Ch4-5: The Nervous System & The Actions of Drugs

What do the four humors represent?

blood - hot/wet, sanguine or passionate nature phlegm - cold/wet, phlegmatic or calm nature yellow bile - hot/dry, choleric, bilious, or bad-tempered nature black bile - cold/dry, melancholic or gloomy nature

What receptors do barbiturates bind to, causing sedative-like effects?

GABAa receptors

How do glia and neurons relate?

Glia provides firmness & structure to the brain, get nutrients in the system (including to neurons), eliminate waste (in between the synapse as well as from neurons I imagine), form myelin which wraps around axons and speed up action potentials, and form the blood-brain barrier which is a semi-permeable membrane between the blood and fluid surrounding neurons and protects the brain from probable toxic chemicals in the blood. Glia also has communication capabilities.

What is homeostasis? What impacts it?

Homeostasis is the body's way of returning itself to the same conditions its meant to be at. For example, the body shivers or perspires to keep the body's temperature around 37 C (98.6 F). Psychoactive drugs can change homeostasis to a new normal. Those with alcohol use disorder have less urine output because alcohol prevents the release of the antidiuretic hormone vasopressin, which causes an increase in urine excretion. And during withdrawal, these people exhibit increased vasopressin release which results in greater water retention.

What is the end organ?

the organ at the terminal end of a nerve conduction pathway

What are sympathomimetic drugs? Give an example.

Drugs that mimic NE, activating the sympathetic nervous system on top of their effects on the brain. For example, amphetamines chemical structure resemble NE.

ataxia

staggering or inability to walk straight

What are nonspecific effects? How are specific effects different?

Nonspecific effects caused by the user's perceptions and the environment it is perceived in. They can be caused by a placebo (an inactive chemical). Specific effects are caused by the chemical itself at certain concentrations in target tissues.

What is the difference between depressants and opioids?

Opioids produces blissful, anxiety relieving effects with none of the recklessness, staggering, & slurred speech that alcohol & other depressants produce. Withdrawal syndrome is life threatening in depressants but not in opioids.

Epidiolex was approved by FDA in June 2018 and is one of four medications acting on endocannabinoids. What does it treat?

Seizures associated with Lennox-Gastaut syndrome & Dravet syndrome

What percentage of the cells in the human brain are glia?

About 90%

What is Lennox-Gastaut syndrome?

Severe form of childhood epilepsy with multiple types of seizures & intellectual disability

What is the life cycle of a neurotransmitter molecule?

1. Active uptake of the precursor though the concentration outside the cell is lower 2. synthesis - precursors changed into NT through 1+ steps helped along by enzymes 3. storage in synaptic vesicles 4. action potential triggers Ca2+ channels to open letting in Ca2+ that triggers exocytosis of several thousand NTs at once 5. NTs bind to receptors on postsynaptic cell, modifying receptor to let in ions that hyperpolarizes/depolarizes the postsynaptic cell 6. NTs removed from the synapse by either reuptake transporters specific to the NT (i.e., DA, 5-HT, or NE transporters) or enzymes

What are the three mechanisms of tolerance? Explain them.

1. Drug disposition tolerance - aka pharmacokinetic tolerance. Enzyme induction making metabolism faster or drugs increasing urine pH (acidity) makes it eliminate faster 2. Behavioral tolerance - drug has the same biochemical effect but a reduced effect on behavior as the body psychologically makes up for the drug's presence/effx 3. Pharmacodynamic tolerance - a change in the release of NT or receptors available to bind to in order to reach a new level of homeostasis, reducing the effect of the drug but also creating physical dependence and withdrawal symptoms if the drug is suddenly not present

What is the two-stage process in which the kidneys work? Why do liver enzymes increase a drug's elimination by changing their chemical structure to a more water soluble one?

1. water and most small and water-soluble molecules are filtered out 2. water is reabsorbed along with some dissolved chemicals, with lipid-soluble molecules being more likely to be reabsorbed

What is the potential influence of protein binding on interactions between different drugs?

