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Lecture 4

Week 4 and 5.docx

23 Pages
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Department
Psychology
Course Code
PSYC 3030
Professor
Taryn Grieder

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Catecholamines Catecholamines include:  Dopamine (DA)  Norepinephrine (NE)  Epinephrine (EPI) - low activity as neurotransmitter so not a lot of talking about it in this class They belong to the group of neurotransmitters called monoamines (or biogenic amines). Monoamines  One amino group  Derived from amino groups  Catecholamines o Dopamine (DA) o Norepinephrine (NE) o Epinephrine (EPI)  Tryptamines o Serotonin (5-HT)  EPI and NE (aka adrenaline and noradrenaline) o Adrenaline stimulates you  NE is main movement neurotransmitter  NE neurons are in the pons and medulla of the brainstem o Locus Coeruleus (LC)  In the pons  Dense collection of NE neurons  Extend to nearly all areas of forebrain, cerebellum and spinal cord Catecholamine Synthesis, Release and Inactivation  Tyrosine is obtained through diet  TH is marker for dopamine neurons o Amount of it determines overall rate of synthesis, it is also the rate limiting step  DBH is marker in NE neurons Activity  Activity of TH (enzyme) regulated by several factors o High catecholamine levels tend to inhibit TH (like negative feedback - high levels of catecholamines inhibit synthesis of more) o Rate of cell firing - neurons firing at a high rate stimulate TH (catecholamine synthesis accelerates) o Catecholamine synthesis can be increased by administering a precursor  L-DOPA used to treat Parkinson’s disease - caused by a decrease in dopaminergic neurons, treated with L-DOPA, can get more dopamine and movement can somewhat be restored  Catecholamines are stored in vesicles (help form predetermined amount of neurotransmitter to release and protects from degradation from enzymes) o Vesicular monoamine transporter (VMAT) is responsible for catecholamine reuptake (VMAT-1 in adrenal medulla and -2 in brain)  Reserpine blocks action of VMAT2 - inhibits storage of monoamines in vesicles and DA and NE temporarily drop to very low levels in the brain  Amphetamine and methamphetamine can cause release of catecholamines without nerve cell firing o Produce increased alertness, heightened energy, euphoria, insomnia Autoreceptors: inhibit release of catecholamines by decreasing cell firing or enhancing opening of K channels (causing hyperpolarization and making it harder to cause an action potential)  Ca won’t enter when autoreceptors are active  reduces exocytosis (calmodulin complex)  DA autoreceptor - D 2ubtype  NE autoreceptor - α 2ubtype  Drugs that stimulate autoreceptors inhibit catecholamine release  Autoreceptor antagonists prevent the normal inhibitory effect of the autoreceptors Inactivation of Catecholamines  Reuptake: DA and NE are removed from the synaptic cleft via specific membrane transporter proteins (DA transporter and NE transporters) o Cocaine inhibits reuptake of DA, NE and 5-HT  Breakdown within cell by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) enzymes o Nicotine acts on MAO to stop breakdown of dopamine which leads to euphoric feelings after nicotine - an example of MAO inhibitor, used to treat depression o COMT inhibitors are being used as supplemental therapy to enhance effectiveness of LDOPA in treatment of Parkinson’s disease o Metabolites enter CSF, then blood stream and are eliminated in urine  Levels of metabolites provide rough indication of catecholaminergic activity in the NS Organization and Function of the Dopaminergic System The ascending DA system is dividing into three pathways:  Nigrostriatal tract (aka mesostriatal) o Axons from the A9 cell group in the substantia nigra extend to the caudate-putamen (dorsal striatum) o Involved in voluntary movement o Loss of dopaminergic neurons here leads to Parkinson’s disease  Mesolimbic pathway o From VTA (A10) to various structures of the limbic system including ventral striatum (nucleus accumbens)  Mesocortical dopamine pathway o From VTA to the prefrontal cortex (PFC)  DA acts on 5 receptor subtypes: D to D 1 5  All are metabotropic (slower acting, interacts with G proteins and function via second messengers)  D 1nd D a5e similar (D -l1ke receptors)  stimulates adenylyl cyclase and ATP synthesis  D 2 D 3 D4are similar (D 2like receptors)  some inhibit adenylyl cyclase and ATP synthesis, some open K channels like the autoreceptors (causing hyperpolarization and decreasing action potential firing) o Most autoreceptors are D rec2ptors (therefore they act as both) o Most schizophrenic drugs are D rece2tors antagonists  DA receptor antagonists suppress exploratory and locomotor behaviour o Dopamine is locomotor neurotransmitter o At higher dosages of these antagonists, such drugs can result in catalepsy (lack of spontaneous movement) - induces Parkinson’s type state o Most act as D R blockers 2  Possibly D 1 o Can induce behavioural supersensitivity - once