Part II Part II
Chapter 4 Chapter 4
Clinical neuroanatomy is the method of studying lesions of the human nervous system as a tool to reinforce and amplify learning of the structure and organization of the cen- tral nervous system (CNS).
Clinical neuropharmacology is the study of drugs that alter processes controlled by the nervous system.
This chapter deals with the basic anatomy and physiology of the CNS, peripheral nervous system (PNS), somatic nervous system, blood–brain barrier, basal ganglia, hip- pocampus, hypothalamus, and neurotransmitters.
Clinical Neuroanatomy of the Brain
Central nerVouS SyStem
Composed of the brain and spinal cord, which are covered by protective mem-
branes (meninges) and have fl uid-fi lled spaces; weighs less than most desktop computers; receives and interprets sensory information and controls simple/com- plex motor behaviors
PeriPheral nerVouS SyStem
Composed of cranial and spinal nerves; the nerves contain nerve fi bers, which
conduct information to (afferent) and from (efferent) the CNS; efferent fi bers are involved in motor function, such as contraction of muscles or activation of secre- tory glands; afferent fi bers convey sensory stimuli from the skin, mucous mem- branes, and deeper structures.
Somatic nervous system
: part of PNS; innervates the structures of the body wall (muscles, skin, and mucous membranes)
Autonomic nervous system
: part of PNS; contains the sympathetic nervous system (SNS) (“fi ght or fl ight”) and the parasympathetic nervous system (PSNS); controls activities of the smooth muscles, glands, and internal organs, including blood ves- sels, and returns sensory information to the brain.
nervous System
Central nerVouS SyStem Brain and Spinal Cord
CNS drugs are used medically to treat psychiatric disorders, seizures, and pain,
and as anesthetics; nonmedically, they are used as stimulants, depressants, eupho- riants, and mind-altering substances.
The CNS drugs include at least 21 neurotransmitters:
Monoamines
: norepinephrine, epinephrine, dopamine, serotonin Amino acids
: aspartate, glutamate, gamma-aminobutyric acid (GABA), glycine Purines
: adenosine, adenosine monophosphate, adenosine triphosphate Peptides
: dynorphins, endorphins, enkephalins, neurotensin, somatostatin, sub- stance P, oxytocin, vasopressin
Others
: acetylcholine (ACh), histamine Blood–Brain Barrier
The blood–brain barrier blocks the entry of some drugs and substances into the brain.
Elements
: supporting cells (neuralgia), particularly the astrocytes, and tight junc- tions between endothelial cells.
Function
: selectively inhibits certain substances in the blood from entering the interstitial spaces of the brain or cerebrospinal fluid. Certain metabolites, elec- trolytes, and chemicals have differing abilities to cross the blood–brain barrier.
This has substantial implications for drug therapy because some antibiotics and chemotherapeutic drugs show a greater ability than others for crossing the barrier.
P-glycoprotein
: a protective element of the blood–brain barrier and a transport molecule that pumps various types of drugs out of cells. In capillaries of the CNS, P-glycoprotein pumps drugs back into the blood, thus limiting their access to the brain.
Passage limited to lipid-soluble substances and drugs that cross by means of
transport systems (protein-bound and highly ionized substances cannot cross).
Protects brain from injury due to toxic substances but also acts as an obstacle to
entry of therapeutic drugs.
the Brain
The brain is able to adapt to prolonged drug exposure, which can alter the thera-
peutic effects and side effects of some drugs (adaptive changes are often beneficial but can be harmful).
Increased therapeutic effects, decreased side effects, tolerance, and physical
dependences may occur.
Acts as a control center by receiving, interpreting, and directing sensory informa-
tion throughout the body.
Composed of cerebrum (
telencephalon—cerebral cortex, subcortical white matter, commissures, basal ganglia; diencephalon—thalamus, hypothalamus, epithalamus, subthalamus), brain stem (midbrain, pons, medulla oblongata), and cerebellum (cerebellar cortex, cerebellar nuclei). Cerebrum and cerebellum are organized into right and left hemispheres.
