4 steps:Synthesis of transmitter,Storage & release of transmitter, Interaction of transmitter with receptor in postsynaptic membrane,Removal of transmitter from synaptic cleft
Takes choline from extracellular fluid (rate limiting step)
A Corticotropin releasing hormone antagonist is a specific type of receptor antagonist which blocks the receptor sites for Corticotropin releasing hormone (also known as Corticotropin releasing factor (CRF)), blocking therefore the consequent secretions of ACTH and cortisol.There are four subtypes of this receptor known at present, defined as CRF-1, CRF-2a, CRF-2b and CRF-2g. Three of these receptors are expressed only in the brain, CRF-1 in the cortex and cerebrum, CRF-2a in the lateral septum and hypothalamus and CRF-2g in the amygdala. CRF-2b is expressed in the choroid plexus and cerebral arterioles in the brain, but is mainly expressed peripherally, on the heart and skeletal muscle tissue.The main research into CRF antagonists to date has focused on antagonists selective for the CRF-1 subtype. Several antagonists for this receptor have been developed and are widely used in research, with the best-known agents being the selective CRF-1 antagonist antalarmin and a newer drug pexacerfont, although several other ligands for this receptor are used in research, such as LWH-234, CP-154,526, NBI-27914 and R-121,919. Antagonists acting at CRF-2 have also been developed, such as the peptide Astressin-B, but so far no highly selective agents for the different CRF-2 subtypes are available.
Heroin one thousand times more powerful and potent than morphine. It also used endorphin receptor site For binding.It caused drug addiction more than others.
Transcript of "Neurotransmitters"
Neurotransmitters Anant Kumar Rathi Final Year Resident, Psychiatry Medical College, Kota (Raj.)
Objectives1- Outline the criteria that need to be met before a molecule can be classified as “neurotransmitter”2- Identify the major neurotransmitter types3- Mechanism of action of important neurotransmitters4- Identify some clinical disorders that can arise as a result of disruption of neurotransmitter metabolism
This is a NEURON. Soma is the cell body of a neuron. It contains a nucleus, ribosomes, mitoch ondria, and other Soma structures. This is whereDendrites are branching fibers much of the metabolicthat receive information from work takes placeother neurons Dendrites Presynaptic terminals PresynapticAxon is a thin fiber terminals are thewhere information point where theis sent from the axon releasesneuron to other chemicalsneurons Axon
Pre-synaptic NeuronNeurotransmittersare sent throughthe axon to pre-synapticterminals, and thento another neuron Post-synaptic Neuron
Summary It travels through the axon Neurotransmitter comes from soma From the pre-synaptic terminal it is taken through the synapse to the next neuron Re-uptake sometimes occurs
NEUROTRANSMITTERSChemical transducers releasedBy electrical impulseInto the synaptic cleftFrom pre-synaptic membraneBy synaptic vesicles. Diffuse to the post-synaptic membrane React and activate the receptors present Leading to initiation of new electrical signals.
Neurotransmitter receptors• Once released, the neurotransmitter molecules diffuse across the synaptic cleft• When they “arrive” at the postsynaptic membrane, they bind to neurotransmitter receptors• Two main classes of receptors: – Ligand-gated ion channels • transmitter molecules bind on the outside, cause the channel to open and become permeable to either sodium, potassium or chloride – G-protein-coupled receptors • G-protein-coupled receptors have slower, longer-lasting and diverse postsynaptic effects. They can have effects that change an entire cell’s metabolism • or an enzyme that activates an internal metabolic change inside the cell • activate cAMP • activate cellular genes: forms more receptor proteins • activate protein kinase: decrease the number of proteins
Neuromodulators• Neurotransmitters transmit an impulse from one neuron to another• Neuromodulator modulate regions or circuits of the brain• They affect a group of neurons, causing a modulation of that group• Neuromodulators alter neuronal activity by amplifying or dampening synaptic activity – eg. dopamine, serotonin, acetylcholine, histamine, glutamate
Dopamine - as NT by Arvid Carlsson 1958 • DOPA is converted so rapidly into Dopamine that DOPA levels are negligible in the brain • Rate of synthesis is regulated by – Catecholamine acting as inhibitor of TH – Availability of BH4 – Presynaptic DA receptors – Amount of activity in nigrostriatal pathway
Metabolism• In rats – DOPAC major metabolite• In primates and human – HVA major metabolite• Accumulation of HVA in brain or CSF used as index of function of dopaminergic neurons
Dopaminergic pathways Mesocortical Nigrostriatal pathway pathway (part of EP system) Mesolimbic pathway Tuberoinfundibular pathway (inhibits prolactin release)Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.
