now in the post-synaptic neurone depolarise the neurone’s membrane causing EPSPs (excitatory post-synaptic potentials). 10. If these EPSPs reach a certain threshold, then an action potential is initiated in the post-synaptic neurone and the impulse has been successfully transmitted from one neurone to the next! If you can remember these 10 steps then you can thoroughly explain transmission of a nervous impulse across a synapse. To help you remember these steps try making a poster showing the process visually, or perhaps try creating a mnemonic.


Drugs and synapses

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What are Antagonist Drugs?

Antagonist drugs are drugs which inhibit the effects of the natural ligand. The natural ligand can be a hormone, neurotransmitter or an agonist.

Types of Antagonist Drugs

Antagonist drugs can be of three main types.

  • Competitive antagonists
  • Non – competitive antagonists
  • Irreversible antagonists

Figure 02: Mechanism of Antagonist drugs

Competitive antagonist drugs are drugs which have the ability to bind at the original binding site and inhibit the binding of the natural ligand. This is due to the shape of the antagonist which mimics the natural ligand. Increasing the ligand concentration can suppress the effect of the competitive antagonist.

Noncompetitive antagonist drugs act allosterically, where it binds to another site other than the true binding site. The binding of the non – competitive antagonist will cause a conformational change in the receptor which will inhibit the binding of the true ligand.

Irreversible agonist drugs bind strongly to the receptor through covalent linkages. This will permanently modify the receptor preventing the binding of the ligand. Examples of antagonist drugs include naltrexone and naloxone. Most often these drugs are used to inhibit the effects of harmful drugs such as cocaine and heroin which are agonist drugs.


Evolution of Resistance to Insecticide in Disease Vectors

Pierrick Labbé Haoues Alout Luc Djogbénou Nicole Pasteur Mylène Weill , in Genetics and Evolution of Infectious Disease , 2011

Acetylcholinesterase

In the cholinergic synapses of invertebrate and vertebrate central nervous system, AChE terminates the synaptic transmission by rapidly hydrolyzing the neurotransmitter ACh. AChE is the target of OP and CX insecticides, which are competitive inhibitors of ACh with a low turnover: when they bind to AChE, their very low release prevents hydrolysis of the natural substrate. Consequently, ACh remains active in the synapse and the nervous influx is continued, leading to the insect death by tetany (see Massoulié and Bon, 1993 ).

In most insects there are two genes, ace-1 and ace-2, coding for AChE1 and AChE2, respectively. In these species, AChE1 is the main synaptique enzyme, and the physiological role of AChE2 is unknown. Diptera of the Cyclorrapha group or “true” flies (such as D. melanogaster and M. domestica) possess a single AChE, which is encoded by the ace-2 gene and is the synaptic enzyme in that case. Phylogenetic analyses have shown that the presence of two ace genes is probably the ancestral insect state ( Weill et al., 2002 Huchard et al., 2006 ).

The first molecular studies on an insensitive AChE conferring resistance to OPs and CXs were carried out on D. melanogaster. Several mutations were identified, each giving a low resistance when alone, and a higher resistance when in combination ( Fournier et al., 1989 Fournier and Mutéro, 1994 ). Similar results were later found with other Diptera that have only the ace-2 gene (e.g., M. domestica, Oakeshott et al., 2005 ).

In mosquitoes where AChE1 is the synaptique enzyme, the most common resistance mutation (G119S) in the ace-1 gene is situated near the catalytic site. In Cx. pipiens, G119S occurred at least 3 times independently, once in Cx. p. pipiens and twice in Cx. p. quinquefasciatus ( Weill et al., 2003, 2004 Labbé et al., 2007a ). However, two other mutations in ace-1 have been identified, both close to the active site: (i) F331W has been observed only in Cx. tritaeniorhynchus ( Nabeshima et al., 2004 Alout et al., 2007 ), (ii) F290V has been observed only in Cx. p. pipiens ( Alout et al., 2009 ). The type of mutation is highly constrained by the codon use: the G119S mutation has never been found in Ae. aegypti, Ae. albopictus, or Cx. tritaeniorhynchus, probably because it requires two mutation steps ( Weill et al., 2004 ).

The ace mutations are responsible for a decreased inhibition of the AChE by the insecticides ( Alout et al., 2008 ). There are only few resistance mutations observed in various species (see Table 14.2 ), suggesting high constraints: those observed in the field are within the active gorge of the enzyme and cause steric problems with bulkier side-chains, while other substitutions (lab-engineered) often result in the inability of enzyme to degrade ACh ( Oakeshott et al., 2005 ). In mosquitoes, these mutations confer a high resistance to OPs and CXs, respectively up to 100 times (e.g., chlorpyrifos) and >9000× (e.g., propoxur) OP resistance conferred by ace alleles is usually higher than COE metabolic resistance ( Raymond et al., 1986 Poirié et al., 1992 Severini et al., 1993 ).

The evolution of insensitive AChE1 has been studied in depth in the mosquitoes Cx. pipiens and An. gambiae. In Cx. pipiens, it was first detected in Southern France in 1978, 9 years after the beginning of OP treatments ( Raymond et al., 1986 ). The gene coding for this G119S mutated AChE1 (ace-1 R ) rapidly spread in treated natural populations. However, its frequency remained low in adjacent untreated areas connected by migration, indicating a fitness cost associated with ace-1 R ( Lenormand et al., 1999 ). The >60% reduction of AChE1 activity in G119S resistant mosquitoes ( Bourguet et al., 1997 ) may explain, at least partially, this cost, which is expressed phenotypically through various developmental and behavioral problems in individuals carrying ace-1 R ( Berticat et al., 2002a, 2004 Bourguet et al., 2004 Duron et al., 2006b ). Similarly, the F290V mutation is probably associated with a fitness cost, although it does not appear to be due to activity reduction ( Alout et al., 2009 ). Recently, several independant duplications of the ace-1 gene, putting a susceptible and a resistant copy in tandem (ace-1 D ), have been identified in Cx. p. pipiens and Cx. p. quinquefasciatus ( Table 14.2 Lenormand et al., 1998a Labbé et al., 2007a ). These alleles are thought to be selected because they reduce the cost of the ace-1 R allele, although not always successfully ( Labbé et al., 2007b ). Several other duplications have been observed recently in the Mediterranean area, with a F290V copy instead of a G119S copy ( Alout et al., 2009 ). In An. gambiae, the recent occurrence of ace-1 R has been detected in West Africa, probably spreading from Côte d'Ivoire to Benin ( Weill et al., 2003 Djogbénou et al., 2008 ). A duplication carrying a G119S copy has also been found, and appears to follow the same trajectory as in Cx. pipiens ( Djogbénou et al., 2009 ).


How does L-dopa effect the actions of neurotransmitters at the synapse in Parkinson's patients?

L-dopa is a drug administered to many Parkinson's patients to attempt to increase an important intercellular antioxidant called glutathione, and to increase cell extension and survival.

Explanation:

L-dopa is Levodopa and is used to alleviate the symptoms of Parkinson's Disease in an effort to reduce suffering and to enhance the lives of patients.

Neurotransmitters at the synapse perform the complicated procedure of carrying information between neurons using chemical transmission. This method is used in conjunction with electrical transmission, which is faster, but it cannot continue as long as chemical transmission over distances.

The continued chemical transmission is dependent on dopamine levels in the synaptic clefts between the neurons, and L-dopa is used to augment these levels where dopamine has decreased.


Watch the video: Παρασκευή ομοιοπαθητικού φαρμάκου (July 2022).


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