A drug with higher affinity for protein molecules in the blood replaces the drug with lower affinity, so that the lower affinity drug exists mostly as unbound molecules and has its duration of action shortened and reaches the sites of action faster, influencing the effect the drug has.

Why do plants produce so many chemicals we use as drugs?

A mutation in a plant could create a new chemical that, when eaten, caused an animal to become ill or die and was thus avoided. Through natural selection, many more of the plants across different types reproduced and spread throughout the planet and in limited, controlled doses, its effects could be useful.

What are the first two identified endocannabinoids?

Anandamide & 2-AG

What are the drawbacks of brain imaging?

Assumptions & statistical analysis are not standardized across different labs and color coding scheme is determined by researcher & may make it seem as though there are enormous differences between regions when only small differences exist. Observed brain differences may be due to normal human variability and are not predictive of cognitive performance, which is why its important to take behavioral data as well as imaging data.

When does the blood-brain barrier fully develop in humans?

At 1 or 2 years of age

Why is the precursor L-dopa used for treatment of Parkinson's and not dopamine itself?

Because dopamine cannot readily cross the blood-brain barrier, but L-dopa can. It then gets quickly converted to dopamine, increasing DA concentrations and relieving symptoms of Parkinson's.

Why don't drugs impact the entire brain if its everywhere?

Because each has a specific structure similar to a specific neurotransmitter, so it only affects those pathways. For example, LSD has similar structure to serotonin and while it goes everywhere in the brain, it only has an effect on serotonin pathways.

Why do 3/4 available treatment medications for Alzheimer's enhances the function of acetylcholine?

Because lower levels of acetylcholine exist in the cortex of these patients and acetylcholine blockers impair memory.

Why does an equilibrium develop quickly for most drugs? Why do drugs eventually leave the brain?

Because the brain is so well supplied with blood the drug concentration in the brain is equal to that in the blood and the number of molecules leaving the brain is the same as the number entering it from the blood. As the liver or kidneys remove molecules from the blood, the drug molecules go from a higher concentration (the brain) to a lower one (the blood) and, thus, is removed from the brain.

Why is the CYP450 family of enzymes the most important drug-metabolizing enzymes found in the liver? How does it differ from an immune system?

Because they specialize in inactivating foreign chemicals an organism might ingest. Unlike an immune system that creates antibodies at the introduction of an antigen, these enzymes are already present in the liver prior to the introduction of a foreign chemical

Why are extended release medications useful? What happens if you take doses too close together?

Because you receive the initial amount of the drug required to receive the response desired and then a gradual release over time to prolong its effect. If you take too many doses too close together, you'll have reached the maximal response so that you don't receive any more therapeutic effect but you may increase the side effects and the maximum blood level will increase with each dose, resulting in cumulative effects.

What makes a drug psychoactive?

Being lipid soluble molecules that surpass the blood-brain barrier and reach the brain, thereby influencing it.

What is the most common way for drugs to be deactivated? What two effects occur?

By enzymes in the liver that changes their chemical structure. This causes metabolites to no longer have the same action as the original drug and for the metabolites to be more likely to be excreted by the kidneys

How can some chemicals act nonspecifically, as in affecting all neurons? Is anything truly nonspecific?

By influencing common characteristics among all neurons. Ex. all neurons have a cell membrane so by acting on the membrane, they can influence their permeability to specific ions and alter its electrical characteristics (i.e., general anesthetics or how local anesthetics alter Na+ ion channels so cells can't communicate). Evidence suggests that alcohol and even gaseous anesthetics might be more selective than previously thought, so the notion that some drugs are nonspecific by altering the membrane's electrical properties is in dispute.

How do local anesthetics work? What was the first local anesthetic?

By selectively blockading Na+ channels, local anesthetics prevents the release of the action potential and disrupts communication between neurons which reduces pain. Cocaine was the first local anesthetic but has since been replaced by simple modifications of the cocaine molecules that do not cross the blood-brain barrier or cause cocaine-like psychoactive effects.

What is the difference between generic, brand, & chemical names for a drug?