Significance of Dopaminergic Pathways• Mesolimbic Pathway – Associated with pleasure, reward and goal directed behavior• Mesocortical Pathway – Associated with motivational and emotional responses• Nigrostriatal Pathway – Involved in coordination of movement (part of basal ganglia motor loop)• Tuberoinfundibular Pathway – Regulates secretion of prolactin by pituitary gland and involved in maternal behavior 19
Parkinson’s Disease• Substantial loss of Dopamine in the striatum (70 – 80%)• Loss of dopamine neurons in other systems also (mesolimbic, mesocortical and hypothalamic systems)• Treatment strategy includes increasing dopamine levels by administering L-Dopa, nerve grafting with dopamine containing cells and deep brain stimulation 21
Dopamine and Addiction • The dopaminergic projection to ventral striatum has often been implicated in the mechanisms for addiction • Increased loco motor activity and stereotypy caused due to psycho stimulant involve dopamine release in striatum • Cocaine binds to DAT (at a different site) preventing the reuptake of dopamine by the cells leading to an increased extracellular levels of dopamine • Amphetamine acts as a false substrate and is transported into the cytoplasm and results in reverse transport of dopamine from cytoplasm to the extracellular space 22
Norepinephrine or NE• In the CNS, norepinephrine is used by neurons of the locus coeruleus, a nucleus of the brainstem with complex modulator functions• In the peripheral nervous system, norepinephrine is the transmitter of the sympathetic nervous system • Involved in sleep, wakefulness, attention and feeding behavior • At least two kinds of NE receptors: NE alpha and NE beta• Indicated effects: – primarily excitatory – appears to modulate Fear/flight/fight system• Too much: over arousal, mania• Too little: under arousal, depression – Chemically extremely similar to Dopamine, serotonin
Removal of Catecholamines• All three catecholamines are removed by selective reuptake by the presynaptic axon terminals• They are either reused or degraded by monoamine oxidase (MAO)
Serotonin Secreted by the nuclei originating in the median raphe of the brain stem and terminate in dorsal horn of the spinal cord and hypothalamus
(Rate limiting) OH COOH COOH Tryptophan C NH2 hydroxylase C NH2 N N In diet. Active Tryptophan CNS transport 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase C COOH OH H N C NH25-Hydroxy Indole N Acetic Acid 5-OH Indole Acetaldehyde 5-Hydroxytryptamine
• Excitatory & Inhibitory• Control the mood of the person and important in sleep• Also present in GIT, platelets & limbic system• Receptors: 1A, 1B, 1D, 2A, 2C, 3, 4, 5, 6, 7• Low levels are associated with depression and other psychiatric disorders• May be involved in migraine
Many antidepressants are specific to this NT SSRI’s Block reuptake of 5HT in the synapse
CHOLINERGIC NEURONIt can be excitatory or inhibitory
Cholinergic receptors• Two kinds of receptors – Nicotinic • Nicotine stimulates • Excitatory; found predominately on neuromuscular junctions – Muscarinic • Muscarine (mushroom derivative) stimulates • Both excitatory AND Inhibitory; found predominately in brain• Indicated effects: – excitation or inhibition of target organs – essential in movement of muscles – important in learning and memory
Cholinergic neurons have interactions with all three monoamine systems. Agonist can produce lethargy, anergia and psychomotor retardation in normal subjects. -can exacerbate symptoms in depression -can reduce symptoms in mania.
MELATONIN• Melatonin is produced by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier• Regulates the sleep-wake cycle paracrine effect – SCN• Antioxidant• Immune system• Autism• Parkinsons disease
• Decreased GABA-A receptor binding in a positron emission tomography (PET) study of patients with panic disorder.• Low plasma GABA has been reported in some depressed patients and, in fact, may be a useful trait marker for mood disorders.
HPA axis (hypothalamo-pituitary-adrenal axis) Elevated HPA activity is a hallmark of mammalian stress responses and one of the clearest links between depression and biology of chronic stress. 50% of depressed patients have elevated cortisol level (resolves with treatment --- persistently increased level indicate a high risk of relapse ) CRH levels are also elevated in CSF of depressed pts. (Central CRH receptor antagonists-possible antidepressants) Elevated HPA activity in depression has been documented via Dexamethasone Suppression Test. Nonsuppresion may implicate a loss of inhibitory hippocampal glucocorticoid receptors resulting in increased CRH drive.
Thyroid axis - Disturbed in about 5 to 10% of persons with depression About 1/3rd of pts have blunted TSH response to iv TRH 10% of pts may have circulating antithyroid antibodies CSF somatostatin levels decreased in depression, and increased in mania.
