Neurotransmitters PDF

Neurotransmitters Chemical substances synthesized in a neuron, released during neuron excitation (dependent on calcium influx) that can create an excitatory or an inhibitory response in cells or tissues Their action occur in POSTSYNAPTIC, POST-GANGLIONIC, or TARGET CELLS (e...

Neurotransmitters Chemical substances synthesized in a neuron, released during neuron excitation (dependent on calcium influx) that can create an excitatory or an inhibitory response in cells or tissues Their action occur in POSTSYNAPTIC, POST-GANGLIONIC, or TARGET CELLS (effectors) Communication mechanism between neurons (through a chemical synapse) Photoreceptors are the ONLY nerve cells that are active during hyperpolarization Functional classification: Excitatory or inhibitory Excitatory: depolarization Inhibitory: hyperpolarization ○ photoreceptors are the exception And whether the effects are direct (ionotropic); or indirect (metabotropic) Direct: NT binds to ionotropic receptor, channel opens. NT released into synaptic cleft (brings about immediate response) Indirect: 1) NT binds to metabotropic receptor. 2) G protein coupled receptor activated and binds to effector protein. 3) Second messenger molecules (such as cyclic AMP or adenyl-cyclase or phospholipase c) produced, activating enzymes that open channel. ○ NT (first messenger) released into synaptic cleft. NT Inactivation: 3 ways Degradation by enzymes from the postsynaptic cell or within the synaptic cleft Reuptake by glial (astrocytes) or the presynaptic cell Diffusion away from the synapse through the bloodstream NTs interrelationships or dual action Acetylcholine (ACh) ○ Excitatory in skeletal muscle, but inhibitory in cardiac muscle ○ Functional regulation of Ach  Movement Cortical excitability Heart and skeletal muscle contraction Arousal and sleep Cognition and reward ○ Acetyl-CoA comes from glycolysis products (pyruvate), that is converted by the enzyme pyruvate dehydrogenase ○ Acetylcholine is synthesized from acetyl-CoA and choline by choline acetyltransferase (ChAT), the rate-limiting step in the pathway ○ ACh is then packaged into vesicles by a vesicular acetylcholine transported (vAChT) ○ Acetate source is Acetyl-CoA ○ Choline source is from the reuptake after cholinesterase enzymatic degradation Dopamine ○ Functional regulation of DA Coordination and movement Attention, memory and learning Pleasure/ reward Arousal and sleep Behavior and cognition Inhibition of prolactin production Nausea and vomiting Inflammation and pain ○ Imbalance… Sleep disturbances Restless legs syndrome Psychosis Apathy/Depression ADHD symptoms ○ Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT) inactivates DA, in the liver, presynaptic or post-synaptic terminal (reuptake-2) Norepinephrine Serotonin Glutamate ○ excitatory vs inhibitory ( depending on the receptor type ) Acetylcholine (ACh) secretion Excitatory NT Location: ○ CNS Cerebral cortex Hippocampus Brainstem  ○ PNS NMJ of skeletal muscle All preganglionic (sympathetic and parasympathetic) and parasympathetic postganglionic fibers of ANS Cholinergic-Acetylcholine Receptors Nicotinic: ○ N1 (NM) At the NMJ of skeletal muscle ○ N2 (NN) Autonomic ganglia, CNS, and adrenal medulla (for catecholamine release) Muscarinic: ○ M1 through M5 Widely distributed in the CNS M1 in the autonomic nervous system, striatum, cortex, and hippocampus M2 in the autonomic nervous system, heart, intestinal smooth muscle, hindbrain, and cerebellum M3: mediated pupil constriction and activation of lacrimal gland secretion Pupil constriction: CN 3 Lacrimal gland: CN 7 Acetylcholine Associated-Effects Exposure to organophosphate insecticides: prolonged effects of ACh leading to tetanic muscle spasms Inhibited by botulinum toxin (Botox) ○ Bacteria * Clostridium botulinum ACh levels decreased in certain brain areas in Alzheimer's disease Nicotinic ACh receptors destroyed in Myasthenia Gravis Atropine, anti-muscarinic cholinergic drug to treat medical conditions like bradycardia, uveitis, and early amblyopia in children ○ stimulates pupil dilation (mydriasis), and to paralyzed the accommodation reflex (cycloplegic) * (used in ophthalmic evaluation) Alzheimer’s Disease (AD) Cholinergic neurons of the basal forebrain are