Applied Pharmacology of the Nervous and Endocrine System Drug Targets

Learning Objectives

• Identify and define the different brain regions and their main functions.
• Identify and define the different cell types found in different brain regions and their main neurotransmitter-receptor systems in the central nervous system.
• Define the different branches of the autonomic nervous system, and its main neurotransmitter-receptor systems.

Brain Regions in Self Reflected

MOTOR CORTEX (MOVEMENT) SOMATOSENSORY CORTEX (SENSATION) SUBTHALAMIC NUCLEUS (MOVEMENT) PARIETAL CORTEX (INTEGRATING MOVEMENT AND VISION) FRONTAL CORTEX (DECISION MAKING, PLANNING, EXECUTIVE FUNCTIONS) VISUAL CORTEX (VISION) CAUDATE NUCLEUS (INTIATION OF MOVEMENT) SUPERIOR AND INFERIOR COLLICULI (VISION AND HEARING) GLOBUS PALLIDUS (MOTOR GATING) LOCUS COERULEUS (AROUSAL AND STRESS) NUCLEUS ACCUMBENS (REWARD) RAPHE NUCLEI (SEROTONIN) CEREBELLUM (MOVEMENT AND PROPRIOCEPTION) PONS (MOVEMENT) OLFACTORY BULB (SMELL) MAMMILLARY BODIES (MEMORY) RETICULAR FORMATION (MOTOR COORDINATION, EXHALATION, AWARENES) RED NUCLEUS (MOVEMENT) DENTATE NUCLEUS (CEREBELLAR OUTPUT) VENTRAL TEGMENTAL AREA (VTA) (DOPAMINE/ REWARD) SUBSTANTIA NIGRA (LEARNING, ADDICTION) MISC BRAINSTEM NUCLEI (BREATHING, HUNGER) INFERIOR OLIVARY NUCLEUS (ERROR CHECKING, MOVEMENT)

WWW.GREGADUNN.COM THALAMUS (SENSORY GATING, RELAY, SIGNAL INTEGRATION)Our brain is a highly complex organ! Neurons in the brainstem Pyramidal neurons in mouse cortex Pyramidal neurons in mouse cortex

Clear Division of Labour Across the Brain

• Cerebral cortex
• Examples of excitatory output in the brain
• Pyramidal neurons with pyramid-shaped cell bodies, long axons and apical dendrites
• Basal ganglia (striatum in particular)
• Examples of inhibitory output in the brain
• Voluntary motor responses and fine- tuning of motor movement

ANTERIOR Lateral ventricle Body of caudate nucleus Frontal lobe of cerebrum Thalamus Putamen Tail of caudate nucleus Occipital lobe of cerebrum (a) Lateral view of right side of brain SUPERIOR Coronal plane Longitudinal cerebral fissure Cerebrum Corpus callosum Septum pellucidum Lateral ventricle Internal capsule View Caudate nucleus Insula Putamen Corpus straitum Thalamus Globus pallidus Subthalamic nucleus Third ventricle Hypothalamus and associated nuclei Optic tract (b) Anterior view of coronal section Head of caudate nucleus

Functional Areas of the Cerebral Cortex

1 Higher Mental Functions Concentration Planning Judgment Emotional expression Creativity Inhibition - Ability to control self 9 Somatosensory Association Area Understanding of weight, texture, temperature, etc. for recognizing and comprehending an object 6 2 4 10 9 8 Visual Areas Sight Ability to recognize pictures Awareness of size and shape 3 1 7 10 5 11 6 Sensory Area Touching and feeling 7 Auditory Area Hearing 8 Wernicke's Area Written and spoken language understanding 11 Motor Functions Coordination of movement Balance Posture 2 Motor Function Area Eye movement and placement of eyes 3 Broca's Area Ability to talk Ability to write 4 Motor Function Area Ability to move muscles 5 Association Area Short-term memory Emotion

Functional Areas of the Cerebellum

Diverse Neuronal Subtypes and Brain Functions

• More than 100 billion neurons in the human brain
• Diverse subclasses of neurons in the brain
• 7 subclasses of S1 pyramidal neurons
• 2 subclasses of CA1 pyramidal neurons
• 16 subclasses of interneurons in S1 and CA1
• ALL are layer-specific: different functions?

