01Neuro Foundations for Neuroscience (1).pdf

1 Basic terms Central Nervous System (CNS) – brain and spinal cord Peripheral Nervous System (PNS) Ganglion – group of neuronal cell bodies with similar function, located outside the CNS. Can be either sensory or motor. Nucleus – group of neuronal cell bodies with similar function, located within th...

1 Basic terms Central Nervous System (CNS) – brain and spinal cord Peripheral Nervous System (PNS) Ganglion – group of neuronal cell bodies with similar function, located outside the CNS. Can be either sensory or motor. Nucleus – group of neuronal cell bodies with similar function, located within the CNS. Autonomic Nervous System (ANS) – 1) sympathetic, 2) parasympathetic Morphology Three basic types of neurons. 2 3 Myelin (lipids and proteins): made by Schwann cell in the PNS and oligodendrocytes in the CNS. Schwann cells myelinate one axon. Oligodendrocytes can myelinate multiple axons. Myelin components different between PNS and CNS. 4 Fiber types 5 Axon – a closer look Axon transport Anterograde, aka orthograde: Kinesin ATPase – fast, dense core vesicles (contains neuropeptides), mitochondria Slow, unknown mechanism. Neurofilaments, microtubules components, e.g., tubulin Retrograde: Dynein ATPase: organelle degradation, e.g., mitochondria, factors taken up at presynaptic terminal, normal, e.g., growth factors, e.g. nerve growth factor (NGF), pathological, e.g., rabies virus, bacterium Clostridium. 6 Resting Membrane Potential (RMP) 2 factors determine resting membrane potential. 1) permeability (sorta like conductance [conductance is the inverse of resistance for movement of charged particles]) of the membrane to a given ion. 2) concentration gradient of that ion. Key terms: electrical potential and capacitance (ability to separate charge) 7 Nernst Equation: E= 61mV [X]outside log z [X]inside An estimate of the resting cell membrane potential (RMP) Chord conduction equation: Em = gKEK gN aEN a gC lEC l + + g g g g = (gK +gNa + gCl) Normally the cell membrane is most permeable to potassium, so potassium concentration gradient has the most influence on RMP. Goldman Equation aka, Goldman-Hodgkin-Katz Equation Em = 61log Pk[K +]o + PNa[ Na+]o + PCl[Cl−]i Pk[K +]i + PNa[ Na+]i + PCl[Cl−]o 8 Action Potential Suppose we have the following cell: 145mM 15mM Na+ 5mM 140mM K+ 110mM 10mM Cl- Proteinsmeasured E = -70mV If only Na+ channels open up and remain open. Assume ENa= +60 mV. 60 mV 0 mV -70 mV 9 If only K+ channels open up and remain open. Assume EK = -88 mV 60 mV 0 mV -70 mV -88 mV If both Na+ and K+ channels open up at the same time and remain open. 60 mV 0 mV -70 mV -88 mV 10 If Na+ channels open up first, then after a certain time lapse the K+ channels open, and both channels remain open. 60 mV 0 mV -70 mV If Na+ channels open up then after a certain time they close, yet before they close, K+ channels open up for a certain time and remain open even after the Na+ channels close and then after a certain time they also close. 60 mV 0 mV -70 mV 11 Voltage sensitive channels (voltage gated channels) 12 Depolarization: An action potential can be generated only if a critical number of Na+ channels are recruited. Voltage sensitive Na+ channels open up in a range of membrane potential (-70mV to +40mV). Threshold is achieved only when enough channels are open at the same time. When the stimulus is larger than the threshold, the size and shape of the action potential does not change. As far as action potentials go it's all or none. 13 Repolarization: caused by voltage sensitive K+ channels (these are different channels from the K+/Na+ leaking channels). These voltage sensitive channels begin to open up as the membrane potential rises above -90 mV (this varies depending upon cell type). They open up more slowly than the activation gates of the Na+ channels. Repolarization occurs within a few msec. Neuroscientists use tetraethylammonium (TEA) to selectively block voltage sensitive K+ channels. Hyperpolarization: voltage sensitive K+ channels are slow to close after repolarization; therefore, the membrane potential becomes more negative than the resting potential. How would TEA affect the voltage change profile of an action potential? 