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CNS Neurotransmitters. Dr. Joan Heller Brown BIOM 255 2012. Gross anatomy of the human brain. Anatomy of a neuron. Figure 1. Peripheral Nervous System (PNS) Autonomic division : neuron to smooth muscle, cardiac muscle and gland Somatic division : neuron to skeletal muscle
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CNS Neurotransmitters Dr. Joan Heller Brown BIOM 255 2012
Peripheral Nervous System (PNS) • Autonomic division : neuron to smooth muscle, cardiac muscle and gland • Somatic division : neuron to skeletal muscle • Central Nervous System ( CNS) • neuron to neuron
Multiple sites of CNS drug action • Conduction • Synthesis and storage • Release and reuptake • Degradation • Receptors, pre-and post-synaptic • Ion channels • Second messengers
Classes of Receptors • GPCR=7 transmembrane spanning = metabotropic • Ligand gated ion channel=ionotropic
Most neurotransmitters can activate multiple receptor subtypes and receptor classes
Neurotransmitter regulation of ion channels affects membrane potential and action potential generation (firing)
Principles of CNS Drug action • Selectivity for the targeted pathway • Receptor subtypes • Allosteric sites on receptors • Presynaptic and postsynaptic actions • Partial/inverse agonist (activity dependent) • Plasticity reveals adaptive changes in drug response • Pharmacokinetic: drug metabolism • Pharmacodynamic: cellular
Monoamine Biosynthesis Catecholamines Indoleamines
Important monoamine metabolites formed in the CNS • NE MAO, COMT MHPG (MOPEG) • DA MAO, COMT HVA • 5HT MAO 5HIAA
Noradrenergic Pathways in the Brain Locus ceruleus to cortical and subcortical sites
Serotonergic Pathways in the Brain Midline raphe nuclei to cortical and subcortical areas 29
CNS functions regulated by NE • Arousal • Mood • Blood pressure control
CNS functions regulated by 5HT Sleep Mood Sexual function Appetite 31
Monoamine Biosynthesis Catecholamines
Major Dopaminergic (DA) pathways • Nigrostriatal (substantia nigra to striatum) • Mesolimbic/mesocortical (ventral tegmental midbrain to n.accumbens, hippocampus, and cortex) • Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary)
CNS functions regulated by DA Nigrostriatal (substantia nigra to striatum) extrapyramidal motor control Mesolimbic/mesocortical (ventral tegmental to n.accumbens, hippocampus, and cortex) emotion cognition Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary) prolactin release 37
Brain Amines and Disease States Biogenic amine theory of depression Dopaminergic theory of schizophrenia Dopaminergic involvement in Parkinson’s disease 38
Brain Amines and Disease States • Biogenic amine theory of depression • Dopaminergic theory of schizophrenia • Dopaminergic involvement in Parkinson’s disease
Brain Amines and Disease States Biogenic amine theory of depression Dopaminergic theory of schizophrenia Dopaminergic involvement in Parkinson’s disease 42
Pathology of disease: DA neurons in nigrostriatal pathway degenerate Replacing DA is a therapeutic approach to treat PD Parkinson like symptoms are side effects of DA receptor blockade with antipsychotic drugs MPTP, a neurotoxin, destroys DA neurons and induces PD DA involvement in Parkinson’s disease (PD)
ACh as a CNS neurotransmitter • Memory (ChEI in Alzheimers disease) • Basal forebrain to cortex/hippocampus(A) • Extrapyramidal motor responses (benztropine for Parkinsonian symptoms) • Striatum (B) • Vestibular control (scopolamine patch for motion sickness)
Cholinergic pathways in the CNS B A Nucleus basalis to cortex (A) and interneurons in striatum ( B)
Amino Acid Neurotransmitters Inhibitory GABA and Glycine Hyperpolarize = don’t fire Excitatory Glutamate ( and Aspartate) Depolarize = fire 50