involved in learning and memory and have been implicated in AD Characterized by extensive neural atrophy in the brain cortex and hippocampal formation, and dramatic loss of cholinergic neurons in the basal nucleus of Meynert Symptoms ○ Memory loss ○ Personality changes  ○ Dementia Tx (replacement therapy) ○ Donepezil (Aricept) ○ Galantamine (Razadyne ER) Huntington’s Disease/Chorea Result from a degeneration of ACh and GABA containing neurons Patients has chorea (sudden, unexpected and purposeless contraction of proximal muscles) and dementia Atrophy of the brain basal ganglia and lateral ventricle enlargement < 20 years; juvenile HD, faster progression Other symptoms may include muscle rigidity, slow or unusual eye movements, problems walking or maintaining posture, and speech and swallowing deficits Myasthenia Gravis Autoimmune syndrome that occurs in the presence of auto-antibodies to the nicotinic ACh receptors (N1/NM- related to the neuromuscular junction) Auto-antibodies reduce the # of receptors in the neuromuscular junction - resulting in paresis (weakness of voluntary movements) Involves extraocular and eyelid muscles (causing diploid and ptosis) Involves bulbar muscles - nasal speech and jaw fatigue Leads to weaker limbs proximally and stronger limbs distally Diagnose test: IV edrophonium (short and rapid-acting anticholinesterase drug) Muscle use results in fatigue (Tensilon test, if muscle strength increases likely to have myasthenia Gravis) ACh clinical correlation Lambert-Eaton Myasthenic Syndrome (LEMS) Autoimmune disease at the NMJ Immune attack of v-gated calcium channels at the pre-synaptic nerve endings, that causes a decrease of ACh release Weakness on the limb muscles (weak contraction) 50% associated w/ neoplasms (lung, breast, prostate) Associated w/ ANS dysfunction (involuntary), most commonly dry mouth Dopamine Receptors Is a catecholamine Function ○ Excitatory or inhibitory depending on the receptor type bound ○ Indirect action via second messengers Secreted at: ○ CNS Sustancia nigra (pars compacta) (SNpc) and VTA of midbrain  Hypothalamus (arcuate nucleus) (control energy metabolism in peripheral tissues) ○ PNS Some sympathetic ganglia D4R: wide functions in the amygdala, hippocampus, pituitary, and RETINA D1R: working memory (short-term memory related to thinking and speaking) D3R: addiction behaviors Structurally G-protein coupled receptors or adrenoreceptors that are classified as D1 through D5 D1-like receptors -> D1R and D5R -> linked to Gs -> activated adenylyl cyclase (AC) ○ Location: Limbic system, corpus striatum, thalamus and hypothalamus; mesenteric and renal blood vessels D2-like receptors -> D2R, D3R, D4R -> linked to Gi/Gs -> inhibits AC and Ca2+ channels, and activates K+ channels ○ Location: Limbic system, corpus striatum, thalamus and hypothalamus, pituitary gland; cardiac mm., sympathetics of the heart Supplements that affect Dopamine levels Receptor AGONISTS: ○ Yohimbine (Tx for erectile dysfunction, lose weight, angina) ○ Ningdong granules Receptors ANTAGONISTS: ○ L-theanine ○ Ginkgo biloba (Tx improves cognitive function, blood circulation, and eye health) ○ Bacopa ○ Mucuna pruriens High DA levels: Tics, involuntary movements, euphoria, hallucinations, and psychosis Low DA levels: Parkinson’s disease Dopamine effects A “feeling good” neurotransmitter L-dopa Tx in Parkinson’s disease Amphetamines enhance DA levels Plays a role in cognitive, motor and neuroendocrine functions Has an increased production in schizophrenics Mainly controls movements and pleasure In nucleus accumbens (receive inputs from the VTA), can modulate behavior by reinforcing learning and evading aversing stimuli Dopamine imbalance  DA Clinical correlation: Parkinson’s Disease Degeneration of dopaminergic neurons in the substantia nigra (reduce release of DA in caudate/putamen) Hands tremors, rigidity, and akinesia (loss of ability to move your muscles voluntarily), dementia Tx: L-DOPA and carbidopa (inhibitor of dopa-decarboxylase) DA Clinical correlations: Psychotic disorders: Most common is schizophrenia (increase activity at dopaminergic synapses) Tx: phenothiazines, butyrophenones (reduce the DA synaptic activity in the límbic forebrain) Cocaine drug abuse: Local anesthetic