60 mV 0 mV -70 mV 14 Presynaptic terminal and release of neurotransmitters Mechanism for synaptic release of NT from vesicles. Action potential travels down the axon and the depolarization of the membrane potential at the presynaptic terminal opens up voltage sensitive Ca+2 channels. This influx of Ca+2 activates proteins in the presynaptic terminal to move the NT vesicles to the synaptic membrane where they fuse with it releasing their NT's. Upon binding to the post-synaptic membrane receptors, they will either cause that membrane to become more positive (excitatory postsynaptic potential [EPSP]) or more negative (inhibitory postsynaptic potential [IPSP]). Vesicles with neurotransmitters pulled towards distal membrane v-SNARES t-SNARES Clinical point: Lambert-Eaton myasthenic syndrome (LEMS) is a condition in which the body's immune system attacks certain isoforms of voltage sensitive calcium channels at the presynaptic terminal compromising release of acetylcholine (ACH). Antibodies are also thought to interfere with the vSNARE and t-SNARE interaction of this motor neurons. It is most often seen in people with small cell lung cancer or other cancers, but it can also occur in people without cancer. 15 Summary of events of action potential and depolarization of the postsynaptic terminal. 16 How does an actional potential get started? Ionotropic receptors: ligand binds to the receptor and the ion channel changes shape Example: nicotinic receptors (nACHR) on skeletal muscle 17 Example: Glutamate receptors on neuron (dendritic spine) Action potential begins at the axon hillock 18 Myelinated vs unmyelinated axons 19 Most axons are insulated with myelin, which is produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. In addition to producing myelin, these glia also provide very important metabolic support for axons. Gaps occur in the myelin sheath every 1 to 2 mm. These gaps are known as nodes of Ranvier, which are about 1 m wide. Very little ion movement occurs in regions of the axon that are wrapped with myelin. Myelin greatly increases the conduction velocity because of greater length constant. This is because there is less charge loss through the myelin. A myelinated nerve fiber, saltatory conduction Because the action potential appears to jump from one node to the next, the process is called saltatory conduction. Latin word saltare, to leap. Nodes of Ranvier Unidirectional because of absolute refractory period Since ion flow is only at the nodes much less Na+ conductance is needed to effect an action potential, by a factor of about 1000. Therefore, myelinated axons are more metabolically efficient because fewer Na+'s have to be pumped back out by Na+/K+ ATPase pumps. 20 Length constant (space constant): distance at which the potential is 37% of the maximum voltage change at the original site of depolarization. 21 Clinical point: Local anesthesia - lidocaine, cocaine, novocaine, tetracaine, benzocaine Blocks voltage gated sodium channels. Often lidocaine is given with epinephrine. Epinephrine causes local vasoconstriction to limit lidocaine absorption in the blood, keeping its effect localized. Saxitoxin (STX): toxin found in shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic shellfish poisoning (PSP). Also found in visceral organs in some pufferfish. Saxitoxin blocks some voltage sensitive sodium channels associate with motor neurons causing skeletal muscle weakness or paralysis. Pufferfish also contains another toxin, Tetrodotoxin (TTX), which also blocks voltage sensitive sodium channels. TTX is found in other various animals, e.g., some frogs and newts, and serves as a defense mechanism. TTX is more toxic compared to saxitoxin. Clinical point: demyelination disrupts action potential propagation Multiple sclerosis (MS) – demyelination of CNS axons, autoimmune issue. Guillain-Barre Syndrome (GBS) - demyelination of PNS axons, autoimmune issues. Another clinical point: Charcot-Marie-Tooth Disease (CMT) A genetic disorder that either affects myelin or axon properties. There are many types. 