There are
three major divisions of the brain—the forebrain, the midbrain, and the hindbrain.
nerVouS SyStem 43
The forebrain is responsible for receiving and processing sensory information,
thinking, perceiving, producing and understanding language, and controlling motor function.
The midbrain is responsible for auditory and visual responses and motor
function.
The hindbrain is responsible for maintaining balance and equilibrium, move-
ment coordination, and the conduction of sensory information.
The limbic system
is often called the “pleasure center.”
It is the group of structures that governs emotions and behavior.
It connects to all areas of the brain, especially the frontal cortex, which is the
learning center.
PeriPheral nerVouS SyStem
PNS is divided into the somatic nervous system (controls movement of skeletal muscles) and the autonomic nervous system. The autonomic nervous system is further divided into the PSNS and the SNS.
PSNS
—housekeeping chores of the body, and stimulation of these nerves slows heart rate, increases gastric secretions, empties bladder and bowel, focuses eye for near vision, constricts pupil, and contracts bronchial smooth muscle.
SNS
—three main functions: regulates the cardiovascular system, regulates body temperature, and implements the fight-or-flight response.
The PNS uses three neurotransmitters to exert its actions: ACh (released by all
preganglionic neurons of the PSNS and SNS, all postganglionic neurons of the PSNS, all motor neurons of the skeletal muscles, and most postganglionic neurons of the SNS that supply the sweat glands), norepinephrine (released by almost all postganglionic neurons of SNS with the exception of postganglionic neurons that supply sweat glands), and epinephrine (released by adrenal medulla).
Two basic categories of PNS receptors and their subtypes (receptor subtypes make
it possible for drugs to act selectively):
Cholinergic-mediated responses to ACh subtypes include the following:
Nicotinic
N activation stimulates parasympathetic and sympathetic postgangli- onic nerves and causes release of epinephrine from adrenal medulla.
Nicotinic
M activation causes contraction of skeletal muscle.
Muscarinic activation causes focus of lens for near vision, miosis, decreased
heart rate, constriction of bronchi, promotion of secretions, increase in bladder pressure, urination, salivation, increased gastric secretions, increased intestinal tone and motility, sweating, erection, and vasodilation.
Adrenergic-mediated responses to epinephrine and norepinephrine subtypes
include the following:
Alpha
1 activation by epinephrine, norepinephrine, or dopamine causes mydriasis, vasoconstriction, ejaculation, and prostate contraction.
Alpha
2 activation by epinephrine or norepinephrine causes inhibition of subse- quent neurotransmitter release.
Beta
1 activation by epinephrine, norepinephrine, or dopamine causes increased heart rate, force of contraction, atrioventricular conduction, and increased renin release from the kidney.
Beta
2 activation (only by epinephrine) causes vasodilation, bronchial dila- tion, uterine relaxation, glycogenolysis, and enhanced contraction of skeletal muscle.
Dopamine (responds only to dopamine) activation causes dilation of kidney
vasculature.
SomatiC nerVouS SyStem Elements:
motor neurons arising from the spinal cord and brain and the neuromus- cular junction.
Neuromuscular junction:
formed by the terminal of the motor neuron and the motor end plates (special sites on the muscle’s membrane). Motor neurons release neu- rotransmitter ACh to the junction; subsequently, ACh activates its receptor (nico- tinicM receptor) on the motor end plates and causes muscle contraction.
Drugs that target the neuromuscular junction:
cholinesterase inhibitors, nondepolariz-
ing neuromuscular blockers, and depolarizing neuromuscular blockers.
Basal Ganglia (or Basal nuclei)
It is a group of nuclei situated at the base of the forebrain and strongly connected to the cerebral cortex, thalamus, and other areas.
Elements:
striatum, pallidum, substantia nigra, and subthalamic nucleus.
Function:
they are associated with motor control and learning functions. The sub- stantia nigra provides dopaminergic input to the striatum. The basal ganglia play a central role in a number of neurological conditions, including several movement disorders. The most notable are Parkinson’s disease, which involves degeneration of the dopamine-producing cells in the substantia nigra, and Huntington’s disease, which primarily involves damage to the striatum.
Drugs are used for Parkinson’s disease to increase the dopamine level at the
striatum.
hippocampus
The hippocampus belongs to the limbic system that forms the inner border of the cortex.