Chemical names give the chemical description of the molecule with organic chemistry rules for naming. Its only used by biochemists and pharmacologists in a lab setting. Generic names are the official name of drugs in the public domain that cannot be trademarked and they refer to a specific chemical in a simpler and shorter way than the chemical name. Brand names are controlled by the FDA, trademarked by the manufacturer, and are simple and as meaningful as the company can make it in terms of the indicated therapeutic use (i.e., Concentra ADHD medication helps with concentration).

Give examples of a drug that alters neurotransmitter availability and of a drug that interacts with neurotransmitter receptors. How do these drugs alter the availability or interact with NT receptors?

Cocaine & most antidepressants block reuptake transporters, leaving the NT in the synapse for longer time & it binds repeatedly. Drugs that act on synthesis, storage, release, reuptake, or metabolism alter the availability. Heroin acts as an opioid agonist, mimicking endorphins' actions at opioid receptor while naloxone is an opioid antagonist that blocks these receptors and is used to reverse opioid overdoses. Drugs are either agonists or antagonists at receptors, mimicking the NT or preventing the NT from activating it.

What is the limbic system? With what other structure does it control behavior at a more primitive level than the cerebral cortex?

Connected structures like the amygdala and hippocampus that are involved in emotion, memory for location, & lvl of physical activity. It and hypothalamus involve mechanisms for behavioral control at a more primitive level.

What neurotransmitters are associated with what key brain structures & chemical pathways?

DA - mesolimbic pathway of VTA (originating in the midbrain) -> NAcC & the nigrostriatal pathway from the substantia nigra (originating in the midbrain) past the hypothalamus and end in the striatum. AcH - pathways from the nucleus basalis (lower part of the brain) to throughout the cerebral cortex. NE - locus ceruleus (in the brainstem) to up and down in the brain 5-HT - raphe nuclei (in the brainstem) to up into the brain and down into the spinal cord GABA - most areas of the CNS (no single pathway) Glutamate - throughout the brain & nearly all neurons have receptors for it Endocannabinoids - throughout the brain

What are the major fxns of the neurotransmitters? What diseases are implicated by each?

DA - reward and motor movement (addiction & Parkinon's) AcH - learning and memory (Alzheimer's disease) NE - lvls of arousal & attentiveness; initiation of food intake, energy balance 5-HT - food intake, regulation of body weight, impulsivity and aggression, alcohol use (low levels associated with excessive alcohol consumption) (alcoholism and depression) GABA - inhibitory fxns (i.e., sedation); (interfering w/normal inhibition fxn -> seizures) Glutamate - excitation (implications in relapse after abstinence due to abnormal transmission) Endocannabinoids - in medication used to treat seizures associated w/Lennox-Gastaut syndrome or Dravet syndrome

What are prodrugs?

Drugs that are inactive when absorbed and become activated by liver enzymes

Where are neurotransmitters stored?

In synaptic vesicles in the axon terminals

What are the two ways in which the drug ceases to have an effect?

It can either be excreted by the body unchanged, usually in the urine, or be chemically changed so that it no longer has the same effect

How important are receptor subtypes in determining the action of a neurotransmitter at a particular site in the brain?

It determines the effect of the NT. Ex. AcH has 5 muscarinic receptor subtypes & 11 nicotinic subtypes & AcH actions at these can either be excitatory or inhibitory depending on the receptor subtype.

What is the action potential?

It is an all-or-nothing electrical impulse that travels down the link of the axon once started. When ligands bind to receptors, Na+ ion channels open allowing Na+ ions to enter and depolarize, make more positive, the cell. Na+ ion channels abruptly close and K+ ion channels open, allowing K+ ions to leave a more positive environment. This brings the cell to a more negative state, hyperpolarizing it. Eventually, it reaches its resting potential once again. As the action potential travels down the axon, more Na+ ion channels open and this process occurs down the length of the axon.

Where is the basal ganglia, its function, and its connection?