90% of CMT are one of 4 types. CMT1, CMT2, CMT4 and CMTX. CMT1, most common of all. Autosomal dominate, altered myelin, usually presents in early childhood. CMT2, Autosomal dominate, altered myelin, presents childhood or early adult CMT4, Autosomal recessive, alters axons, presents childhood or early adult CMTX, second most common after CMT1, altered myelin, X linked dominant or recessive. Compromised action potential propagation of peripheral nerves. Causes muscle weakness, typically begins in lower extremities. Abnormal muscle contraction balance across joints causing high foot arches, curled toes (hammertoes), muscle atrophy, sensory deficit of lower extremities. Can affect upper extremities as well. 22 Receptors for neurotransmitters Receptors have many binding sites for different molecules, e.g., neurotransmitters, hormones, drugs, toxins The effect of a neurotransmitter on the downstream cell depends on the receptor. It’s all about the receptor. The effect of some neurotransmitters is to promote action potential, other neurotransmitters inhibit action potentials. We’ve already seen how acetylcholine promotes action potentials by allowing sodium to flow into the cell and possibly bringing it to threshold. Here’s an example of a neurotransmitter that is inhibitory. GABA: Gamma aminobutyric acid (an amino acid) 23 Ionotropic – ligand activated ion channel binding of the ligand alters the structure of the channel which may alter the flow of ions Metabotropic – not an ion channel. Ligand binding alters the structure of the receptor that effects change in the associated cell involving the second messenger system. The end result may affect other ions channels, or turning genes off or on which up or down regulates protein production, or alter other proteins in the cell via phosphorylation or de-phosphorylation. 24 Synapse Unlike a synapse on skeletal muscle where one action potential from the motor neuron can effect an action potential of the muscle fiber, one excitatory action potential from one neuron synapsing on a another neuron cannot effect an action potential of the distal neuron in and of itself. 25 Graded postsynaptic potential change EPSP: excitatory postsynaptic potential – moves the postsynaptic membrane closer to threshold IPSP: inhibitory postsynaptic potential – moves the postsynaptic membrane farther away from threshold by hyperpolarization 26 27 Spatial summation Temporal summation 28 Neurotransmitters and receptors Monoamines: dopamine, serotonin (5HT), norepinephrine, epinephrine, melatonin, histamine Catecholamines: dopamine, norepinephrine, epinephrine Cholinergic: acetylcholine 1. GABA: synthesized in the presynaptic terminal in the presents of appropriate enzymes. Synthesis: glutamine glutamate GABA 1/3 of the synapses in the CNS use GABA Presynaptic vesicles are made in the golgi apparatus in the neuronal soma then transported to the presynaptic terminal (fast antegrade). GABA transported into the vesicle via VGAT protein in the presynaptic terminal. GABA receptors: three main types: GABAA, GABAB, GABAc. All inhibit depolarization of the postsynaptic membrane. GABAA is an ionotropic chloride channel. Inhibits the depolarization of membranes. GABAB is a metabotropic receptor. Its binding leads to opening of potassium channels and inhibition of membrane depolarization. GABA binding to GABAB-R can also cause hyperpolarization of a membrane. GABAC is an inotropic chloride channel. Not as common as A or B and less characterized. GABA is controlled in the synaptic cleft by re-uptake by both the presynaptic terminal and astrocytes via GABA reuptake receptors (GAT). In the presynaptic terminal, GABA is either broke down or transported back into a vesicle. In the astrocyte, GABA is broken down to glutamine and transported back to the neuron. 29 GABA receptors are found on the presynaptic terminals of motor neurons. GABA-A receptors have multiple binding site for various molecules. 30 GABAB can function as an autoreceptor. 31 Drugs Drugs that interact with GABAA receptors: benzodiazepines: Diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), midazolam (Versed), triazolam (Halcion), chlordiazepoxide (Librium) Benzodiazepines are considered anxiolytics. They can be used as hypnotics, muscle relaxants, antiepileptics, alcohol withdrawal. They have amnestic qualities. They bind to benzodiazepine binding sites on GABAA receptor. They don’t cause the GABAA to open, but rather they potentiate the opening of the chloride channel when GABA binds to it by increasing the frequency of opening when bound by GABA. Long term use can cause down regulation of GABAA receptor, such that abrupt cessation of taking the medication can cause a “rebound” effect. The greatest danger is causing seizures. Long use can also result in tolerance to the drug due to down regulation of the receptor. Benzodiazepines can be