D rece2tor antagonist treatment is blocked and agonist is given for D 2 organisms have a stronger response Mutant Mice Lacking the Dopamine Transporter (DAT)  KO mice: lack specific receptor subtype  Wildtype - no KO  Homozygous - no dopamine transporters  Heterozygous - only 1 dopamine transporter Mice were tested in a photocell apparatus; the number of photobeam breaks was recorded every 20 minutes. All groups showed gradual habituation. Wildtype and heterozygote mice acted the same - suggesting you only need one copy of gene. Homozygotes have no transporter - more dopamine hanging around therefore takes longer to habituate. Organization and Function of the Noradrenergic System (Norepinephrine) Conversion of dopamine to NE occurs within synaptic vesicles by dopamine beta- hydroxylase (DBH). Adrenergic receptors (adrenoceptors, sensitive to EPI as well) are metabotropic and there are 2 subtypes:  Alpha 2receptors reduce synthesis of cAMP by inhibiting adenylyl cyclase (like D2receptors) o Act as both post synaptic receptor or autoreceptor o NE acts more on these receptors (has higher affinity)  Alpha 1receptors operate via phosphoionositide second-messenger system o Acts of phospholipase C instead of adenylyl cyclase  Beta and beta -adrenoceptors stimulate adenylyl cyclase and enhance 1 2 synthesis of cAMP (like D 1eceptors) The central noradrenergic system is involved in many behavioural functions…  LC neurons fire more rapidly during waking than sleep (most well known for this - remember it stimulates synthesis of cortisol and cortisol peaks when you wake up)  LC projections to prefrontal cortex have a role in cognitive functions like attention and working memory  Peripheral NE system also has a lot of functions  NE and EPI (as well as glucocorticoids) released from adrenal gland are involved in negative feedback with HPA axis stress response Antagonists  General agonists that activate both alpha and beta receptors have been used to treat bronchial asthma (can cause many side effects) o Therefore is more commonly treated with beta agon2st because beta receptors in airways are of beta 2ubtype  Beta-antagonists (beta blockers) used to treat generalized anxiety disorder o Reduce physical symptoms (palpitations, flushing, tachycardia - racing heart) through action on peripheral NE system  Can also treat high blood pressure and autonomic functioning Serotonin Synthesis, Release and Inactivation Serotonin is synthesized from the amino acid tryptophan in 2 steps:  Tryptophan hydroxylase converts tryptophan to 5-hydroxytryptophan (5- HTP)  Aromatic amino acid decarboxylase (AADC) converts 5-HTP to 5-HT (serotonin)  Rate limiting step is also tryptophan hydroxylase (only in serotinergic neurons, a way you can stain and mark neurons)  Can stimulate serotonin synthesis by giving either of the precursors  Get serotonin from diet - low serotonin leads to lack of arousal, unhappiness  Ratio of tryptophan to other competitors for transport determines stimulation of 5-HT synthesis o Low protein- high carb meal will give you lots of tryptophan o High sugar meal - more larger amino acids will be made and there will be more competition for tryptophan - won’t feel as well  VMAT-2 reuptakes serotonin into vesicles (same channel as catecholamines, vesicular monoamine transporter) o Reserpine blocks VMAT2 - will deplete serotonin  MAO - breaks serotonin down to yield 5-HIAA  Serotonin transporters also brings serotonin back into the cell (SERT)  Can indirectly inhibit serotonin release by autoreceptors at the cell body which decrease cell firing (less action potentials  less neurotransmitter released) or at terminal which inhibit release of serotonin  5-HT release is stimulated by a drug family based on amphetamine o 3,4-methylenedioxymethamphetamine (MDMA aka ecstasy) o Studies on squirrel monkeys showed that repeated high doses of MDMA resulted in depletion of 5-HT axons in the brain - even after 7 years there were some neurons that came back but it never fully recovered  After release 5-HT is rapidly removed from the synaptic cleft via reuptake by the 5-HT transporter, or SERT  SERTs blocked by selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine [Prozac]) o Treats depression, anxiety - depression might be lack of serotonin, block reuptake of serotonin, more hanging around in synaptic cleft and start to feel better, start with larger dose and then taper them off  Cocaine and MDMA also block SERT but are not selective (also affect DA transporters) o Cocaine more effects DA and MDMA blocks more serotonin not selective to serotonin (but goes both ways)  Almost all serotonergic neurons in CNS are found along midline of brainstem, associated with the dorsal and median raphe nuclei o Project to many areas of the brain - main serotonergic area  At least 14 receptors for 5-HT (most are metabotropic) o Serotonin 3 receptor is the only one that is ionotropic o 5-HT 1Areceptors reduce cAMP synthesis by inhibiting adenylyl cyclase or increasing opening of K channels