Transcript week4bam
some controversy…….. some controversy…….. Muscarinic agonists – Muscarine some controversy…….. Muscarinic agonists – Muscarine Muscarinic antagonists Synthetic and natural- DA – dopamine NE – norepinephrine 5HT - serotonin 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 In CNS- arousal; role in depression, possible role in spinal analgesia, possible motivated behaviors such as hunger, thirst, sex, anxiety, attention? NE is in both the CNS and PNS receptor subtypes ◦ alpha 1 and 2; β 1 – 3 Catecholamines removed by reuptake: ◦ DAT – DA transporter ◦ NET – NE transporter metabolism – ◦ far slower than ACh by AChE metabolism – ◦ far slower than ACh by AChE ◦ MAO enzymes (monoamine oxidase) metabolism – ◦ far slower than ACh by AChE ◦ MAO enzymes (monoamine oxidase) MAOA AND MAOB enzymes MAO A – more selective for NE and 5HT 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) 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…… behavioral role (CNS): sleep, aggressive behavior abnormal function implicated in: ◦ schizophrenia, depression, phobic disorders, OCD, eating disorders, migraine, etc synthesis ◦ amino acid precursor – tryptophan synthesis ◦ amino acid precursor – tryptophan ◦ elimination of dietary tryptophan can significantly lower brain 5HT levels 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 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 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 linked to chloride channel 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? 2005 – first non AChE inhibitor for treating AD Only approved for advanced (not early stage) uncompetitive low-to-moderate affinity NMDA receptor antagonist Multiple other uses possible ◦ 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 Overview of nervous system 1. autonomic nervous system - “involuntary” role in emotion and stress controls smooth muscles, cardiac muscles and glands 1. Sympathetic NS “fight or flight” activated during emergencies, stress and/or arousal Maintain homeostasis, energy restoration ◦ physiological changes: voluntary nervous system ◦ sensory and motor nerves ◦ connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses CNS – Central Nervous System ◦ brain, spinal cord PNS – Peripheral Nervous System ◦ Somatic, autonomic 3 main divisions of brain ◦ hindbrain; midbrain; forebrain hindbrain Medulla medulla ◦ Contains part of the reticular formation – (nuclei involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) medulla ◦ Contains part of the reticular formation – (nuclei involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as ◦ Nuclei important for vital functions medulla ◦ Contains part of the reticular formation – (nuclei involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as ◦ Nuclei important for vital functions ◦ Various ascending and descending pathways hindbrain medulla pons ◦ Contains part of the reticular formation Nuclei important for sleep and arousal pons ◦ Contains part of the reticular formation Nuclei important for sleep and arousal ◦ Specific nuclei include Raphe (5HT) – sleep and dreaming Locus coerulus (NE) - arousal pons ◦ Contains part of the reticular formation Nuclei important for sleep and arousal ◦ Specific nuclei include Raphe (5HT) – sleep and dreaming Locus coerulus (NE) - arousal Cerebellum Sensory information ◦ reticular formation movement ◦ substantia nigra - cortical and subcortical structures frontal parietal temporal occipital Frontal ◦ Motor function ◦ Prefrontal – higher “executive function” Frontal ◦ Motor function Prefrontal – higher “executive function” Parietal Temporal Occipital ◦ Somatosensory function ◦ Audition ◦ emotion ◦ vision Prefrontal cortex Prefrontal cortex thalamus The thalamus communicates with much of the cerebral cortex serving as a sensory and motor information relay. thalamus hypothalamus thalamus hypothalamus limbic system thalamus hypothalamus limbic system basal ganglia Mesolimbic/cortical – ◦ Involved in reward, possible role in schizophrenia Projects to nucleus accumbens and parts of the limbic system nigrostriatal – ◦ Important in initiation of movement; system that degenerates in Parkinsons disease projections from the substantia nigra to the basal ganglia tuberofundibular – ◦ Important for hormonal release via hypothalamus and pituitary gland Peptides Opioids ◦ ◦ ◦ ◦ Mu Delta Kappa Endorphins and enkephalins are opioids Substance P