used for managing status epilepticus. Flunitrazepam (Rohypnol) (street name roofies, R2 or forget me pills) is a benzodiazepine, not legal in the US. Very potent benzodiazepine. Used on the street a recreational drug. Has significant amnesic qualities and is used as a “date rape” drug. Mixed with ethanol potentiates its effect. Nonbenzodiazepines, commonly known as Z drugs: Used for sleep problems. These drugs have a different molecular structure compared to benzodiazepines. They interact at the benzodiazepine binding site of the GABAA receptor. Examples of these are zolpidem (Ambien), zaleplon (Sonata) and eszopiclone (Lunesta). Advantages of these are short half-life, less chance for dependence. Barbiturates: phenobarbital, sodium thiopental. In the past used as hypnotics and anxiolytics. Overdose can be lethal because it depresses the respiratory system. Still used in general anesthetics control of seizures and euthanizing small animals. Barbiturates interact with GABAA receptor potentiating the action of GABA by increasing the length of time the GABAA receptor is open. They also depress the activity of some glutamate receptors lowering the release of glutamate and inhibit some voltage sensitive calcium channels. The interaction of barbiturates with receptors/channels is dose dependent. At low dose, it potentiates GABA’s effect on the receptor. At higher does it can open the GABAA receptor on its own without GABA General anesthetics: gases - Sevoflurane, Desflurane, Isoflurane. Anesthetics for conscious sedation: Given IV - Etomidate and Propofol. Typically given along with midazolam to relax the patient and potentiates amnestic effect of sedation. Drug that interacts with GABAB receptors: Baclofen, used to reduce muscle spasms. 32 2. Glycine: amino acid. Synthesized from the amino acid serine in the presynaptic terminal. Glycine receptor (GlyR) is an ionotropic chloride channel. Glycine also binds to a type of glutamate receptor. More latter. Glycine is removed from the synaptic cleft by reuptake transporters. It is transported into vesicles VGAT, the same transporter that handles GABA therefore neurons that release both GABA and glycine can do so in the same synaptic vesicles. Glycine is removed from the synaptic cleft by reuptake receptors (Gly-T), on both presynaptic terminals and astrocytes. Autoreceptors on presynaptic terminal enhances glycine release. Clinical point: Tetanus toxin is a bacterial protein toxin produced by Clostridium tetani. The toxin is taken up by the motor presynaptic terminal at the neuromuscular junction and by retrograde transport taken to the spinal cord or brain stem. The toxin is taken up by interneurons that use glycine/GABA and blocks glycine and GABA release by interfering with the v-SNARES and t-SNARES. Causes tetany of skeletal muscles. Strychnine: poison use for rodent control, binds to GlyR blocking its function (glycine antagonist), leading to muscle spasm and tetany. 33 3. Acetylcholine: synthesized from acetyl-CoA and choline. It is put into vesicles via VAChT. After release, it is broken down in the synaptic cleft by acetylcholinesterase into to acetyl-CoA and choline. Choline undergoes reuptake into the presynaptic terminal and astrocytes. Two major receptors: nicotinic (nACHR) and muscarinic (mACHR) nAChR is ionotropic receptor – There are two subtypes, N1 (NMJ) and N2 (PNS/CNS) mAChR is a metabotropic receptor. Very complex cell biology. Subtypes: M1, M2, M3, M4, M5. M1 and M4 is found primarily in the nervous system. M1 depolarizes the postsynaptic membrane by closing potassium channels creating EPSP. This receptor is found on the ANS ganglia along with n2ACHR. M4 is an inhibitory receptor by opening potassium channels and inhibiting voltage sensitive calcium channels. M2 is found in cardiac tissue and smooth muscles, and M3 is associated with smooth muscle contraction. M2 inhibits contraction of smooth muscle. M5 found in CNS and smooth muscle of peripheral organs. One mechanism for regulating the amount of ACH released is by way of mACHR autoreceptors. mAChR autoreceptors pre-synaptic membrane and can inhibit neurotransmitter release if amount of ACh in the synaptic cleft reaches a certain level. However, nAChR autoreceptors enhance release of ACh. Clinical points: bacterium Clostridium botulinum toxin cleaves v-SNARES and t-SNARES preventing release of acetylcholine resulting