It is underneath the cortex and a primary component of the striatum which is part of the nigrostriatal pathway. It helps maintain proper muscle tone and too much output from basal ganglia causes muscle rigidity in muscles which occurs from damage by Parkinson's or as a side effect of psychoactive drugs acting on basal ganglia. It also receives widespread input from the cortex and are critical for specific aspects of learning.

Where was chemical neurotransmission first studied? What was discovered?

It was first studied in the autonomic nervous system and it found that the vagus nerve (the 10th cranial nerve) causes a chemical release, now known as Ach, in a frog's heart muscle by stimulating the nerve in one frog heart which causes it to slow, and withdrawing the fluid surrounding the heart (containing Ach), and transferring it to another frog's heart which then would also slow.

What kinds of drugs easily pass the blood-brain barrier?

Lipophilic or fat-soluble molecules because the blood brain barrier is tightly bound compared to other areas of the body, making it harder for water soluble molecules to pass, but it is still a semipermeable membrane and fat-soluble molecules can easily pass through. I.e., heroin is morphine with the addition of two acetyl groups and the extra group makes it more fat-soluble, so that it reaches the brain faster and is more potent than morphine

What are forms of structural and functional imaging that we use? What are their pros and cons?

MRI (structural) - pro: high resolution image & non-invasive; con: no info. on brain functioning PET (function) - pro: direct measure of brain activity & an indirect measure of toxicity (indirect because neuron toxicity can't be determined by PET scans alone); con: injection of radioactive chemicals & no info about brain structures fMRI (function) - pro: real-time info about changes in blood flow which indirectly measure neuron activity in brain regions and noninvasive; con: no info about the anatomy of the brain.

How do each of the forms of imaging work?

MRI - radio frequency pulses move H atoms throughout the brain and body in alignment and when it turns off, the time it takes for it to become random again is measured. Time varies by location & that info. gives us an image of the brain. PET - radioactively labeled chemicals are injected into the bloodstream and bind/enter different areas of the brain and a computerized scanning device determines where. Ex. radioactively labeled glucose enters and cells requiring more energy due to being more active at a moment require more glucose. The radioactive glucose decays releasing positrons and other electrons and the computer scans it and creates a colored statistical map of the most active part of the brain. Activity also affects blood flow with increased blood flow to areas that are more active, so oxygen & other gases can also be labeled. Labeled drugs that bind to NTs can determine changes in binding capabilities/number of receptors available. (i.e., drug abuse reduces number of DA receptors so a radioactive dopamine-binding drug would show less binding in these individuals compared to healthy individuals). fMRI - measures the blood oxygen level dependent signal & uses it to create a statistical map of brain region activity. Oxyhemoglobin increasing & deoxyhemoglobin decreasing means increased blood flow & oxygen consumption due to increased activity & this creates a bigger blood oxygen level dependent signal.

What are active metabolites?

Metabolites that produce effects similar to the parent drug and prolong its effects

How many neurons does the nervous system contain? What influences them?

More than 100 billion, each influenced by hundreds of other neurons and glia

Where is the hypothalamus and its functions?

Near the base of the brain just above the pituitary gland. Serves as a link between the brain & hormonal output of the pituitary. Involved in feeding, drinking, temperature regulation, & sexual behavior

What is the importance of placebo effects and the necessity of double-blind studies?

Placebo effects are especially important for treating pain and major depression and it can question how effective an actual medication is; they are caused by the user's perception rather than the actual chemical compound. To minimize the possibility of a confound, people randomly assigned to receive either an active compound or the placebo and the experimenters are oblivious to who receives what until the end of a double blind study when its time to analyze the results.

Why is pharmacological potency not synonymous with effectiveness?

Potency refers to the amount of drug needed for a particular effect. However, it does not refer to its effect. For example, LSD is the most potent drug requiring a small amount to produce its psychedelic effect but it does not cause overdose while alcohol can cause more serious effects at much higher doses, making it more effective but less potent.

What are the typical effects of drugs in each of the six categories?

