Pharmacology 4th semester

1. PHARMACOLOGY OF PERIPHERAL NERVOUS SYSTEM
SATYAJIT GHOSH
B. PHARM 4TH
SEMESTER

2. Autonomic Nervous System: General Consideration
 Organisation and Function OF ANS:
The ANS consists following nerve fibre: -
 Sensory Information: Afferent Fibers and Reflex Arcs: -
i. Afferent fibers from visceral structures are the first link in the reflex arcs of the autonomic system. With certain exceptions, such as local axon reflexes,
most visceral reflexes are mediated through the CNS.
ii. Visceral Afferent Fibers:
 Information on the status of the visceral organs is transmitted to the CNS through two main sensory systems:
a- the cranial nerve (parasympathetic) visceral sensory system
b- the spinal (sympathetic) visceral afferent system.
 The cranial visceral sensory system carries mainly mechanoreceptor and chemosensory information, whereas the afferents of the spinal visceral
system principally convey sensations related to temperature and tissue injury of mechanical, chemical, or thermal origin.
 Cranial visceral sensory information enters the CNS by four cranial nerves: the trigeminal (V), facial (VII), glossopharyngeal (IX), and vagus(X)
nerves.
 These four cranial nerves transmit visceral sensory information from the internal face and head (V); tongue (taste, VII); hard palate and upper
part of the oropharynx (IX); and carotid body, lower part of the oropharynx, larynx, trachea, esophagus, and thoracic and abdominal organs (X),
with the exception of the pelvic viscera. The visceral afferents from these four cranial nerves terminate topographically in the STN.

3.  Sensory afferents from visceral organs also enter the CNS from the spinal nerves. Those concerned with muscle chemo sensation may arise at all
spinal levels, whereas sympathetic visceral sensory afferents generally arise at the thoracic levels where sympathetic preganglionic neurons are
found.
 In general, visceral afferents that enter the spinal nerves convey information concerned with temperature as well as nociceptive visceral inputs
related to mechanical, chemical, and thermal stimulation.
 Substance P and CGRP, present in afferent sensory fibers, dorsal root ganglia, and the dorsal horn of the spinal cord, communicate nociceptive
stimuli from the periphery to the spinal cord and higher structures.
 Central autonomic connections:
i. There are no purely autonomic or somatic centres of integration, and extensive overlap occurs. Somatic responses always are accompanied by visceral
responses and vice versa.
ii. Autonomic reflexes can be elicited at the level of the spinal cord. The hypothalamus and the solitary tract nucleus (STN) generally are regarded as
principal loci of integration of autonomic nervous system functions, which include regulation of body temperature, water balance, carbohydrate and fat
metabolism, blood pressure, emotions, sleep, respiration, and reproduction. Signals are received through ascending spinobulbar pathways, the limbic
system, neostriatum, cortex, and toa lesser extent other higher brain centers.
iii. Stimulation of the STN and the hypothalamus activates bulbospinal pathways and hormonal output to mediate autonomic and motor responses. The
hypothalamic nuclei that lie posteriorly and laterally are sympathetic in their main connections, whereas parasympathetic functions evidently are
integrated by the midline nuclei in the region of the tuber cinereum and by nuclei lying anteriorly.

4.  Autonomic efferent:
i. The output part of ANS has two divisions: the sympathetic division and the parasympathetic division. Most organ have dual innervation, i.e., they
receive impulses from both sympathetic and parasympathetic division and the two divisions are functionally antagonistic.
ii. The level of activity of innervated organ at a given moment is the algebraic sum of sympathetic and parasympathetic tone.
iii. The sympathetic division is also known as fight – flight division. Sympathetic activity results in increased alertness and metabolic activities in order to
prepare the body for an emergency situation.
iv. The parasympathetic division is also known as rest – and – digest division because its activities conserve and restore body energy during time of rest or
digesting a meal.
v. Each division of ANS has two motor neurons
1- Preganglionic Neuron: It is the first motor neuron in any autonomic motor pathway. Its cell body is present in the brain or spinal cord; its axon
exits the CNS as part of cranial or spinal nerve. The preganglionic neuron is a myelinated type B fibre extend to the autonomic ganglion, where it
synapses with a post ganglionic neuron.
2- Postganglionic neuron: It is the second neuron of the autonomic motor pathway. Its cell body and dendrites are located in an autonomic ganglion,
where it forms synapses with one or more presynaptic ganglion. The axon of post synaptic neuron is an unmyelinated type C fibre. that terminate
in the visceral effector.
 Divisions of the Peripheral Autonomic System: -
 On the efferent side, the autonomic nervous system consists of two large divisions:
a- the sympathetic or thoracolumbar outflow