Function
: emotion, behavior, and long-term memory. Beta-amyloid, neuritic plaques and neurofibrillary tangles, and tau in the hippocampus and cerebral cortex are the prominent features of Alzheimer’s disease (AD). Another characteristic of AD is that the level of ACh, an important neurotransmitter in the hippocampus and cerebral cortex, is significantly below normal.
Drugs used to treat AD include cholinesterase inhibitors and N-methyl-D-aspartate
(NMDA) receptor antagonist.
hypothalamus
The hypothalamus is located below the thalamus and above the brainstem.
The
pituitary gland is located below the third ventricle of the brain and the hypo- thalamus, composed of anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis). The pituitary stalk connects the hypothalamus to the pituitary gland.
nerVouS SyStem 45
Function:
The hypothalamus controls the anterior pituitary by hypothalamic- releasing factors, while it synthesizes oxytocin and antidiuretic hormone and projects its neuronal axon to the posterior pituitary. The hypothalamus controls body temperature, hunger, thirst, fatigue, and circadian cycles.
Drugs that target the pituitary stimulate or inhibit the synthesis and release of hor-
mones from the anterior pituitary gland. In addition, some drugs act as agonists or antagonists of pituitary gland hormone receptors.
Both in the PNS and CNS, neurons regulate physiological processes in the same way through two steps:
Axonal conduction
—an action potential is sent down the axon of a neuron.
Drugs that influence axonal conduction are not selective, so they stop transmis-
sion in the axon of any neuron they reach.
The only group of drugs that affects axonal conduction are local
anesthetics.
Synaptic transmission
—a transmitter is released from the neuron carrying informa- tion across a synapse, or gap, to a postsynaptic cell receptor causing a change in that cell.
Most drugs work by affecting synaptic transmission.
Drugs that work by affecting synaptic transmission are very selective due to dif-
ferent types of transmitters and receptor sites.
To work, drugs must have either a direct or an indirect effect on target cell
receptors.
Synaptic transmission includes five steps:
Transmitter synthesis—
synthesis of the transmitter in the neuron Drugs work here by
Increasing the amount of transmitter synthesized
Decreasing the amount of transmitter synthesized
Synthesizing a “super” transmitter that is more potent than the naturally
occurring transmitter Transmitter storage—
the transmitter is stored in vesicles in the axon terminal for later use.
Drugs work here by
Reducing the amount of transmitter stored
Transmitter release—
axonal conduction causes release of the transmitter into the synapse between the neuron and the target cell.
Drugs work here by
Increasing the amount of transmitter released
Decreasing the amount of transmitter released
Receptor binding—
the transmitter binds to receptor sites on the postsynaptic, or target, cell causing a change in that cell.
Drugs work here by
Mimicking the natural transmitter and binding to additional target cell recep-
tor sites to increase the effects on a target cell (agonist)
Binding to target cell receptor sites to block the naturally occurring transmit-
ter from binding to the target cell and decreasing the effect that the naturally occurring transmitter has on the target cell (antagonist)
Binding to the same target cell receptor sites together with the naturally occur-
ring transmitter to increase the target cell’s response to the transmitter
Termination of transmission—
the transmitter is depleted by reuptake, enzymatic degradation, or diffusion.
Drugs work here by
Stopping the reuptake of the transmitter, allowing more transmitter to be
available to bind to the target cell receptor sites
Stopping the enzymatic degradation of the transmitter, allowing more trans-
mitter to be available to bind to the target cell receptor sites
Neurotransmitters are chemicals that account for the transmission of signals from one neuron to the next across a synapse. They are also found at the axon endings of motor neurons, where they stimulate the muscle fibers to contract.
Chemical substances stored in the terminal end of a neuron, released when the
storing neuron “fires”; have the potential to influence the activity of a receiving cell (either increasing or decreasing likelihood of action).
Present in the synaptic terminal.
Action may be blocked by pharmacological agents.