A Somatosensory Cell capture Biclustering cortex (S1) Whole tissue cell suspension O Single-cell RNA-seq 3,005 cells 9 classes 47 subclasses Hippocampus CA1 A S1PyrL23 S1PyrL4 S1PyrL5a S1PyrL5 S1PyrL6 S1PyrL6b S1PyrDL ClauPyr Tbr1 Rasgrf2 Pvrl3 Cux2 Rorb Plcxd2 Thsd7a Kcnk2 Cplx3 Sulf2 Foxp2 Pde1a Lphn2 Kcnip2 Rgs10 Synpr Pcp4 Rasgrf2. Crh Plcxd2 Kcnk2 Sulf2 Rprm Cplx3 DL II/III IVVa V VI VIb C 5HT3aEGFP PAX6 ALDOC I - 250ms = PAX6Biotin IV V VI 0 B Interneuron subclasses Int Int16 Gad1 Pvalb Sst T Htr3a Vip Rein Cck Npy Lhx6 Calb2 Syt6 Rprm Nr4a2 Nov Cpne5 I Slc5a7 __ Pax6 Cxcl14 H Gda_ Sema3e S1 CA1 FACS S1 Pia D 60mV 7

Neuronal Subtypes and Gene Expression

• Distinct gene expression in each subclass of neurons
• Express distinct patterns of neurotransmitter-receptors in different neuronal subtypes across different brain regions
• Unique biochemical and functional properties
• Unique firing pattern

A Somatosensory Cell capture Biclustering cortex (S1) Whole tissue cell suspension O Single-cell RNA-seq 3,005 cells 9 classes 47 subclasses Hippocampus CA1 A S1PyrL23 S1PyrL4 S1PyrL5a S1PyrL5 S1PyrL6 S1PyrL6b S1PyrDL ClauPyr Tbr1 Rasgrf2 Pvrl3 Cux2 Rorb Plcxd2 Thsd7a Kcnk2 Cplx3 Sulf2 Foxp2 Pde1a Lphn2 Kcnip2 Rgs10 Synpr Pcp4 Slc5a7 __ Rasgrf2. Crh Plcxd2 Kcnk2 Sulf2 Rprm Cplx3 DL II/III IVVa V VI VIb C 5HT3aEGFP PAX6 ALDOC I - 250ms = PAX6 Biotin IV 25 um V VI 0 B Interneuron subclasses Int Int16 Gad1 Pvalb Sst T Htr3a T Vip Rein Cck Npy Lhx6 Calb2 Syt6 Rprm Nr4a2 Nov Cpne5 I Pax6 Cxcl14 H Gda_ Sema3e S1 CA1 FACS S1 PAX6 neurons by layer (%)g Pia D 60mV T 8

Neuronal Connections and Synapses

• Unique connections formed between these functionally and chemically diverse neurons
• Each neuron can form thousands of synapses with other neurons
• Purkinje cell in cerebellum or monoamine-containing neuron in brainstem forms more than 100,000 synapses!
• More than 100 trillion synapses
• Form diverse circuitry - small local neuronal groups to long-distance projections
• Specific brain circuit - specific brain function

A A A 2-3 Drawings of typical neurons in the CNS. 'A' marks the axons of some of these neurons.

How Neurons are Interconnected

Fig. 38.2 Simplified scheme of neuronal interconnections in the central nervous system. Neurons 1, 2 and 3 are shown releasing transmitters a, b and c, respectively, which may be excitatory or inhibitory. Boutons of neuron 1 terminate on neuron 2, but also on neuron 1 itself, and on presynaptic terminals of other neurons that make synaptic connections with neuron 1. Neuron 2 also feeds back on neuron 1 via interneuron 3. Transmitters (x and y) released by other neurons are also shown impinging on neuron 1. Even with such a simple network, the effects of drug-induced interference with specific transmitter systems can be difficult to predict. b 3 a C X a y 1 2 a b a

• Principal cells (cell #1): process information within their brain region, and project their axons to other brain regions, thereby innervating and regulating other brain regions
• Interneurons (cell #2): process information within their brain region, and project their axons to local neurons only, thereby regulating activity of neighbouring principal cells