5. b- the parasympathetic or craniosacral outflow.
 The neurotransmitter of all preganglionic autonomic fibers, most postganglionic parasympathetic fibers, and a few postganglionic sympathetic fibers is
ACh. Some postganglionic parasympathetic nerves use NO as a neurotransmitter and are termed nitrergic.
 The majority of the postganglionic sympathetic fibers are adrenergic, in which the transmitter is NE. The terms cholinergic and adrenergic describe
neurons that liberate ACh or NE, respectively.
 Sympathetic Nervous System: -
i. The cells that give rise to the preganglionic fibers of the sympathetic nervous system division lie mainly in the intermediolateral columns of the
spinal cord and extend from the first thoracic to the second or third lumbar segment.
ii. The axons from these cells are carried in the anterior (ventral) nerve roots and synapse, with neurons lying in sympathetic ganglia outside the
cerebrospinal axis.
iii. Sympathetic ganglia are found in three locations: paravertebral, prevertebral, and terminal. The 22 pairs of paravertebral sympathetic ganglia form
the lateral chains on either side of the vertebral column.
iv. The ganglia are connected to each other by nerve trunks and to the spinal nerves by rami communicantes. The white rami carry the preganglionic
myelinated fibers that exit the spinal cord by the anterior spinal roots. The gray rami arise from the ganglia and carry postganglionic fibers back to
the spinal nerves for distribution to sweat glands and pilomotor muscles and to blood vessels of skeletal muscle and skin.
v. The prevertebral ganglia lie in the abdomen and the pelvis near the ventral surface of the bony vertebral column and consist mainly of the celiac
(solar), superior mesenteric, aorticorenal, and inferior mesenteric ganglia.
vi. The terminal ganglia are few in number, lie near the organs they innervate, and include ganglia connected with the urinary bladder, rectum and the
cervical ganglia in the region of the neck.

6. vii. Preganglionic fibers issuing from the spinal cord may synapse with the neurons of more than one sympathetic ganglion. Many of the preganglionic
fibers from the fifth to the last thoracic segment pass through the paravertebral ganglia to form the splanchnic nerves. Most of the splanchnic nerve
fibers do not synapse until they reach the celiac ganglion; others directly innervate the adrenal medulla.
viii. Postganglionic fibers arising from sympathetic ganglia innervate visceral structures of the thorax, abdomen, head, and neck. The trunk and the limbs
are supplied by the sympathetic fibers in spinal nerves.
ix. The prevertebral ganglia contain cell bodies whose axons innervate the glands and smooth muscles of the abdominal and the pelvic viscera.
x. Many of the upper thoracic sympathetic fibers from the vertebral ganglia form terminal plexuses, such as the cardiac, oesophageal, and pulmonary
plexuses. The sympathetic distribution to the head and the neck (vasomotor, pupillodilator, secretory, and pilomotor) is by means of the cervical
sympathetic chain and its three ganglia.
xi. All postganglionic fibers in this chain arise from cell bodies located in these three ganglia.
 Parasympathetic Nervous System: -
i. The parasympathetic nervous system consists of preganglionic fibers that originate in the CNS and their postganglionic connections. The regions of
central origin are the midbrain, the medulla oblongata, and the sacral part of the spinal cord.
ii. The midbrain, or tectal, outflow consists of fibers arising from the Edinger-Westphal nucleus of the third cranial nerve and going to the ciliary
ganglion in the orbit.
iii. The medullary outflow consists of the parasympathetic components of the VII, IX, and X cranial nerves. The fibers in the VII (facial) cranial nerve
form the chorda tympani, which innervates the ganglia lying on the submaxillary and sublingual glands. They also form the greater superficial
petrosal nerve, which innervates the sphenopalatine ganglion.

