Nervous System Divisions

• Central Nervous System (CNS) comprises the brain and spinal cord.
• Peripheral Nervous System (PNS) includes all nerves carrying signals to muscles.

Afferent and Efferent Systems

• The afferent system conveys information from receptors to the CNS.
• The efferent system conveys information from the CNS to muscles and glands.

Somatic and Autonomic Nervous Systems

• The Somatic Nervous System (SNS) conveys information from the CNS to skeletal muscles.
• The Autonomic Nervous System (ANS) conveys information from the CNS to smooth muscle, cardiac muscle, and glands
• The ANS includes the sympathetic and parasympathetic nervous systems.

Brain Divisions

• The brain is divided into the forebrain, midbrain, and hindbrain.
• The Forebrain consists of the telencephalon (cerebral hemispheres) and the diencephalon.
• Telencephalon includes the neocortex, basal ganglia, and limbic system.
• Diencephalon includes the thalamus and hypothalamus.
• The Midbrain is the mesencephalon.
• The Hindbrain consists of the metencephalon and myelencephalon.
• Metencephalon includes the cerebellum and pons.
• Myelencephalon is the medulla.

Telencephalon

• Includes the cortex, basal ganglia, and limbic system.
• The cortex is the highest brain region

Myelencephalon (Medulla)

• The lowest part of the brain.
• Contains ascending and descending pathways.
• Contains cranial nerves (8-12), including the vagus nerve (parasympathetic).
• Contains the caudal reticular formation.
• Controls vital functions like heart rate, blood pressure, respiration, and digestion.
• Controls non-vital functions like vomiting (area postrema), coughing, swallowing, sneezing, and hiccupping.

Cranial Nerves

• There are twelve cranial nerves with sensory and/or motor functions.
• Olfactory nerve (I) provides the sense of smell
• Optic nerve (II) provides vision
• Oculomotor nerve (III) controls eye movements, pupillary constriction, and eyelid movement
• Trochlear nerve (IV) controls eye movements (intorsion, downward gaze)
• Trigeminal nerve (V) provides somatic sensation from the face, mouth, and cornea, and controls muscles of mastication
• Abducens nerve (VI) controls eye movements (abduction)
• Facial nerve (VII) controls facial expression muscles, taste from the anterior tongue, and lacrimal and salivary glands
• Vestibulocochlear nerve (VIII) provides hearing and balance
• Glossopharyngeal nerve (IX) provides sensation and taste from the posterior tongue and pharynx, and controls the baroreceptors, chemoreceptors and salivary gland
• Vagus nerve (X) controls autonomic functions of the gut, cardiac inhibition, sensation from the larynx and pharynx, and muscles of vocal cords and swallowing
• Spinal accessory nerve (XI) controls shoulder and neck muscles
• Hypoglossal nerve (XII) controls movements of the tongue

Metencephalon

• Cerebellum is the second largest part of the brain
• Cerebellum controls unconscious skeletal muscle coordination, balance, posture, movement, and motor learning as well as cognition and affect
• Pons contains the reticular formation, locus coeruleus, and raphe nuclei, which has high serotonin concentration

Mesencephalon

• Periaqueductal gray is involved in analgesia
• Substantia nigra is involved in movement and is subject to drug-induced damage
• Ventral tegmental area is involved in reward; pleasure system

Diencephalon

• Thalamus serves as a sensory relay
• Hypothalamus regulates the 4 F's: feeding, fighting, fleeing, and mating.
• Hypothalamus controls the autonomic nervous system (ANS) and pituitary gland.

Autonomic Nervous System (ANS)

• Includes sympathetic and parasympathetic divisions, is a 2-neuron organization.
• Sympathetic division is responsible for "fight or flight" responses.
• Actions of "fight or flight" include catabolic processes, increased heart rate/BP, dilated blood vessels in skeletal muscle, constricted visceral blood vessels, digestion shutdown, and open airways.
• Parasympathetic division mediates "rest and restoration".
• Actions of "rest and restoration" include anabolic processes, decreased heart rate and BP.
• No parasympathetic innervation for most blood vessels, vasodilation of genitals.
• Parasympathetic system stimulates digestion and constricts airways.

Neural Tissue Composition

• Neuroglia (glial cells) support neural tissue.

• Glial cells include astrocytes, oligodendrocytes, Schwann cells, microglia, and radial glia.

• Neurons are the functional units of the nervous system.

• Electrical states of neuron membranes include resting potential, postsynaptic potential, and action potential.

• The resting potential of a nerve cell is -65mV.