causing membrane hyperpolarization (like D2receptors and alpha a2renergic receptors)  In forebrain, these are postsynaptic receptors  In raphe nuclei they are cell body autoreceptors  5 different subtypes of 5-HT1receptors (A, B, …) o 5-HT receptors activate the phosphoinositide second messenger 2A 2+ system (phospholipase C  Ca , like alpha a1renergic receptors)  This increases calcium levels in postsynaptic cells and also activates protein kinase C  LSD hallucinations - related to serotonin 2A receptor which LSD stimulates  Antagonists of 2A receptors also improve symptoms of schizophrenia  3 different subtypes of 5-HT2receptors (A, B, C) o 5-HT *3ot metabotropic, excitatory ionotropic receptor  Antagonists are sometimes used to counteract nausea and vomiting associated with cancer treatments o 5-HT 4 o 5-HT (5, B) o 5-HT 6 o 5-HT 7  Many other 5-HT receptors have roles in learning and memory (e.g. fear conditioning, receptor antagonists help with novel object recognition task), pain (5-HT inhibits pain transmission), anxiety (increased anxiety when lacking 1A receptor), food intake (can cause excessive or reduced food intake depending on the receptor and whether it is an antagonist or agonist), thermoregulation (no serotonergic neurons, cannot maintain body temp when in cold environment), aggression (low levels of serotonin associated with increased aggression) Acetylcholine Synthesis, Release and Inactivation  Loss of cells associated with Alzheimer’s disease  Antagonists are basis of botox (paralysis)  ACh formed from choline and acetyl coenzyme A (acetyl CoA) o Catalyzed by choline acetyltransferase (ChAT) - rate limiting step because it is the only step  ChAT only found in ACh neurons - how you would mark cells (staining for ChAT)  ChAT is blocked by organophosphates  Similar to other neurotransmitters, rate of ACh synthesis is controlled by o Availability of precursors - more precursors, more ACh synthesis o Rate of cell firing - more cell firing, more ACh synthesis  It moves into vesicles via vesicular ACh transporters (VAChT) in vesicle membrane and is released by exocytosis o Can be blocked by vesamincol - decreases ACh in vesicles and increases cytoplasmic ACh  Levels of ACh are controlled by acetylcholineasterase (AChE) which breaks down to choline and acetic acid o AChE in presynaptic cells can metabolize excess ACh that may have been synthesized before it has been released o On the membrane of the postsynaptic cell, AChE breaks down ACh after release into the synaptic cleft  Then brought back up by choline transporter o Also found at neuromuscular junctions were ACh is released by motor neurons to stimulate muscular contractions, muscles secrete AChE to allow for precise transmission processes  In the brain, cholinergic cell bodies are clustered in only a few areas o Striatal interneurons - regulation of movement, depends on the balance between ACh and DA (this is also one of the terminal areas of VTA and substantia nigra dopaminergic neurons) o Basal forebrain cholinergic system (BFCS) - neurons are in several brain areas (terminals in cortex, limbic structures), plays significant role in cognitive function o PPT (pedunculopontine tegmental nuclei) / LDT (laterodorsal tegmentum)  Project to the VTA, important in regulating DA release  Important for nicotine, alcohol, food motivation and for arousal  Dorsolateral pons - excitatory influence on midbrain DA neuron firing  Other pathways from the dorsolateral pons project to the brainstem and thalamic areas and play important roles in behavioural arousal, sensory processing and initiation of rapid eye movement sleep (REM) Cholinergic receptors  Nicotinic receptors (nAChRs) - respond selectively to nicotine (agonist) o Ionotropic (fast - don’t activate second messenger system), activation causes sodium and calcium to enter neuron and cause depolarization o Made of 5 subunits (10 alpha and 4 beta discovered in brain)  (α4) (β2) receptor has highest affinity for nicotine (higher 2 3 than ACh, most common receptor, heteromeric - made of both alpha and beta subunits)  Binding site is always between alpha and beta subunits and there are 2 binding sites (both must be bound)  Homomeric - only alpha subunits make it up, (α7) i5 most common, lots of binding sites o Desensitization - continuously activated by agonists, channels will remain closed  Further stimulation and binding of agonist will not open channel, just temporary o Curare blocks nicotinic receptors - causes paralysis because these receptors are the ones present at neuromuscular junctions  Muscarinic receptors (mAChRs) - respond selectively to muscarine (agonist) o Metabotropic (slower) o Five types (M -1 ) 5 o Important in morphine and cocaine reward and dependence- producing effects also stimulated in terms of nicotine motivation as well (but nicotinic receptors are more involved) o Operate via second messengers or by stimulation of K channel opening (hyperpolarization
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