in skeletal muscle paralysis. Food poisoning. Wound poisoning. Botox treatment – originally used in ophthalmology for eye strabismus. Use for muscle twitches or other movement disorders. Later use for cosmetics and migraine headaches. Sarin gas – inhibits acetylcholinesterase. Myasthenia gravis, autoimmune disorder. Antibodies attack nACHR causing muscle weakness. Alpha-neurotoxins in snake venom: binds nACHR on skeletal muscle blocking its function (antagonist for nACHR). Leads to skeletal muscle weakness or paralysis. Curare obtained from the bark and stems of some South American plants, functions as an antagonist for nACHR. Leads to skeletal muscle weakness or paralysis. Anticholinergic drugs- 1) Atropine: antagonist to all 5 mAChR subtypes. Used to dilate pupils of eyes. Major receptor M3 causing muscle contraction. 2) Scopolamine. Most M1 receptor. Used for motion sickness. Succinylcholine: common drug used as a paralytic during deep anesthesia for surgery. Agonist for nACHR in neuromuscular junction. Two mechanisms. 1) Prolonged opening of AChR inactivates Vna channels. 2) Binds to the receptor and keeps it in a deactivated state not allowing any additional depolarizations. This is called a “depolarizing neuromuscular blocking agent”. Rocuronium (newer drug): common drug used as a paralytic during deep anesthesia for surgery. Antagonist for the nAChR in neuromuscular junction. This is called a “nondepolarizing neuromuscular blocking agent”. 34 4. Glutamate: most common neurotransmitter in the CNS. Synthesis: glutamine glutamate GABA Removed (reuptake) from synaptic cleft by neuronal and astrocyte transporters. The major transporters are EAAT’s. EAAT’s are found on both the pre and post synaptic membranes as well as astrocytes. Astrocytes convert glutamate (Glu) to glutamine (GluN) which is then transported back to the neuron. VGLUT1 and VGLUT2 transport glutamate into vesicles. Excessive glutamate in synaptic cleft can lead to excitotoxicity causing neuronal death. 35 Four types of Glutamate receptors 1) NMDA receptor (GluN) 2) Kainate receptor (GluK) 3) AMPA receptor (GluA) 4) mGluRs The major excitatory action of glutamate on motor neurons is produced by Kainate and AMPA receptors. AMPA receptors are permeable to sodium and potassium, but not to calcium. Kainate is permeable to calcium. Many cells have both NMDA and non-NMDA receptors on them, but since Mg+2 at physiological levels block activation of NMDA receptors, most of the EPSP is a function of non-NMDA receptors. However, the more the neuron is depoloarized by the activation of nonNMDA receptors, the more current flows through the NMDA receptors. The NMDA receptor (NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function. The NMDAR is a specific type of ionotropic glutamate & glycine receptor. NMDA (N-methyl Daspartate) is the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. 36 Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations such as Calcium, Sodium and Potassium. A unique property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg+2 ions. In other words, at normal membrane potential, glutamate does not open this channel. But if the membrane is being depolarized by other ionotropic receptors, the glutamate and glycine together will open the NMDA receptor. Both glutamate and glycine must be present. The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor increases the concentration of Ca+2 in the cell. The Ca+2 can in turn function as a second messenger in various signaling pathways. Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. 37 Some postsynaptic membranes have only AMPA, most have both. AMPA and NMDA receptors. Kainate receptors are mostly on the presynaptic membrane. Long Term Potentiation (LTP): The pre and postsynaptic terminal change such that more NT is released from the presynaptic terminal per action potential and/or the postsynaptic terminal become more sensitive to the excitatory NT by upregulation of receptors. LTP can last from hours to days or weeks. It is thought that LTP plays a role in memory. Most of the kainate receptors in the CNS are found on the presynaptic membrane and therefore function as an autoreceptor. High levels of glutamate, when binding to kainate receptors actually inhibit glutamate release. The mechanism is unclear and may involve second messenger signaling whose effect is to lower calcium current into the presynaptic member. mGluRs (metabotropic) can either have an EPSP or IPSP effect depending upon the subtype. Found on both postsynaptic and presynaptic membranes. Widely distributed throughout the CNS, found also on astrocytes. 