Transcript neurons
Communication between neurons Neurotransmitters CNS and neurotransmitter pathways within neurons – between neurons- within neurons – electrically between neurons - chemically 1. neurons – 10 to 100 billion neurons ◦ Role: can vary tremendously in size and shape but all have 3 components cell body or soma contains genetic material, provides nutrients, dendrites axons Figure 3.3 Major parts of a neuron General Principles Synthesis 1. Formation of transmitters 2. Precursors are the main ingredient. Brought to the neuron by the bloodstream. Taken up by cell body and/or terminal. Often come from substances in the diet. 3. Enzymes put the ingredients together. Transmitters Stored in Vesicles 1. Concentration 2. Protection Release = exocytosis ◦ Vesicles fuse with presynaptic membrane and release transmitters into the synapse. Figure 3.5 A. Photomicrograph of a synapse in action, taken with the electron microscope. B. Schematic of the process Julien: A Primer of Drug Action, Eleventh Edition Copyright © 2008 by Worth Publishers Release = exocytosis ◦ Vesicles fuse with presynaptic membrane and release transmitters into the synapse. Binding = attachment of transmitter to receptor Role of autoreceptors protein embedded in membrane mechanism for neurotransmitter to influence postsynaptic activity by binding to receptor There are different varieties of receptors. ◦ Some respond fast ◦ Called Ionotropic ◦ Direct reaction to the transmitter Neurotransmitters and Receptors Different varieties of receptors: ◦ Other types of receptors respond more slowly. ◦ Indirectly ◦ Called Metabotropic, or G protein-coupled ◦ Initiates a second signal (messenger) inside the neuron. Inactivation: Termination of Synaptic Transmission 1. Metabolism 2. Re-uptake E Acetylcholine—first to be recognized, because of peripheral actions • Synthesis – Acetyl-CoA (in mitochondria) + choline (from diet) Acetylcholine Choline+ Acetyl cOA cHat (choline acetyl transferase) Acetylcholine (ACh) Choline +acetate AChE (Acetylcholinesterase) Inactivation: ◦ Acetylcholinesterase (AChE) ◦ After action in postsynaptic cleft, AChE degrades ACh to choline and acetate, which are taken back up into the neuron. ◦ found in both CNS (brain and SC) and PNS (Somatic and autonomic NS) Functions (in CNS) ◦ memory, sensory processing, movement, REM sleep Functions (in PNS) many psychotropics have anti ACh effects Where is ACh produced? Septal nucleus and nucleus basalis Ach ◦ Projects to forebrain. Midbrain ◦ Projects to reticular formation, pons, cerebellum, and cranial nerve nuclei. Ach NE Ach Ach cholinergic receptor subtypes ◦ 2 classes ◦ labeled by agents that act as agonists at receptor ◦ nicotinic – muscle, neuronal - majority are ionotropic at least 17 subtypes some muscular; some CNS ◦ number of nicotinic receptors are growing….. nicotinic agonists – ◦ varenicline (Chantix) – smoking cessation partial agonist nicotinic antagonist ◦ “botox”- botulism toxin muscarinic – 5 subtypes discovered so far; all metabotropic (M1-M5) scopolamine – motion sickness some meds for asthma treating side effects of some PD meds ways to alter ACh activity AChE inhibitors ◦ some “irreversible” AChE inhibitors: malathion, parathion, (pesticides) nerve gas (Sarin) “reversible cognitive enhancers donepezil (Aricept) MG – myasthenia gravis autoimmune disease affecting NMJ Alzheimers Disease - AD ◦ temporary “fixes” for these disease states “reversible” AChE inhibitors -tacrine (Cognex), donepezil (Aricept) Strategy in both cases……… can include confusion, blurred vision, constipation, dry mouth, light-headedness, urinary retention, loss of bladder control. choline rich foods Whole eggs, liver, beef steak, and soy are among foods naturally rich in choline. Dopamine (DA) Norephinephrine (NE) NE and E are synthesized from their precursor DA with the appropriate enzymes present tyrosine hydroxylase DA decarboxylase DA β hydroxylase PNMT Catecholamines removed by reuptake: ◦ DAT – DA transporter ◦ NET – NE transporter Catecholamines Synthesis ◦ Tyrosine Dopamine Norepinephrine Termination ◦ Re-uptake ◦ Monoamine oxidase (MAO) metabolism – ◦ far slower than ACh by AChE ◦ MAO enzymes (monoamine oxidase) MAOA AND MAOB enzymes MAO A – more selective for NE