7. iv. The autonomic components of the IX (glossopharyngeal) cranial nerve innervate the otic ganglia. Postganglionic parasympathetic fibers from these
ganglia supply the sphincter of the iris (pupillary constrictor muscle), the ciliary muscle, the salivary and lacrimal glands, and the mucous glands of
the nose, mouth, and pharynx. These fibers also include vasodilator nerves to these same organs.
v. Cranial nerve X (vagus) arises in the medulla and contains preganglionic fibers, most of which do not synapse until they reach the many small
ganglia lying directly on or in the viscera of the thorax and abdomen. In the intestinal wall, the vagal fibers terminate around ganglion cells in the
myenteric and submucosal plexuses.
vi. Thus, in the parasympathetic branch of the autonomic nervous system, preganglionic fibers are very long, whereas postganglionic fibers are very
short.
vii. The parasympathetic sacral outflow consists of axons that arise from cells in the second, third, and fourth segments of the sacral cord and proceed as
preganglionic fibers to form the pelvic nerves (nervi erigentes). They synapse in terminal ganglia lying near or within the bladder, rectum, and
sexual organs. The vagal and sacral outflows provide motor and secretory fibers to thoracic, abdominal, and pelvic organs.
 Enteric Nervous System: -
i. The processes of mixing, propulsion, and absorption of nutrients in the GI tract are controlled locally through a restricted part of the peripheral
nervous system called the ENS.
ii. The ENS comprises components of the sympathetic and parasympathetic nervous systems and has sensory nerve connections through the spinal and
nodose ganglia.
iii. The ENS is involved in sensorimotor control and thus consists of both afferent sensory neurons and a number of motor nerves and interneurons that
are organized principally into two nerve plexuses: the myenteric (Auerbach) plexus and the submucosal (Meissner) plexus.
iv. The myenteric plexus, located between the longitudinal and circular muscle layers, plays an important role in the contraction and relaxation of GI
smooth muscle.

8. v. The submucosal plexus is involved with secretory and absorptive functions of the GI epithelium, local blood flow, and neuroimmune activities.
vi. Parasympathetic preganglionic inputs are provided to the GI tract via the vagus and pelvic nerves. ACh released from preganglionic neurons
activates nAChRs on postganglionic neurons within the enteric ganglia.
vii. Excitatory preganglionic input activates both excitatory and inhibitory motor neurons that control processes such as muscle contraction and
secretion/absorption.
viii. Postganglionic sympathetic nerves also synapse with intrinsic neurons and generally induce relaxation. Sympathetic input is excitatory (contractile)
at some sphincters. Information from afferent and preganglionic neural inputs to the enteric ganglia is integrated and distributed by a network of
interneurons.

11. Comparison of the Somatic and Autonomic Nervous System
Somatic Nervous System Autonomic Nervous System
Sensory input From somatic senses and special senses Mainly from interoceptors; some from somatic senses and special senses.
Control of motor
output
Voluntary control from cerebral cortex, with
contributions from basal ganglia, cerebellum,
brain stem, and spinal cord.
Involuntary control from hypothalamus, limbic system, brain stem, and spinal cord;
limited control from cerebral cortex.
Motor neuron
pathway
One-neuron pathway: Somatic motor neurons
extending from CNS synapse directly with
effector.
Usually two-neuron pathway: Preganglionic neurons extending from CNS, synapse with
postganglionic neurons in autonomic ganglion, and postganglionic neurons extending
from ganglion synapse with visceral effector. Alternatively, preganglionic neurons may
extend from CNS to synapse with chromaffin cells of adrenal medullae.
Neurotransmitters
and hormones
All somatic motor neurons release only
acetylcholine (ACh).
All sympathetic and parasympathetic preganglionic neurons release ACh. Most
sympathetic postganglionic neurons release NE; those to most sweat glands release
ACh. All parasympathetic postganglionic neurons release ACh. Chromaffin cells of
adrenal medullae release epinephrine and norepinephrine.
Effectors Skeletal muscle Smooth muscle, cardiac muscle, and glands.
Responses.
Contraction of skeletal muscle Contraction or relaxation of smooth muscle; increased or decreased rate and force of
contraction of cardiac muscle; increased or decreased secretions of glands.