drug that inhibit the reuptake of DA and NE into the nerve terminals Responsible for the euphoric effects DA projections from the VTA to the NAcc (involve in emotional reinforcement and motivation associated with cocaine drug addiction) DA Boost by Drugs-Abuse The most common illicit drugs that boost dopamine levels include: ○ Heroin cocaine (crack and powder) ○ Crystal meth ○ Ecstasy (MDMA derivative) ○ Pure MDMA ○ Bath salts ○ Marijuana  ○ LSD Other legal drugs that act on dopamine include alcohol, prescription painkillers, benzodiazepines, and even caffeine. Prolonged use of dopamine increasing drugs are responsible for the “withdrawal” symptoms that come from quitting these drugs. This happens because the brain becomes accustomed to these high levels of feel-good chemicals. When it suddenly stops getting these chemical rewards, the brain sends pain and sickness (nausea) causing signals to the central nervous system. Norepinephrine A catecholamine Function: excitatory or inhibitory depending on receptor type bound ○ Indirect action via second messengers Pathway of catecholamines biosynthesis: ○ Dopamine, NE, and E comes from the biosynthetic pathway of the phenylalanine and tyrosine amino acids Location: ○ CNS Brainstem (pons)- locus coeruleus nuclei (A6 group of neurons) Limbic system Some areas of cerebral cortex ○ PNS Main neurotransmitter of postganglionic neurons in the sympathetic nervous system FEF is responsible for saccadic eye movements for the purpose of VF perception and awareness, as well as for voluntary eye movement NE Effects May play a role in the genesis and maintenance of mood Amphetamines enhance the release Catecholamine hypothesis - reduced norepinephrine activity is related to depression Increased NE activity is related to mania Epinephrine (E) (E) synthesis occur in the same way as NE PNMT, enzyme that converts NE to E E origin can be synthesized in neurons or in adrenal medulla, that is transported back to neurons or used in tissues C1 neurons: rostral ventrolateral medulla C2 neurons: nucleus tracts solitarius or solitary nucleus Serotonin; 5-Hydroxytryptamine; 5-HT An indoleamine Dietary tryptophan serves as a substrate for serotonin synthesis Must know aromatic amino acid decarboxylase Function: ○ mainly inhibitory ○ indirect action via second messengers ○ direct action at 5-HT receptors Location: ○ CNS Brainstem (dorsal and medial raphe nuclei): midbrain, medulla, pons ○ Send projections to: Hypothalamus Limbic system Cerebellum Pineal gland Serotonin is synthesized in the pineal gland, also serves as a precursor of melatonin (sleep patterns) Spinal cord Serotonin receptors ○ Receptor families from 5-HT1-5 with family subtypes ○ Receptors types 1, 5, and 6 are inhibitory receptors ○ Receptors types 2, 3, and 4 are stimulators receptors ○ Second messenger for all families is cyclic AMP (cAMP) Serotonin effects ○ May play a role in sleep, appetite, nausea, migraine headaches, regulation of mood, body temperature ○ Severe depression and insomnia are associated with low 5-HT levels (eg: Prozac, blocks reuptake of serotonin) ○ Mania is associated with high 5-HT activity ○ Obsessive-compulsive disorder related to a dysfunction of 5-HT ○ Tricyclic antidepressant and fluoxetine (Prozac) increase 5-HT availability so relieve anxiety and depression ○ Selective serotonin receptor agonists (for 5-HT10) (eg: sumatriptan (Imitrex)) can abort migraines (due to a vasoconstrictive and anti-inflammatory effect) Glutamate Derived from AA Function: Excitatory NT Sources: ○ Kreb’s Cycle α-oxoglutarate is converted to glutamate by α-oxoglutarate transaminase ○ Reuptake of Glu Glial or presynaptic cells or glutamine conversion Effects: ○ May play a role in Alzheimer’s disease (AD), and the loss of neurons by overexcitation and glutamate-induce activation of NMDA receptors Namenda, NMDA receptor antagonist as a treatment for AD In retina: (turn off or turn on the photoreceptors in retina related to glutamate circuits) Activation of photoreceptors and mGluR6 @ night, rods are on and activated by mGluR6 and cones are off at the same time. During the time or seeing something w/ a lot of colors, cones are activated via mGluR6 and rods are off and activated through AMPA/kainate receptors. ○