and 5HT MAO B- more selective for DA Major metabolites: ◦ Important when trying to study potential differences ◦ DA - dopac and HVA ◦ NE - MHPG -(3-methoxy-4-hydroxyphenethyleneglycol) Tyrosine catecholamines Tyrosine hydroxylase (rate limiting step) TH DOPA Aromatic acid decarboxylase mao homovanillic acid (HVA) Dopamine (DA) DA-β-hydroxylase MHPG Norepinephrine (NE) pnmt Epinephrine (E) CNS - reward, movement, motivated behaviors, executive function? numerous DA pathways in CNS of importance for psychotropics….. DA receptor subtypes ◦ 2 major families – D1 and D2 families DA Pathways ◦ 3 important circuits Hypothalamus to pituitary gland tuberofundibular; hormonal Substantia nigra to basal ganglia nigrostriatal pathway - movement VTA to cortex and limbic system mesolimbic mesocortical mesolimbicortical Receptors ◦ Dopamine Two families: D1 and D2 D1 – D5 In CNS- arousal; role in depression, possible role in spinal analgesia, possible motivated behaviors such as hunger, thirst, sex, anxiety, drug reward? NE is in both the CNS and PNS receptor subtypes ◦ alpha 1 and 2; β 1 – 3 Pathways ◦ Norepinephrine Projects from brainstem to cortex, limbic system, hypothalamus, and cerebellum. Figure 3.11 NE projection system in the human brain more recent in our history of studying NT similarity to LSD found early in high concentrations in the gut found in many non neuronal cells (only ~ 1 – 2% of 5HT in whole body is in brain) cannot cross bbb so…… synthesis ◦ amino acid precursor – tryptophan ◦ elimination of dietary tryptophan can significantly lower brain 5HT levels ◦ foods high in tryptophan; nuts (ie walnuts, almonds), tofu, milk, eggs, certain cheeses, turkey, seafood, seeds behavioral role (CNS): sleep, aggressive behavior abnormal function implicated in: ◦ schizophrenia, depression, phobic disorders, OCD, eating disorders, migraine, etc receptor subtypesmany – at least 18 subtypes have been identified - probably best way to group 5HT1 and 5HT2 families; - some are metabotropic; some ionotropic reuptake main mechanism for terminating ◦ SSRIs breakdown – major metabolite 5HIAA Serotonin Synthesis ◦ Tryptophan Receptors ◦ Ionotropic - 5-HT3 ◦ G protein-coupled - 5-HT1, 5-HT2, 5-HT4 Pathways ◦ Largely parallel DA Figure 3.14 Serotonin pathways in the human pervasive throughout the brain classified into 2 general categories ◦ excitatory (glutamate, aspartate) ◦ inhibitory (GABA, glycine) amino acids are more difficult to classify as nt first identified in leg of lobster causes hyperpolarization of neurons highest concentrations in brain and spinal cord and virtually absent in peripheral nerve or other organs does not cross bbb easily stored in synaptic vesicles (like other nt) usually removed from synapse via transporter (GAT) GABA also found in glia receptor subtypes: ◦ GABA A – ionotropic – clinically important ◦ GABA B - metabotropic mediates anxiolytic, sedative, anticonvulsant, muscle-relaxant and amnesic activity subunit compositions appear to vary from one brain region to another and even between neurons within a given region anticonvulsants are being considered for various psychiatric disorders modulatory effects found in high concentrations in brain serves many functions GAD (enzyme – can convert glutamate to GABA) found in high concentrations in brain serves many functions GAD (enzyme – can convert glutamate to GABA) receptor subtypes: ◦ tremendous work done in recent years receptor subtypes: ◦ NMDA, ionotropic, various other receptors including metabotropic GLU R (mGLUR) ◦ families within these ◦ role of neuromodulators current potential interests ◦ reducing neurotoxicity, psychiatric disorders, substance use disorders, Alzhemiers Disease? discussed here because many psychotropics have antihistaminergic action examples of antihistamines – ◦ diphenhydramine (Benadryl) ◦ acts as a neurotransmitter; also released during immune response; also found in gut ◦ antihistaminergic effects: drowsiness, dry mouth, dizziness, sleepiness, upset stomach, decreased coordination, fatigue, weight gain, dry mouth and throat, upset stomach, fluttery heartbeat, loss of appetite, hives, sleepiness, vision problems Peptides Opioids ◦ ◦ ◦ ◦ Mu Delta Kappa Endorphins and enkephalins are opioids Substance P