Neurotransmission and psychopharmacology
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What are the different types of physiological receptors in the post-synaptic neuron?
- 1.) Intracellular receptors: receptors for nitric oxide, steroids, and thyroid hormones.
- 2.) Transmembrane enzymes: tyrosine kinase receptors for insulin and growth factors.
- 3.) Receptors that lack enzyme activity, but agonist binding activates intracellular enzymes: Receptors for cytokines
- 4.) Ion channels: Receptors for ligands
- 5.) G-protein-coupled-receptors: receptors for ligands
What are the characteristics of an intracellular receptor? What type of molecule utilizes intracellular receptors?
An intracellular receptor is a receptor within the cytoplasm. When it's activated, it translocates to the nucleus and aids in transcription of mRNA for protein synthesis. By doing this, it regulates gene expression.
An example of a molecule that utilizes intracellular receptors is a corticosteroid. It is released by the adrenal cortex, typically providing an anti-inflammatory effect.
What is a transmembrane enzyme receptor? What are the characteristics? Give an example.
It is a membrane receptor that has a cytoplasmic catalytic domain.
An example is a tyrosine kinase receptor. They are receptors for growth factors and tranduce their signals from them. The Growth factors (ligands) attach to an inactive, unliganded, tyrosine kinase receptor, which is a monomer.
When the growth factor binds to the binding site, two tyrosine kinase receptors that are next to each other join and they form a functional unit - a diamer.
- This diamerization a causes an
- autophosphorilation of tyrosine residues.
Now the diamer is active. Through an adaptor, they activate the effector
What are the characteristics of ionotropic receptors? How do they work?
- They are ligand gated ion channels in which the receptor directly alters membrane potentials. The effects are really rapid and are responsible for EPSPs and IPSPs and APs.
- They can be regulated by multiple extracellular and intracellular signals including changes in membrane voltage, or voltage gating.
This receptors are made out of 5 distinct proteins, with each protein being a subunit. Each subunit is combined via protein loops that serve as receptors or regulate the opening and closing of a channel.
What is a G-protein-coupled-receptor? What is another name for it? Why? What are some characteristics? How do they work?
They are a receptor on the post-synaptic cell. They are often called metabotropic receptors because they initiate metabolic processes in cells. The response is slower than Ionotropic, but are longer lasting.
The receptors are not connected directly to the effectors. So, the g-protein is the transducer- the link b/w receptor and effector.
The ligand binds to the receptors, that creates an affinity b/w receptor and transducer and the transducer slides over the membrane and binds to the receptor.
A molecule called GDP attached to the alpha subunit of the G-protein in its inactivated state.
When the ligand binds to the receptor and the transducer is activated, the GDP molecule dissociates from the alpha subunit and is replaced with GTP, activated the subunit.
The alpha subunit completely leaves the beta and gamma subunits and goes to the effector. It phosphorilates the effector and then the alpha unit recombines with beta and gamma and it starts all over.
What are some signals regulated by G-protein-coupled-receptors?
What are the two principal signal transduction pathways involving G proteins?
Cyclic AMP (cAMP) and Phosphatidylinositol
What are the steps involved in the cAMP pathway?
Depending upon which alpha subunit, s or i, is activated, the effector adenylyl cyclase is activated or inhibited (respectively to s or i).
IF it is activated, the enzyme catalyzes to cAMP, a second messenger via phosphodiesterase. cAMP, in turn, activates protein kinases- phophorolation proteins.
This subunit (cAMP + protein kinase) enters the nucleus, where it phosphorolates CREB, a protein that regulates genetic expression.
Drug effects have sites of action. What are these?
The locations at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells.
What is pharmacokinetics?
THe process by which drugs are absorbed, distributed within the body, metabolized, and excreted.
What is a dose-response curve?
A graph of the magnitude of an effect of a drug as a function of the amount of drug administered.
With the exception of intracerebral or intracerbroventricular administration, the routes of drugs administration vary in what ways?
The vary in the rate/speed and the amount of drug that gets into the blood stream - bioavailability.
Why does heroin enter the brain more readily than morphine? What does it do once it gets there?
Heroin is more lipid-soluble than morphine, allowing it to cross the BBB. Once it gets there, it gets turned back into morphine.