38 Clinical points: Huntington’s Disease, an autosomal dominant neurodegenerative disorder characterized by motor disturbances, cognitive decline, and neuropsychiatric symptoms, may involve and excess number of NMDA receptors, thus resulting in too much calcium flow into neurons, which kills them. Phencyclidine, (PCP) aka Angel Dust inhibits NMDA receptors. NMDA over-activation may play a role in Alzheimer’s Disease. Beta amyloid and NMDA receptors interact that leads to deleterious effects. Ketamine, first used as an anesthetic during surgery. Antagonist to NMDA R by binding to PCP sites. It interacts with many other NT receptors. Can be use with opioids as an analgesic (pain control). Recently its analog, esketamine, has been used as a rapidly acting anti-depressant. Ketamine can induce euphoria, possibly by inhibiting dopamine reuptake. Probably other mechanisms involved as well. Nitrous Oxide (laughing gas), inhibits NMDA receptors, stimulates dopamine, opioid and alpha 1 and 2 receptors. Ethanol inhibits glutamate release by interfering with all glutamate receptors and potentiates GABA activity by interacting with the GABAA receptor. 39 Monoamines: serotonin (5HT), dopamine, norepinephrine, epinephrine, melatonin, histamine 5. Serotonin (5HT), (5-hydroxytryptamine) Synthesized in presynaptic terminal: tryptophan 5HT, transported into vesicles via VMAT2. VMAT2’s transport all monoamines into vesicles. Most of VMAT1 is found outside of the CNS. Many types of 5HT receptors. All are metabotropic except 5HT3. 5HT3 is a sodium/potassium channel. When 5HT binds to this receptor, it opens, allowing sodium influx resulting in depolarization of the postsynaptic membrane. Some of the metabotropic receptors are stimulatory and some are inhibitory. 5HT levels in the synaptic cleft is controlled by a reuptake transporter, SERT, found in presynaptic membranes and astrocytes. Once the 5HT has undergone reuptake by the neuron, it is either transported back into a vesicle, via VMAT2 or degraded by Monoamine oxidase – A, (MAO-A), located on the outer membrane of the mitochondria. 5HT Autoreceptors play a role in 5HT release by inhibiting it. In the CNS, 5HT is involved in modulating mood, cognition, reward, learning, memory, emesis/nausea and pain modulation. 5HT is thought to play major roles in anxiety and depression. 90% of 5HT is in the GI tract. It’s involved in gut motility. 40 Clinical points: Serotonin is thought to play a role in many behaviors such as mood, depression and anxiety. The theory is that some mood disorders may involve low levels of 5HT. To address this some drugs function to elevate 5HT in the CNS. One class of drugs, selective serotonin reuptake inhibitors (SSRI’s), inhibit SERT, thereby increasing serotonin levels in the synaptic cleft. 5HT Autoreceptors play a role in 5HT release and may push against the effect of any drug that inhibits the reuptake of 5HT. SSRI’s: sertraline (Zoloft), fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil), fluvoxamine (Luvox). Tricyclic antidepressants (TCA): inhibits SERT and NET. NET is the transporter that is involved in the reuptake of norepinephrine. Thus, TCA’s elevate both 5HT and norepinephrine the synaptic cleft. An example drug would be Imipramine (Tofranil). TCA’s tend not to be used as much as other drugs. Serotonin and norepinephrine reuptake inhibitors (SNRI’s): like the TCA’s, they inhibit 5HT and norepinephrine reuptake. TCA’s also block the reuptake of other neurotransmitters where as SNRI’s are more specific to 5HT and norepinephrine. SNRI’s are newer drugs. An example drug would be Venlafaxine (Effexor XR) Monoamine Oxidase Inhibitors (MAOIs): these drugs increase monoamines release by blocking monoamines that have undergone reuptake. There are two types of MAO’s, MAO-A and MAO-B. MAO-A has a greater affinity for 5HT and norepinephrine. MAO-B has a greater affinity for dopamine. Some MAOI’s are nonselective for MAO A or B thus may affect 5HT, norepinephrine and dopamine. Others are specific for one or the other. Example drugs: Selegiline specific for MAO-B, therefore, elevates dopamine levels. Phenelzine (Nardil), non-selective MAOI. MAOI’s are not used that often. Patients on these drugs have diet restrictions and have to avoid food high in the amino acid tyramine. Foods such as yogurt, some cheeses, some processed meats. MAO’s play a role in breaking down tyramine. This amino acid, when elevated, can cause hypertension. Atypical Antidepressants: Bupropion (Wellbutrin), blocks the reuptake of 5HT (SERT), norepinephrine (NET) and dopamine (DAT). Trazodone (Oleptro), is both an agonist and antagonist of 5HT receptors. It depends on which 5HT receptor. It mildly inhibits 5HT reuptake. It also is an alpha-1 and alpha-2 antagonist therefore reduces norepinephrine activity associate with those receptors. Serotonin syndrome: a group of symptoms that may occur with the use of certain serotonergic medications or drugs. This is typically a result of using two or more serotonergic drugs or overdose of SSRI’s. Symptoms may include mental confusion, hallucinations, coma, hyperthermia, hypertension, tachycardia, nausea, diarrhea, hyperreflexia and tremors. 41 3,4-Methylenedioxymethamphetamine (MDMA) known as ecstasy. Alters sensation, increases energy, empathy and pleasure. Following use people report feeling tired and depressed. It can cause death. Long term use can lead to memory problems, paranoia an insomnia. MDMA increases levels of 5HT by two mechanisms. 1) inhibits reuptake by blocking SERT and 2) high levels of MDMA will reverse SERT and cause transport of 5HT out of the presynaptic terminal. MDMA raises the level of 5HT in the cytosol of the presynaptic terminal by 2 means. It inhibits the transport of 5HT into the vesicles and inhibits MOA-A activity [minor effect]. MDMA also inhibits NET (norepinephrine reuptake transporters and DAT [minor effect] (dopamine reuptake transporters). 42 6. Norepinephrine: synthesized from tyrosine in the presynaptic terminal. Norepinephrine undergoes reuptake via NET by presynaptic terminal or astrocytes. If it undergoes reuptake by the neuron, then it is either degraded by MAO-A or is transported back into a vesicle by VMAT2. COMT (Catechol-O-methyltransferase), which is associated with the postsynaptic cell, degrades norepinephrine. It is degraded in astrocyte by MAO-A and COMT. There are two classes of norepinephrine receptors, alpha and beta, both of which are metabotropic. Two subtypes of alpha receptors are alpha 1 and alpha 2. Three subtypes of beta receptors are beta-1, beta-2 and beta-3. Beta-3 can be found in white and brown adipocytes. Alpha 1 and 2, and beta 1 and 2 are found throughout the CNS. Their function is wide and extensive. Alpha 2 receptors have been localized on some presynaptic terminals therefore can function as autoreceptors, inhibiting the release of norepinephrine from the presynaptic terminal. 43 7. Dopamine: synthesis (see above) Dopamine undergoes reuptake via DAT by the presynaptic terminal and astrocytes. In some areas of the brain NET can reuptake dopamine. Dopamine is degraded in the synaptic cleft by COMT. Once taken up by the presynaptic terminal, it is either put into a vesicle via VMAT2 or broken down by MAO-B. Main receptors for dopamine are D1-like and D2-like. These are broader classifications. Under D1like, falls D1 and D5 receptors. Under D2-like are D3 and D4 receptors. All these receptors are metabotropic. D1-like and D2-like receptors tend to have opposite effect on the neuron. D1like receptor increase the levels of cAMP and may stimulate the neuron and D2-like receptors decrease cAMP and may inhibit in the neuron. Autoreceptors are D2/D3 and they inhibit dopamine release. Dopamine in the CNS has a wide range of effects, mood, behavior, motor function. Clinical points: Dopamine plays a critical role in movement. Loss of dopamine neurons leads to Parkinson’s disease. Two pharmacological approaches are 1) to supply the CNS with exogenous dopamine 2) utilize a dopamine agonist. Dopamine cannot cross the blood brain barrier. Levo-dopa (L-dopa), a precursor can cross the blood brain barrier, therefore L-dopa is given orally to Parkinson’s patients. Pramipexole and Ropinirole are dopamine D2-like agonist given for Parkinson’s. Entacapone and Tolcapone inhibit COMT thereby elevating dopamine. Selegiline specific for MAO-B, therefore, elevates dopamine levels. Often these approaches are given in combination. These drugs are also given with a decarboxylase inhibitor (carbidopa) to prevent L-dopa from being converted to dopamine in the periphery thereby keeping the plasma L-dopa levels high. Dopamine is very involved in mood and is responsible for the sense of pleasure. Therefore, some drugs and simulate dopamine release engenders a sense of pleasure/euphoria. Cocaine inhibits DAT, NET and SERT thereby increasing dopamine levels at the synapse as well at serotonin and norepinephrine. Dopamine elevation seems to be the major factor. There are some conditions where dopamine is too high and may play a role in ADHD, addictive behavior, anxiety, hallucinations, schizophrenia and bipolar disorder. Antipsychotics aka, neuroleptics used for an array of psychiatric disorders, blocks D2-like receptors. Examples: Haloperidol (Haldol) and Chlorpromazine (Thorazine). Common side effect is Tardive Dyskinesia (TD) can manifest a year of continuous use of neuroleptics. Not reversible. 44 Atypical antipsychotics aka, atypical neuroleptics are a newer drug class developed after classic antipsychotics. These drugs have some D2-like antagonistic actively but are more active on the 5HT2 receptor. These drugs have fewer side effect compared to the older antipsychotics, lower risk for TD. Examples: olanzapine and clozapine. Lysergic acid diethylamide (LSD) is a D2-like agonist and serves as an agonist for many of the 5HTR’s. Causes hallucinations. Another drug use to treat psychiatric disorders is reserpine which is a VMAT2 inhibitor, keeping dopamine from being put in vesicles thereby lowering dopamine release. It affects other monoamines as well. Amphetamines: raises the levels of monoamines by several mechanisms. DAT, SERT and NET transport amphetamines into the presynaptic terminal, thus competing with dopamine, 5HT and norepinephrine. Also, amphetamines block VMAT2 so free monoamines accumulates in the presynaptic terminal. At some point DAT, SERT and NET begin to export the monoamine from the presynaptic terminal (reverse transport), flooding the surrounding fluid with them. 45 8. Neuropeptide neurotransmitters: synthesized in the neuronal soma and transported down to the presynaptic terminal. Examples of neuropeptides, oxytocin, arginine vasopressin (AVP) [aka ADH], endorphins (opioid), enkephalins (opioid). Oxytocin and vasopressin (aka arginine vasopressin [AVP] aka ADH) play a role in regulating the complex social cognition and behavior. They play significant role in social interactions, in maternal care and closeness, development of general trust and cooperation, controlling of labor and breastfeeding, regulation of blood pressure, social recognition, sexual behaviors and response to stress. Effects of AVP are sexually dimorphic. It is more important in males than females. Pair bonds also involves dopamine and opioids. Prairie voles, monogamous (social pair bonding). Meadow voles sexually promiscuous. The distribution of oxytocin and AVP receptors in the reward center of the brain is involved. Oxytocin also exerts anxiolytic and antidepressant effects whereas vasopressin promotes anxiety and stress response. They find applications for several treatment approaches in mental disorders in the form of autism, borderline personality disorder, social anxiety disorder and schizophrenia. All oxytocin and vasopressin receptors are metabotropic. Opioids play an important role in the CNS involve both pain modulation and pleasure/euphoric feels. Pain modulation will be covered later where we will see how both opioids and 5HT are involved. The pleasure/euphoric sensation via opioids may involve the inhibition of GABA release on dopaminergic neurons thus disinhibition, increasing the release of dopamine. There are many opioid receptors in the CNS. The major opioid receptor is mu. Opiates such as morphine, heroin, oxycodone and hydrocodone (Vicodin) opioids like fentanyl all interact with the mu receptor. All opioid receptors are metabotropic. Naloxone is a short acting mu antagonist and is use for heroin or other opioid overdoses. Naltrexone is a long-acting mu antagonist and is most commonly used to reduce alcohol cravings and to prevent euphoria from opioids in patients attempting sobriety. 46 A few closing comments Dale’s Principle. (Sir Henry Dale, Noble prize for discovering/characterizing ACH as a neurotransmitter) Co-transmission: release of multiple types of neurotransmitters from the same presynaptic terminal.