Examples of CNS neurotransmitters include the following:
ACh
—widely distributed throughout the CNS and the primary transmitter at the neuromuscular junction
Dopamine
—involved in a wide variety of behaviors and emotions associated with parkinsonism and, perhaps, schizophrenia
Serotonin
—involved in sleep regulation, dreaming, mood, eating, pain, and aggression and associated with depression (i.e., selective serotonin reuptake inhibitor)
Glutamate
—an excitatory transmitter, associated in memory, arousal, and pain GABA
—widely distributed, largely an inhibitory transmitter
Neuropharmacology is the study of drugs that alter processes regulated by the nervous system. The nervous system regulates almost all bodily processes and, therefore, almost all bodily processes can be influenced by drugs that alter neu- ron regulation. By blocking (antagonist) or mimicking (agonist) neuron regulation, neuropharmacological drugs can modify skeletal muscle contraction, cardiac out- put, vascular tone, respiration, gastrointestinal function, uterine motility, glandular secretion, and functions of the CNS, such as pain perception, ideation, and mood.
Neurons regulate physiological processes through a two-step process involving
axonal conduction and synaptic transmission.
Axonal conduction
—process of conducting an action potential down the axon of the neuron.
Drugs (local anesthetics) that alter this conduction are not very selective,
because the process of axonal conduction is almost the same in all neu- rons; therefore, a drug that alters conduction will alter conduction in all cells.
neurotransmitters
neuropharmacology
neuroPharmaColoGy 47
NeurotraNsmitter Focused areas
ACh Neuromuscular junction, autonomic ganglia, parasympathetic neurons, motor nuclei of cranial nerves, caudate nucleus and putamen, basal nucleus of Meynert, portions of the limbic system
Receptor: N, action: excitatory
Receptor: M, action: excitatory or inhibitory
Action: CNS—memory, sensory processing, motor coordination
Muscarinic—found at postganglionic parasympathetic endings (heart, smooth muscle, glands); five subtypes of muscarinic receptors:
M1 receptors found in ganglia and secretory glands
M2 receptors predominate in myocardium and in smooth muscle M3 and M4 receptors found in smooth muscle and secretory glands M5 receptors have been identified in the CNS along with the other four types
Nicotinic receptors found in ganglia and at neuromuscular junction.
Identified as:
NM receptors found at the neuromuscular junction in skeletal muscle
NG receptors found in autonomic ganglia, adrenal medulla, and CNS Norepinephrine SNS, locus coeruleus, lateral tegmentum
Action: CNS—positive mood and reward, orienting and alerting responses, basic instincts (sex, eating, thirst)
C-receptors:
Alpha1 (postsynaptic) causes contraction of blood vessels, sphincters, radial muscle of eye
Alpha2 (presynaptic): negative feedback loop inhibiting subsequent release of neurotransmitter; up regulation and downregulation occur in response to decreased or increased activation of receptors;
present at extrasynaptic sites in blood vessels and the CNS;
stimulation in the brain stem decreases sympathetic outflow;
stimulation in the pancreas inhibits insulin release
Beta1 (predominately cardiac) stimulation increases heart rate or strength of contraction
Beta2 (predominately noncardiac) found on smooth muscle (bronchi;
large blood vessels) causes relaxation and promotes insulin release, liver and muscle gluconeogenesis and glycogenolysis, and lipolysis in fat cells.
Beta3 receptors are expressed in visceral adipocytes Dopamine Hypothalamus, midbrain nigrostriatal system
Receptors: D1 and D2, action: inhibitory
Dopamine1 (postsynaptic) receptors responsible for vasodilation in splanchnic and renal circulations; stimulation in chemoreceptor trigger zone causes nausea and vomiting.
Dopamine2 (presynaptic) receptors initiate a negative feedback loop;
Five forms are found in the brain.
Action: Regulation of hormonal balance, voluntary movement, reward Serotonin (5-HT) Parasympathetic neurons in gut, pineal gland, nucleus raphe magnus of
pons
Action: CNS—sleep and emotional arousal, impulse control, cognition, pain processing, dreaming, homeostatic processes
(continued)
Synaptic transmission
—process of carrying information across the synapse between the neuron and the postsynaptic cell and requires release of neurotrans- mitters and binding of these transmitters to receptors on the postsynaptic cell.