Stimulants - moderate doses: wakefulness, sense of energy, well-being; high doses (i.e., cocaine and amphetamines): manic state of excitement, paranoia, hallucinations Psychedelics - perceptual & emotional changes, including unusual pattern of visual sensations & sense of connectedness w/fellow humans Cannabinoids - relaxant, depressive type of drug that can produce altered perceptions at high doses Depressants - low doses: depresses inhibitory parts of the brain -> disinhibition/relaxation & talkativeness -> recklessness; increased dose: slow reaction times, uncoordinated movements, unconsciousness; w/chronic high dose, abrupt discontinuous provides withdrawal syndrome that can be restlessness, shakiness, hallucinations, & sometimes convulsions which can cause death Opioids - analgesics producing relaxed, dreamlike state; moderately high doses for nontolerant people induces sleep; withdrawal syndrome isn't life threatening & includes diarrhea, cramps, chills, & profuse sweating Nicotine - mild stimulant w/some of the relaxant properties of a low dose of a depressant Psychiatric Medications - variety of drugs prescribed to treat mental disorders, i.e., antipsychotics/neuroleptics calm patients experiencing psychosis & unwanted thoughts and antidepressants help recovery from seriously depressed mood states

What important regions exist in the medulla oblongata and how do drugs impact them?

The area postrema detects foreign substances in the blood like alcohol or opioids and triggers vomiting. The respiratory center regulates the rate of breathing and large doses of sedatives, opioids, & other drugs can suppress this center and cause respiratory depression which can lead to death.

What is the role of homeostatic mechanisms in pharmacodynamic tolerance and withdrawal symptoms?

The brain attempts to reach homeostasis, so if a drug creates the presence of too much DA, the brain will reduce the number of DA made and released or reduce the number of receptors available to bind to reach a new level of normal. This reduces the effect of the drug but it also means that if the drug would suddenly not be used, the brain would have less levels of DA than normal and create a feeling of anhedonia. It creates a physical dependence and withdrawal symptoms.

How long is a drug patented for? How do patented medication benefit the company?

The company that discovered and patented the drug can manufacture and sell it without competition for 20 years.

How does protein binding impact drug effects? What is the most common blood protein involved?

The greater the affinity of a drug to bind to a protein, keeping it inactive but also unable to be inactivated or metabolized by enzymes, the more of a dose is needed to feel an effect but also, the longer the effect would last because of the "storage" of molecules on blood proteins, with albumin being the most common protein involved.

What structures does the brain stem contain? What is its role? What neurotransmitters are produced and released from cell bodies in the nuclei in brainstem like structures?

The midbrain, pons, & medulla oblongata connect the larger structures of the brain to the spinal cord and hold many groups of cell bodies (nuclei) that play roles in sensory & motor reflexes & coordinated control of complex movements. Nuclei here contain most of the cell bodies for the neurons producing & releasing dopamine, norepinephrine, & serotonin.

How does enzyme induction or inhibition impact drug relations?

The presence of a drug can increase the number of enzymes present for it so that it is metabolized faster and tolerance is built. Related drugs then have a smaller therapeutic effect. Drugs can also occupy the enzyme, inhibiting them from acting, so that other drugs go un-metabolized and higher blood levels of concentration of the drug can exist.

How do the sympathetic & parasympathetic nervous systems relate? What are their associated neurotransmitters?

The sympathetic nervous system starts the "fight or flight" response while the autonomic nervous system often, but not always, opposes it and calms the body back down. Ach, which slows the heart rate, is the neurotransmitter at the end organ and NE is the neurotransmitter at the end organ of the sympathetic nervous system.

Compare and contrast the most important routes of drug administration relate.

They all reach the brain by way of blood stream. Taking drugs orally takes the longest amount of time to absorb and it is less effective as it passes through the liver & experiences first-pass metabolism. Nasally is faster but users can experience nasal necrosis. Injection is faster than oral. With intravenous, it goes directly into the blood stream and is best for irritating substances as the vessel is insensitive. The risk is the vein collapsing in and shriveling, stopping blood flow which means you have to look for another injection site. Another risk involves the spread of disease like HIV/AIDS through sharing needles. Subcutaneous injections have slower absorption than intramuscular and if the material is irritating to the skin, the skin around the site can die and be shed, known as "skin popping." Intramuscular injections are faster than subcutaneous due to a better blood supply than the layers of skin and has more area of absorption. Smoking is faster than intravenous because it immediately enters the lungs which reaches the brain faster than from the veins. However, the material can't be irritating to the lungs & mucous membranes, there is little control over the dose, and as soon as administration stops, the effect decreases rapidly as there is no place to hold the drug like in intramuscular injections that could have a slow release. Sublingual is fast like intranasal administration but some drugs don't work this way, such as extended release drugs that need enzymes to activate it throughout the body.