• Concentrations of ions in intra- and extra-cellular fluids determine the electrical state.

Ion Concentrations

• Intracellular fluid contains 15mM Na+, 100mM K+, 13mM Cl-.
• Extracellular fluid contains 150mM Na+, 5mM K+, 150mM Cl-.
• Active transport (sodium-potassium pump) helps maintain the resting potential.
• The resting potential is also affected by diffusion and electrostatic forces.
• Membrane resistance also affects the resting potential.

Nernst Potential

• K+ is held at higher concentration inside the cell due to electrostatic force that opposes diffusion
• At equilibrium, the opposing forces are equal, and no net movement of ions
• Can calculate the amount of electrostatic force to create equilibrium
• The value in mV is the Nernst or equilibrium potential.
• Nernst Potential Formula: Eion=61.54log([Ion]out/[Ion]in)
• A signal in a neuron is a transient fluctuation in membrane voltage that spreads from one point in the neuron to another.

Postsynaptic Potentials (PSPs)

• Changes in membrane voltage in a localized area of the postsynaptic neuron when it receives an input.

Types of Signals

• Postsynaptic (AKA local) potential
• Action potential

Character of Postsynaptic Potentials

• Origin is in the dendrite.
• Spreads toward the soma.
• Propagation is passive.
• Travels short distances.
• Amplitude is graded.

Types of Postsynaptic Potentials

• Depolarizing PSPs drive membrane voltage towards zero, depolarizing the cell.
• Hyperpolarizing PSPs drive membrane voltage away from zero.
• In a resting state, cells polarize
• The cell decides based on depolarization (EPSP).

Types of Postsynaptic Potentials (Names)

• Depolarizing PSP = Excitatory Postsynaptic Potential (EPSP).
• Hyperpolarizing PSP = Inhibitory Postsynaptic Potential (IPSP).

Generation of PSPs

• Transmembrane ion currents cause PSPs.
• Ions move across cell membranes, causing depolarization (post-synaptic potential)
• Influx of Na+ and Ca++ produces EPSPs.
• Influx of Cl- produces IPSPs.
• Efflux of K+ produces IPSPs.

Changing Ion Movement

• Increased conductance causes transmembrane currents.
• Increasing conductance is accomplished by gating ion channels.

Ion Channels

• Ligand gating -> molecule interacts with receptor to cause effect for PSP.
• Voltage gating -> determined by membrane potential -- triggers action potential.

Characteristics of PSPs

• Decrease as they move away from their point of origin
• Intracellular currents carried by K+ cause dissipation due to K+ leakage.
• IPSPs and EPSPs are additive.

Action Potentials

• A signal in a neuron is a transient fluctuation in membrane voltage
• Originates at the axon hillock
• Spreads towards the axon terminal
• Method of propagation: active
• Travel long distances
• Amplitude is fixed.

Form of the Action Potential

• Begins at -65mV then shoots up over 0 to +65mV

Ionic Basis of Action Potential

• Resting state: K+ blocked out of cell
• A stimulus causes K channels to open allowing Na+ in

Characteristics of channels during Depolarization

• Na >>K

Characteristics of channels during Repolarization

• K>>Na
• Slower than PSPs and inefficient, speed is 1 to 100 meters/second.
• Energy is expended to maintain concentration gradients.
• Ways to increase speed and efficiency: increase axon diameter, myelination, which decreases K+ conductance and membrane capacitance

Saltatory Conduction

• Reduces conduction for K+
• Chemical signaling classification is based on distance, how it travels, and target

Chemical Communications

• Paracrine: nearby cells
• Neurocrine: between neurons
• Autocrine: same cell
• Pheromone: another member same species
• Allomone: different species
• Endocrine: released into circulatory system

Endocrine System

• Endocrine glands release bloodstream chemicals.
• Hormone* - secretion of an endocrine gland.

Endocrine Glands

• Pituitary, Hypothalamus, Pineal, Thyroid, Pancreas, Testes/Ovaries, Adrenal

The Pituitary Gland

• Located at the brain's bottom, made of 2 distinct glands (anterior and posterior).
• Neurosecretory cells in the hypothalamus control the posterior and anterior pituitary glands.