12. Comparison of Sympathetic and Parasympathetic Division
Sympathetic (Thoracolumbar) Parasympathetic (Craniosacral)
Distribution
Wide regions of body: skin, sweat glands, arrector pili
muscles of hair follicles, adipose tissue, smooth muscle of
blood vessels.
Limited mainly to head and to viscera of thorax, abdomen, and
pelvis; some blood vessels.
Location of preganglionic neuron
cell bodies and site of outflow
Lateral gray horns of spinal cord segments T1–L2. Axons of
preganglionic neurons constitute
thoracolumbar outflow.
Nuclei of cranial nerves III, VII, IX, and X and lateral gray
matter
of spinal cord segments S2–S4. Axons of preganglionic neurons
constitute craniosacral outflow.
Associated ganglia Sympathetic trunk ganglia and prevertebral ganglia Terminal ganglia
Ganglia locations Close to CNS and distant from visceral effectors Typically, near or within wall of visceral effectors.
Axon length and
divergence
Preganglionic neurons with short axons synapse with many
postganglionic neurons with long axons that pass to many
visceral effectors.
Preganglionic neurons with long axons usually synapse with
four
to five postganglionic neurons with short axons that pass to
single visceral effector.
White and gray rami
communicantes
Both present; white rami communicantes contain
myelinated preganglionic axons; gray rami communicantes
contain unmyelinated postganglionic axons.
Neither present
Neurotransmitters
Preganglionic neurons release acetylcholine (ACh), which is
excitatory and stimulates postganglionic neurons; most
postganglionic neurons release norepinephrine (NE);
postganglionic neurons that innervate most sweat glands
and some blood vessels in skeletal muscle release ACh.
Preganglionic neurons release ACh, which is excitatory and
stimulates postganglionic neurons; postganglionic neurons
release ACh.
Physiological effects Fight-or-flight responses Rest-and-digest activities

13. EFFECT OF SYMPATHETIC AND PARASYMPATHETIC DIVISION OF ANS
Visceral Effector
Effect of Sympathetic stimulation
(α, β – Adrenergic Receptor)
Effect of Parasympathetic Stimulation
(Muscarinic ACh receptor)
GLANDS
Adrenal medullae Secretion of epinephrine and norepinephrine
(nicotinic ACh receptors).
No Innervation
Lacrimal (tear) Slight secretion of tears (α). Secretion of tear
Pancreas Inhibits secretion of digestive enzymes and the hormone insulin (α2)
Promotes secretion of the hormone glucagon (β2)
Secretion of digestive enzymes and the hormone insulin.
Posterior pituitary Secretion of ADH (β1) No innervation.
Pineal Increases synthesis and release of melatonin (β) No innervation.
Sweat Increases sweating in most body regions
(muscarinic ACh receptors)
Sweating on palms and soles (α1)
No innervation
Adipose tissue Lipolysis (β1)
Release of fatty acids into blood (β1 and β3)
No innervation
Liver Glycogenolysis
Gluconeogenesis
Decreased bile secretion (α and β2)
Glycogen synthesis
Increased bile secretion
Kidney,
Juxtaglomerular
Cell
Secretion of renin (β1) No innervation
HEART
Cardiac Muscle Increased Ionotropic Action
Increased Chronotropic Action
Increased Dromotropic Action
Increased Heart Rate, C.O, B.P (β1)
Decreased Ionotropic Action
Decreased Chronotropic Action
Decreased Dromotropic Action
Decreased Heart Rate, C.O, B.P (M2)
SMOOTH
MUSCLE
Iris, radial muscle Contraction → dilation of pupil (α1) No innervation
Iris, circular
muscle
No innervation Contraction → constriction of pupil
Ciliary muscle of
eye
Relaxation to adjust shape of lens for
distant vision (β2).
Contraction for close vision
Lungs, bronchial
muscle
Relaxation → airway dilation (β2),
Decreases bronchial mucus secretion
Contraction → airway constriction,
Increases bronchial mucus secretion