Most drugs act by altering this synaptic transmission because they are able to
produce more selective effects by altering the following:
Transmitter synthesis and receptor activation can be increased; transmitter
–
synthesis and receptor activation can be decreased; or transmitters that are more effective than the natural transmitter, which will cause receptor activa- tion to increase, can be synthesized.
Transmitter storage can cause receptor activation to decrease by decreasing
–
the amount of transmitter available.
Transmitter release can promote release and increase receptor activation or
–
can inhibit release and reduce receptor activation.
Termination of transmitter action blocks transmitter reuptake or inhibition
–
of transmitter degradation; both these actions will increase concentration of transmitter and cause receptor activation to increase.
In order for a drug to exert its effect, it must be able to directly or indirectly
influence the receptor activity on the target cell. Drugs act on receptors by Binding to them and causing activation (agonist)
–
Binding to them and blocking their activation by other agents (antagonists)
–
Binding to their components and indirectly enhancing their activation by the
–
natural transmitter
CliniCal neuroanatomy: rationale for unDerStanDinG
Understanding neuroanatomy helps guide pharmacological approaches to treat-
ment. A key goal of pharmacotherapy is to modify a patient’s pathogenic nervous system activity.
The nervous system (CNS and PNS) regulates our bodily processes. Therefore,
our body processes can be affected by the drugs that regulate neuronal activity.
Understanding clinical neuroanatomy helps in the development of neurophar- macological drugs and treatment selection to modify a patient’s pathogenic nervous system activity.
NeurotraNsmitter Focused areas
GABA Cerebellum, hippocampus, cerebral cortex, striatonigral system Receptor: GABAa, action: inhibitory (postsynaptic)
Receptor: GABAb, action: inhibitory (presynaptic)
Glycine Spinal cord
Action: inhibitory
Glutamic acid Spinal cord, brainstem, cerebellum, hippocampus, cerebral cortex ACh, acetylcholine; CNS, central nervous system; SNS, sympathetic nervous system; 5-HT, serotonin;
GABA, gamma-aminobutyric acid.
neuroPharmaColoGy 49
CliniCal neuroanatomy: aSSoCiation With DruG aCtion Drug enters the body through various
routes of administration—injection, oral, sub-
lingual, inhalation, and transdermal What the body does to the drug (
pharmacokinetics)
Absorption
(transfer of drug from the site of application to the blood stream) Affected by the rate of dissolution, surface area, blood flow, lipid solubility,
and pH partitioning
Bioavailability (the fraction of unchanged drug that reaches site of action)
affected by anything that alters absorption, distribution, or metabolism Distribution
(drug leaves blood stream → interstitial space of tissues → target cells responsible for therapeutic and adverse effects)
Determined by the blood flow to tissues, ability to exit the vascular system
(capillary beds, blood–brain barrier, placental drug transfer, and protein bind- ing), and ability to enter cells (lipid solubility and presence of transport system) Metabolism
(enzymatic alteration of drug structure or “bagging the trash,” usu- ally by liver)
Hepatic drug-metabolizing enzymes
Excretion
(removal of drugs from body) What the drug does to the body (
pharmacodynamics)
Dose–response relationship
Size of administered dose
Intensity of the response produced
Drug–receptor interactions
(drugs interact with chemical)
Receptor
(chemicals in the body to which the drug binds to produce effects) Regulated by endogenous compounds or macromolecules (body’s own
–
receptors for hormones, neurotransmitters, and other regulatory molecules Can be turned on or off
–
Turned on by interaction with other molecules
–
When the drug binds to receptors, it either mimics (
– agonists) or blocks
(antagonists) the action of endogenous regulatory molecules such as neu- rotransmitters (supplied to receptors by neurons of the nervous system).
There are receptors for each neurotransmitter, each hormone, and all other
–
regulatory molecules.
Drugs are selective to specific receptors (a receptor is analogous to a lock and
–
a drug is analogous to a key for that lock), so only drugs with proper size, shape, and properties can bind to a receptor.
BiBlioGraPhy
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Myers, D. G. (2004). Psychology (7th ed.). New York, NY: Worth Publishers.
Tortora, G. J., & Grabowski, S. R. (2003). Principles of anatomy and physiology (10th ed.).
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