Drugs need to be lipid soluble to get into the brain. How does this interfere with removal?
It interferes with elimination through the kidneys, so the drugs must be metabolized by the liver into byproducts that the kidney can eliminate.
What is the therapeutic index? What doesn't it take into consideration?
It is the ratio between the median effective dose, or the dose at which 1/2 your subjects respond, and the median lethal dose, or the dose at which 1/2 of your subjects die.
However, this does not consider side effects, just death.
What are the two reasons that drugs vary in their effectiveness?
- - Different sites of action
- - Affinity of the drug w/ its site of action: or, the strength of the attractive force between a ligand and a receptor.
What is a problem with affinity that drugs can have?
Ligands can have affinity for a receptor, but not activate it...so it blocks the receptor so nothing else can use it.
How is intrinsic activity used to explain antagonistic and agonistic responses?
Intrinsic activity is the strength w/ which a ligand bound to a receptor activates that receptor. An antagonist is a drug that has little or no intrinsic activity. An agonist, does.
What is tolerance?
A decrease in the effectiveness of a drug that is administered repeatedly.
What is sensitization?
An increase in the effectiveness of a drug that is administered repeatedly.
What is a withdrawal symptom? How are they produced?
A withdrawal symptom is the opposite of the symptom produced by a drug when the drug is administered repeatedly and then suddenly no longer taken.
They can be caused by the same mechanisms that cause tolerance, or the body's attempt to compensate for the drug and return to equilibrium. However, this is not always the case. There are many things that will create tolerance, but not withdrawal symptoms.
What are two compensatory mechanisms that are involved in the symptoms of withdrawal?
The first involves a decrease in the effectiveness of binding - the receptors become less sensitive to the drug or the receptors decrease in number.
The second involved the process that couples the receptors to ion channels in the membrane or to the production of second messengers.
How does an agonistic drug effect synaptic transmission?
- The drug can serve as a precursor to a NT
- It can promote synthesis of NT
- It can stimulate release of NT
- It can stimulate postsynaptic receptors
- It can block autoreceptors, thus increasing the synthesis/release of NT
- It can block reuptake
- It can block enzymes that would normally break down the NT
How does an antagonistic drug effect synaptic transmission?
- It can inactive the synthetic enzyme, inhibiting synthesis of NT
- It can prevent storage of NT in vesicles
- It can stimulate autoreceptors, inhibiting the synthesis/release of NT
- It can inhibit the release of NT
- It can block postsynaptic receptors
What is an allosteric modulator?
An indirect agonist/antagonist that either inhibits or facilitates the action of the receptor by binding to a site on it. It doesn't interfere with the binding site for the principal ligand
Competitive and noncompetitive binding are not what they sound like. What are they?
- Competitive binding is reversible binding to a site
- Noncompetitive binding is irreversible binding
What is a presynaptic heteroreceptor?
It is a receptor located in the membrane of a terminal button that receives input from another terminal button by means of an axoaxonic synapse; binds with the NT released by the presynaptic terminal button.
What is a neuromodulator? What is the difference from a NT?
Neuromodulators are chemicals released by another cell that's diffused throughout the extracellular fluid. The difference is that NT are close to what they influence, neuromodulators are far away from what they affect.
In the brain, most synaptic communication is accomplished by two NT; one with excitatory effects and one with inhibitory effects. What are they?
- Glutamate: exitatory
- GABA: inhibitory
What do the other NT do if GABA and Glutamate control information flow?
Other NTs still transmit info, but they have modulating effects that can activate or inhibit entire circuits of neurons that are involved in particular brain functions.
What is the primary NT secreted by the efferent axons of the PNS?
AcH. It is also found in the ganglia of the ANS and at the target organs of the parasympathetic branch of the ANS.
AcH is made from acetate and choline. How?
Acetate is transferred from a molecule of acetyl-CoA. In the presence of the enzyme choline acetyltransferase (ChAT), the acetate ion is transferred from the acetyl-CoA molecule to the choline molecule, yielding ACh and CoA.
What is neostigmine? What is it used for?
It is a drug that inhibits the activity of acetylcholinesterase, or the enzyme that breaks down AcH. It is used to treat MG, by allowing more AcH to get to the existing receptors.