Hormones released by the Anterior Pituitary

• Thyroid stimulating hormone
• Follicle stimulating hormone
• Luteinizing hormone
• Growth hormone (somatotropin)
• Prolactin
• Adrenocorticotropic hormone (ACTH)

Actions of ACTH

• Involved in theory of depression

*Hypothalamic-Pituitary-Adrenal Axis

• Principle hormones released are epinephrine, norepinephrine and glucocorticoids (cortisol)
• Important for mediating fight or flight

Synaptic Transmission

• Synapse is the specialized zone of contact between neurons. Involves sending a signal

Parts of Synapse

• Presynaptic element
• Postsynaptic element
• Synaptic cleft

Neurotransmitter Definition

• NT should be synthesized in neurons that release it
• NT should be released upon neuronal excitation
• NT should act on specific receptors
• There should be mechanisms for terminating the action of NT after release so signals are not prolonged

Dale's Principle

• Two meanings:
• Neurons release one and the same neurotransmitter at each synapse
• Neurons release the same set of neurotransmitters at all synapses
• The first meaning is false
• Second meaning may hold "rule of thumb" but is not consistent

Synaptic Transmission (cont.)

• Neurons can be classified by their presumed primary neurotransmitter
• Chemical synapse involves steps: Action potential, depolarization, influx of Ca2+, vesicles fuse and transmitter is released, transmitter binds, producing/inhibiting a postsynaptic potential.

Neurotransmitter Inactivation

• Essential for regulating synaptic signaling
• Mechanisms: Diffusion, catabolism (enzymatic breakdown), reuptake by membrane transporters

Presynaptic Inhibition

• Occurs via autoreceptor activation, reduces neurotransmitter synthesis/release, increased catabolism.

Drug Mechanisms of Action

• Translate chemical messenger (drug, hormone) into an intracellular response
• Two aspects: ligand binding to receptor and initiation of biologic response in the postsynaptic neuron (effector)
• Mediating the communication = transducers, which can result in 2nd messengers

Classical Pharmacology

• Receptors are proteins that serve as receptors for endogenous signaling ligands.
• Known today as physiological receptors
• Drugs that bind and mimic natural effects: agonists
• Those that block and interfere: antagonists

Physiological Receptors

• Can include Enzymes or carrier/channel proteins
• Structurally, drugs must be pharmacologically close to receptors
• Drugs mostly interact with receptors on the extracellular surface not in cells by using random kinetic energy to contact the receptors

Forces of Affinity (in order of strength)

• Covalent: Strongest. NOT reversible
• Electrostatic: Strong but weaker. Sometimes
• Hydrogen bond: Weak. Yes
• Other: Weaker. Yes

Reversibility

• A drug that can unbind

Occupancy Theory

• Interaction between drug and receptor is reversible.
• All receptor molecules equivalent and independent

Receptors

• Drug receptor = reaction, DR is drug receptor, and is drug/receptor complex
• Various aspects of drug interaction can be quantified with the "Law of Mass Action"

Fractional Receptor Occupancy

• Drug fraction = fraction of receptors occupied, and is proportional to the fraction of receptors
• ( r = [DR]/[Rt] total receptors
• To insert [Rt] into the equation: Kd = [D][R] / [DR] requires substituting and finding unknowns

Classical Occupancy Theory

• Fails to account for spare receptors, allosteric modulation, intrinsic/inverse activity

Allosteric Modulation

• Causes direct or inverse action

Intrinsic Activity

• Drug with ability to activate the receptor
• Full agonist: intrinsic activity = 1
• Partial agonist : intrinsic activity <1 fraction of response produced by a high agonist

Pure Antagonist

• Intrinsic activity = 0

Inverse Agonists

• Have the opposite effects as an agonist
• Not neutral, goes instead down in activity

Two State Theory

• Suggests receptors exist spontaneously in dynamic equilibrium between active/inactive states
• Agonists have a differential affinity for the two states
• Agonist binding shifts the equilibrium between the active and inactive states

Types of Antagonism

• Pharmacokinetic
• Physiological – two drugs working at different receptors to antagonize
• Pharmacodynamic – one drug preventing action of another thru competitive / non-competitive pathways
• Competitive Pharmacologic Antagonism can be overcome depending on affinities
• Affinity is variable and concentration is fixed

Drug Efficacy

• Efficacy = maximum effect produced by drug

Drug Potency

• Potency = Amount of drug needed to produce a given effect
• Potency is typically defined as amount by 50% maximal effet

Dose response curves

• Relate dose to observable effects, which is graded/dichotomous
• Under assumptions, DRC's have same form as curves relating concentration receptors
• On a dose curve, position is on the x axis for potency - related to amount of drug needed to produce an effect

Characteristics of Dose Curve

• Characteristics on a quantal dose are the all or none effects
• Includes effects such as death, pregnancy, can be broken into more variables
• All based on distribution of a population