Brain Derived Neurotrophic Factor (BDNF)• Protein is coded by the BDNF gene located on chromosome 11• It is active in the hippocampus, cortex and basal forebrain—areas vital to learning, memory, and higher thinking.• BDNF itself is important for long-term memory• Help to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses• Various studies have shown possible links between BDNF and conditions such as depression, schizophrenia, obsessive- compulsive disorder, Alzheimers disease, Huntingtons disease, Rett syndrome, and dementia as well as anorexia nervosa and bulimia nervosa
BDNF & Depression• Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats• If exposure is persistent, this leads to an eventual atrophy of the hippocampus.• Atrophy of the hippocampus and other limbic structures has been shown to take place in humans suffering from chronic depression• Excitatory neurotransmitter glutamate, voluntary exercise, caloric restriction, intellectual stimulation, curcumin and various treatments for depression antidepressants and electroconvulsive therapy and sleep deprivation increase expression of BDNF in the brain.
Alzheimer’s disease• Post mortem analysis has shown lowered levels of BDNF in the brain tissues of people with Alzheimers disease• Neurotrophic factors have a protective role against amyloid beta toxicity• A connection between depression and dementia has been suggested to be mediated by BDNF• Depression causes shrinkage of the hippocampus. When antidepressants are administered, the levels of BDNF are raised to protect and increase the volume of hippocampal and other cells• In Alzheimers, the hippocampus is also damaged, lowering levels of the neurotrophic factor• Another possible link between BDNF and dementia is through fitness, since exercise can release BDNF and preserve cognition in older people
• Drug dependency - Animals chronically exposed to drugs of abuse show increased levels of BDNF in the ventral tegmental area (VTA) of the brain• When BDNF is injected directly into the VTA of rats, the animals act as if they are dependent on opiates• Epilepsy - levels of both BDNF mRNA and BDNF protein are known to be up-regulated in epilepsy• BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor-mediated post-synaptic currents
Glial cell line Derived Neurotrophic Factor(GDNF) family of ligands• Four neurotrophic factors: – Glial cell line-derived neurotrophic factor (GDNF), – Neurturin (NRTN), – Artemin (ARTN) – Persephin (PSPN)• Play a role in cell survival, neurite outgrowth, cell differentiation and cell migration• In particular signaling by GDNF promote the survival and differentiation of dopaminergic neurons in culture, and was able to prevent apoptosis of motor neurons
• GDNF has shown promising results in – Parkinsons disease – Amytrophic Lateral Sclerosis – Recent results- drug addiction and alcoholism treatment• NRTN can also be used for Parkinson’s disease therapy and for epilepsy treatment• NRTN promotes survival of basal forebrain cholinergic neurons and spinal motor neurons. Therefore, NRTN has a potential in the treatment of Alzheimer’s disease and ALS• ARTN also has a therapeutic perspective, for it is considered for chronic pain treatment• PSPN may be used for the treatment of Alzheimer’s disease & stroke.
Endorphins - endogenous morphine• A peptide hormone named Endorphin produced in the brain and anterior pituitary • High concentrations of endorphins in the brain produce a sense of euphoria, enhance pleasure, and suppress pain, both emotionally and physically. • Low concentrations of endorphins in the brain people feel anxious and they are also more aware of pain.
• Human body produces at least 20 different endorphins• alpha (α) endorphin• beta (β) endorphin - Most powerful• gamma (γ) endorphin• sigma (σ) endorphin
Environmental •Step 1: Cue perceived by CNS Cue Central Nervous “Stressor” System •Step 2: Signal sent to hypothalamus (in brain) ( pain) Hypothalamus •Step 3: Hypothalamus secretes CRF Corticotropin releasing factor (peptide), travels to (CRF) pituitary •Step 4: CRF causes protein pro- Anterior Pituitary Opiomelanocortin hormone Pro-Opiomelanocortin (POMC) to be cleaved, releasesBrain Beta lipotropin (POMC) •Step 5: lipotropin gets convert into Endorphin. Beta-lipotropin •Step 6: Endorphin binds to the nerve fiber. Endorphin Hormone (EP)
TRANSPORT AND DISTRIBUTION β-endorphin is released by :1. Pituitary (into blood ) and2. Hypothalamus ( into the spinal cord and brain ) Beta endorphin containing nerve fibres spread widely from neurones in the hypothalamus, to make inhibitory Hypothalamus contacts with target neurones to reduce pain. Free hormones are rapidly eliminated from circulation through kidney or liver.
FUNCTION AS ANALGESIC PAIN IMPULSE STOP BY ENDORPHIN : MECHANISMBefore endorphin release After endorphin release hypothalamus
WHAT IS DRUG ADDICTION ?In the normal course OpiateReceptors and Endorphins arekept in balance with one another.When the brain is flooded withexogenous opiates, (heroin amorphine derivative) it mimic ofendorphins so system getsconfused. Heroin addictionIt thinks it is making too manyendorphins and shuts thatdown, But it still has all this excess(heroin) and thinks that it alsoneeds to make more receptors.
What Happens Next….• As more Opiate Receptors are made you need more heroin to get the same effect so you use more.• And more receptors are made to accommodate the extra what the brain thinks is endorphins.• For decreasing this effect- You need more substance to get the same effect.
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