Pyramidal Neurons

• Principal cells in the cerebral cortex are called 'pyramidal neurons', which have pyramid-shaped cells
• Major excitatory neurons (70-85% of all neurons) in the mammalian cortex)
• Receive input from different brain regions
• Project to different brain regions and their targets

FIGURE 12.4 Two examples of CNS neurons. Arrows indicate the direction of information flow. The dendritic branching pattern often is distinctive for a particular type of neuron. Dendrites Cell body 1 Axon Axon terminal (a) Purkinje cell (b) Pyramidal cell

Organization of Cerebral Cortex Neurons

1 I = Ch Il III Sp Asp Py IV V V Py VI ·VI Bas mPy 4Thalamocortical terminals Thalamus Cortex Claustrum Spinal cord Thalamus Striatum Cortex Brainstem Cortex (callosal) Corticocortical terminals

Types of Interneurons in the Cerebral Cortex

IVTypes of interneurons in the cerebral cortex A Layer 1 has no pyramidal neurons and very few somas. II Layer II and III pyramidal neuron somas are grouped together. Layer II contains the smallest somas in this group. III Layer III contains pyramidal neurons whose somas are largest at the lower surface of the layer and then gradually decrease in size moving towards Layer II. Layer IV contains pyramidal neurons as well as spiny stellate neurons (though spiny stellates are absent in the motor cortex). This is the densest of the layers in terms of cell body occupancy. V Layer V contains the largest pyramidal neuron somas. Similarly to layer III, the larger somas are located in the lower half of the layer. Compared with Layer VI, this layer has sparsely packed somas. VI Layer VI, similarly to Layer IV, has densely packed somas.

• Diverse neuronal subtypes based on: . Allows for highly complex patterns of regulating pyramidal neuronal activity
• Morphology
• Physiology
• Neurochemistry

VI Interneurons Excitatory Spiny Neurons Inhibitory Aspiny Neurons neuroglial cell - double bouquet cell chandelier cell Vasointestinal Peptide (VIP, CR, 5HT3aR) Somatostatin- Calretinin (SST-CR) Calretinin (CR) Parvalbumin (PV) multipolar cell bipolar cell IV RorB, MDGA1, Eag1/2, Parvalbumin (PV) Reelin (RLN, 5HT3aR) Parvalbumin (PV) Somatostatin (SST) chandelier cell small basket cell nest basket cell FIRST Reelin (RLN, 5Ht3aR) I Martinotti cell large basket cell small basket cell V Martinotti cell neuroglial cell large basket cell Somatostatin- Calretinin (SST-CR)

Neurotransmitter-Receptors in Pyramidal Neurons

• Pyramidal neurons are excitatory in nature
• Primarily release glutamate from their axons
• Main source of neuronal excitation in the brain
• Diverse synaptic inputs onto different dendritic and somatic regions
• Excitatory: glutamate receptors (NMDA, AMPA, kainate), acetylcholine (M1, nicotinic ACh), dopamine (D1 and D5), noradrenaline (a1, B1, B2), serotonin (5-HT2A)
• Inhibitory: GABAA receptors (mainly on cell bodies and dendritic shafts)

A Dendritic Spines B Inhibitory Synapses

Basal Ganglia

• A group of interconnected nuclei located in the subcortical brain region
• Caudate nucleus and putamen form the dorsal striatum (MOST important integrating centre)
• initiating and controlling movements of the body, limbs, and eyes
• The ventral striatum consists of the nucleus accumbens and the olfactory tubercle.
• motivation, reward, reinforcement, and aversion

GLU GLU Cerebral cortex Brainstem and spinal cord GLU GLU DA GLU Thalamus Caudate nucleus Putamen ACh GABA/SP Pars compacta Pars reticulata Substantia nigra GABA/SP GABA/ENK GLU Subthalamic nucleus A Globus pallidus GABA GABA GABA Figure 12.19 . Major pathways of the basal ganglia and their neurotransmitters. ACh, acetylcholine; DA, dopamine; ENK, enkephalin; GABA, gamma aminobutyric acid; GLU, glutamate and/or aspartate; SP, substance P. (Modified from Fix, JD (1995) Neuroanatomy, 2nd edn. Williams & Wilkins, Baltimore; fig. 21.4.)