How do neuropeptides and neurotransmitters relate?

They both are neuroactive substances found in the brain. Neuropeptides are small protein-like substances produced in the soma while neurotransmitters are chemicals produced in the axon terminal.

How do psychoactive drugs interact with neurons to produce effects in the brain?

They can either alter the availability of the NT by increasing/decreasing the rate of synthesis, metabolism, release from vesicles, or reuptake, or they can act on the receptor of the post synaptic neuron as either an agonist or antagonist. Some drugs can work in a combination of these ways.

How does a company remain competitive after their patent expires and the drug "goes generic"?

They lower the price of their brand name product.

What must other companies do to sell the "same" drug after the patent of a company expires?

They must apply to the FDA, use the generic name or make their own brand name since the original brand name is trademarked, and submit samples that shows their drug is chemically equivalent to the original, and studies that show that the tablets or capsules dissolve appropriately and result in blood levels similar to those of the original drug.

What are precursors molecules derived from?

They're amino acids derived from proteins in the diet.

How do the somatic and autonomic nervous systems relate?

They're both part of the peripheral nervous system. The somatic nervous system is our interaction with the environment and involves voluntary movements. The autonomic nervous system is the internal interaction between our body and brain and regulates visceral, or involuntary, functions of the body like heart rate or blood pressure.

True or false. Virtually all of the brain's supply of DA, NE, & 5-HT is produced by a relatively small number of neurons (a few thousand for each NT) located in the brain stem regions.

True

True or false. The same neurotransmitter can have different effects depending on the receptor being activated.

True. Ach contracts muscles in our arms and legs but inhibits heart muscle contraction.

True or false. The ED50 of a potent drug is lower than the ED50 of a less potent drug.

True. LSD is less effective than alcohol but more potent for its response.

How has the chemical theories of behavior evolved over time?

We went from ancient Greek physician Hippocrates' believe that behavior is due to the balance of four humors and the Chinese belief in the balance of yin and yang to neurochemical imbalances having something to do with mental disorders/diseases. However, as drugs only provide relief and are not a cure, we still do not know the complexities and actual cause of these diseases. Our best theory of depression or schizophrenia is from the 1960s, and despite going from a few known NTs to more than 100, it hasn't changed.

What is the dose-response relationship, ED50, LD50, and therapeutic index?

dose response curve - graph showing the relationship btwn the dose and its effect at varied doses dose-response relationship - at very low doses, there are no effects. A particular low dose where the effect is first seen is the threshold. From there, as the dose of the drug increases, the effect increases until it reaches a point of maximal response where further additions of the drug has no effect. Depending on the effect being measured, the threshold may differ. ED50 - the effective dose for 50% of users LD50 - lethal dose for 50% of users therapeutic index = LD50/ED50, which should always be greater than 1 as the LD should be larger than the ED; if the drug has a greater therapeutic index than existing drugs, its likely safer than humans

What is Dravet syndrome?

rare, severe form of epilepsy appearing during the first year of life as frequent fever-related seizures

What effects do neuropeptides have? What drugs do they relate to?

they have pleasure and pain effects in several places in the brain and circulate in the blood. Some have effects similar to morphine and other drugs derived from opiom (AKA endorphins). Oxytocin has effect on social bonding and MDMA, an amphetamine-based drug, increases oxytocin levels in the urine and plasma and is known for enhancing feelings of connectiveness and sociability.

True or false. Malfunctions of neurotransmitter systems lead to disease states, which can be treated with drugs that target the affected system.

true