14. Gallbladder and
ducts
Relaxation to facilitate storage of bile in
the gallbladder (β2).
Contraction → release of bile into small intestine
Stomach and
intestine
Decreased motility and tone (α1, α2, β2),
Contraction of sphincters (α1)
Decreased Peristalsis
Increased motility and tone
Relaxation of sphincters
Increased Peristalsis
Spleen Contraction and discharge of stored blood
into general circulation (α1).
No innervation
Ureter Increases motility (α1). Increases motility (?).
Urinary bladder Relaxation of muscular wall (β2)
Contraction of internal urethral sphincter (α1).
Contraction of muscular wall
Relaxation of internal urethral sphincter
Uterus Inhibits contraction in nonpregnant women (β2);
Promotes contraction in pregnant women (α1).
Minimal effect
Sex organs In males: contraction of smooth muscle of vas deferens, prostate, and
seminal vesicle resulting in ejaculation (α1).
Vasodilation; erection of clitoris (females) and penis
(males).
Hair follicles,
arrector pili
muscle
Contraction → erection of hairs resulting in
goose bumps (α1)
No innervation
VASCULAR
SMOOTH
MUSCLE
Salivary gland
arterioles
Vasoconstriction, which decreases secretion of saliva (α1) Vasodilation → Increases secretion of saliva
Gastric gland
arterioles
Vasoconstriction, which inhibits secretion (α1) Secretion of Gastric juice
Intestinal gland
arterioles
Vasoconstriction, which inhibits secretion (α1) Secretion of Intestinal juice
Coronary (heart)
arterioles
Relaxation → vasodilation (β2)
contraction → vasoconstriction (α1, α2)
contraction → vasoconstriction (muscarinic Ach receptors)
Contraction → Vasoconstriction
Skin and mucosal
arterioles
Contraction → vasoconstriction (α1) Vasodilation
Skeletal muscle
arterioles
Contraction → vasoconstriction (α1)
relaxation → vasodilation (β2)
relaxation → vasodilation (muscarinic ACh receptors)
No Innervation
Abdominal viscera
arterioles
Contraction → vasoconstriction (α1, β2) No Innervation
Brain arterioles Slight contraction → vasoconstriction (α1) No Innervation
Kidney arterioles Constriction of blood vessels → decreased
urine volume (α1)
No Innervation
Systemic veins Contraction → Constriction (α1)
Relaxation → Dilation (β2)
No Innervation

15.  Neurohumoral Transmission: -
I. Neurohumoral transmission refers to the transmission of impulse through synapse and neuro – effector junction by release of humoral or chemical
substance.
II. Neurohumoral transmitter a substance must fulfil the following criteria:
1. It should be present in the presynaptic neurone (usually along with enzymes synthesizing it).
2. It should be released in the medium following nerve stimulation.
3. Its application should produce responses identical to those produced by nerve stimulation.
4. Its effects should be antagonized or potentiated by other substances which similarly alter effects of nerve stimulation.
 Steps in Neurohumoral Transmission: -
 Axonal Conduction: -
1. Conduction refers to the passage of an electrical impulse along an axon or muscle fiber. At rest, the interior of axon is about 70 mV negative to
the exterior.
2. In response to depolarization to a threshold level, an action potential is initiated at a local region of the membrane. The action potential consists
of two phases.
a- The initial phase is caused by a rapid increase in the permeability and inward movement of Na+
through voltage-sensitive Na+
channels, and a
rapid depolarization from the resting potential continues to a positive overshoot.
b- The second phase results from the rapid inactivation of the Na+
channel and the delayed opening of a K+
channel, which permits outward
movement of K+
to terminate the depolarization.
3. The transmembrane ionic currents produce local circuit currents such that adjacent resting channels in the axon are activated, and excitation of
an adjacent portion of the axonal membrane occurs, leading to propagation of the action potential without decrement along the axon.

16. 4. The region that has undergone depolarization remains momentarily in a refractory state. With the exception of the local anaesthetics, few drugs
modify axonal conduction in the doses employed therapeutically.
5. The puffer fish poison, tetrodotoxin, and a close congener found in some shellfish, saxitoxin, selectively block axonal conduction by blocking the
voltage-sensitive Na+
channel and preventing the increase in Na+
permeability associated with the rising phase of the action potential.
6. In contrast, batrachotoxin, an extremely potent steroidal alkaloid secreted by a South American frog, produces paralysis through a selective
increase in permeability of the Na+
channel, which induces a persistent depolarization.
7. Scorpion toxins are peptides that also cause persistent depolarization by inhibiting the inactivation process.
 Junctional Transmission: -
The term transmission refers to the passage of an impulse across a synaptic or neuroeffector junction. The arrival of the action potential at the axonal
terminals initiates a series of events that trigger transmission of an excitatory or inhibitory biochemical message across the synapse or neuroeffector
junction.
These events are the following:
1. Storage and release of transmitter: -
 The nonpeptide (small-molecule) neurotransmitters, such as biogenic amines, are largely synthesized in the region of the axonal terminals
and stored there in synaptic vesicles.
 Neurotransmitter transport into storage vesicles is driven by an electrochemical gradient generated by the vesicular proton pump (vesicular
ATPase).
 Synaptic vesicles cluster in discrete areas underlying the presynaptic plasma membrane, termed active zones. Proteins in the vesicular
membrane (e.g., synapsin, synaptophysin, synaptogyrin) are involved in development and trafficking of the storage vesicle to the active zone.