What are the two types of ACh receptors? What's the difference? What blocks them?
- Nicotinic receptors: the ionotropic ACh receptor that is stimulated by nicotine and blocked by curare.
- Muscarinic receptor: a metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine. They are controlled by second messengers, and thus, have longer lasting effects.
The Monoamine NTs are categorized into three different categories. What are they?
What NTs are in the Catecholamine group?
WHat NT is in the Indolamine group?
What NT is in the Ethylamine group?
The brain contains several systems of dopaminergic neurons. The three most important originate in the midbrain. What are they?
- Nigrostriatal system: a system of neurons originating in the substantia nigra and terminating in the neostraitum (the caudate nucleus and putamen). Involved in the control of movement.
- Mesolimbic system: A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus. Important in the role of the reinforcing effects of certain categories of stimuli, including highly abused drugs.
- Mesocortical System: a system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex. Excitatory effects on the frontal cortex and affect functions such as formation of short-term memories, planning, and strategy prep for problem solving.
What is the biosynthesis of Catecholamines?
- Tyrosine is turned into L-DOPA by tyrosine hydroxlyase
- L-DOPA + aromatic amino acid decarboxylase = dopamine
- DA + DA Beta-hydroxylase inside vesicles = Norepinephrine
What is reserpine?
It was the first anti-psychotic. It works by blocking the storage of catecholamines and serotonin in the synaptic vesicles.
There are several different types of dopamine receptors. They are all ___. What are the most common and where are they found?
- D1 and D2 receptors
- D1 = exclusively postsynaptic
- D2 = pre and postsynaptic
The production of the catecholamines is regulated by which enzyme? Where is it found?
- monoamine oxidase (MAO).
- IT is found within monoaminergic terminal buttons, where it destroys excessive amounts of NT.
What is Chlorpromazine?
A D2 receptor blocker that alleviates the symptoms of schizophrenia.
The efficacy of ADHD drugs is thought to be due to an action on ___ receptors
What is fusaric acid?
A drug that inhibits the activity of the enzyme dopamine-b-hydroxylase and thus blocks the production of norepinephrine.
Most neurons that release norepinephrine don't do so through terminal buttons on the ends of axonal branches. Instead, they usually release them through___. What are these?
Norepinephrine is usually released through axonal varicosities, which are beadlike swllings of the axonal branches.
What is idazoxan?
A drug that blocks presynaptic noradrenergic alpha2 receptors and hence acts as an agonist, facilitating the synthesis and release of NE.
How is Serotonin manufactured?
- The precursor tryptophan is hydrolyzed by Tryptophan hydroxylase, becoming 5HTP.
- 5HTP couples with 5HTP decarboxylase, removing the carboxyl group.
What is PCPA?
A drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5HT
What is another term for Serotonin?
The effects of halluncinogenic drugs are thought to be due to ___.
What is histamine?
An Ethylamine that plays an important role in wakefulness.
What is a NMDA receptor?
A specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by magnesium ions. It has several other binding sites, but only opens when glutamate is present and the postsynaptic membrane is depolarized. THus, the NMDA receptor is a voltage and NT dependent ion channel.
What is PCP
Phencyclidine; a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist.
What is allylglycine?
A druge that inhibits the activity of GAD and thus blocks the synthesis of GABA.
What is muscimol?
A direct agonist for the GABA binding site on the GABAa receptor
What is bicuculline?
An antagonist for the GABA binding site on the GABAa receptor.
What is Glycine?
An amino acid; an important inhibitory NT in the lower brain stem and spinal cord.
What is strychnine?
An antagonist for the glycine receptor.
What are endogenous opiods?
A class of peptides secreted by the brain that act as opiates.
What is the difference between an opioid and an opiate?
- An opioid is an endogenous chemical
- An opiate is a drug
Adenosine is a nucleoside. What is it made out of? What does it do?
It is a combination of ribose and adenine. It serves as a neuromodulator in the brain and is released by astrocytes when neurons in the brain are short of fuel or oxygen.
Adosine receptors are coupled to G proteins and their effect is to ___
Open potassium channels, producing inhibitory PSP.
Adenosine is a sedative. So, Caffeine must be a ___
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