17.  The processes of priming, docking, fusion, and exocytosis involve the interactions of proteins in the vesicles and plasma membranes and the
rapid entry of extracellular Ca2+
and its binding to synaptotagmins.
Life Cycle of a Storage Vesicle, Molecular Mechanism of Exocytosis: -
 Fusion of the storage vesicle and plasma membrane involves formation of a multiprotein complex that includes proteins in the membrane of
the synaptic vesicle, proteins embedded in the inner surface of the plasma membrane, and several cytosolic components.
 These proteins are referred to as SNARE proteins. Through the assembly of these proteins, vesicles draw near the membrane (priming,
docking), spatially prepared for the next step, which the entry of Ca2+
initiates.
 When Ca2+
enters with the action potential, fusion and exocytosis occur rapidly. After fusion, the chaperone ATPase N-ethylmaleamide
sensitive factor (NSF) and its soluble NSF attachment protein, synaptosome-associated Protein (SNAP) adapters catalyse dissociation of the
SNARE complex.

18.  During the resting state, there is continual slow release of isolated quanta of the transmitter; this produces electrical responses (miniature
end-plate potentials or mepps) at the postjunctional membrane that are associated with the maintenance of the physiological responsiveness
of the effector organ.
 The action potential causes the synchronous release of several hundred quanta of neurotransmitter. In the exocytosis process, the contents of
the vesicles, including enzymes and other proteins, are discharged to the synaptic space.
 Synaptic vesicles may either fully exocytose with complete fusion or form a transient, nanometer-size pore that closes after transmitter has
escaped, “kiss-and-run” exocytosis.
 In full-fusion exocytosis, the pit formed by the vesicle’s fusing with the plasma membrane is clathrin-coated and retrieved from the
membrane via endocytosis and transported to an endosome for full recycling.
 During kiss-and-run exocytosis, the pore closes, and the vesicle is immediately and locally recycled for reuse in neurotransmitter
repackaging.
Modulation of Transmitter Release: -
 A number of autocrine and paracrine factors may influence the exocytotic process, including the released neurotransmitter itself.
 Adenosine, DA, glutamate, GABA, prostaglandins, and enkephalins influence neurally mediated release of neurotransmitters. Receptors for
these factors exist in the membranes of the soma, dendrites, and axons of neurons:
A- Soma-dendritic receptors, when activated, primarily modify functions of the soma-dendritic region, such as protein synthesis and
generation of action potentials.
B- Presynaptic receptors, when activated, modify functions of the terminal region, such as synthesis and release of transmitters. Two main
classes of presynaptic receptors have been identified on most neurons:

19. a- Heteroreceptors are presynaptic receptors that respond to neurotransmitters, neuromodulators, or neurohormones released from
adjacent neurons or cells.
For example, NE can influence the release of ACh from parasympathetic neurons by acting on α2A, α2B, and α2C receptors, whereas
ACh can influence the release of NE from sympathetic neurons by acting on M2 and M4 receptors.
b- Autoreceptors are receptors located on axon terminals of a neuron through which the neuron’s own transmitter can modify
transmitter synthesis and release.
For example, NE released from sympathetic neurons may interact with α2A and α2C receptors to inhibit neurally released NE.
Similarly, ACh released from parasympathetic neurons may interact with M2 and M4 receptors to inhibit neurally released ACh.
2. Interaction of the transmitter with postjunctional receptors and production of the postjunctional potential: -
 The transmitter diffuses across the synaptic cleft and combines with specialized receptors on the postjunctional membrane; results in a
localized increase in the ionic permeability, or conductance, of the membrane.
 With certain exceptions, one of three types of permeability change can occur:
 Generalized increase in the permeability to cations (notably Na+
but occasionally Ca2+
), resulting in a localized depolarization of the
membrane, that is, an EPSP.
 Selective increase in permeability to anions, usually Cl–
, resulting in stabilization or actual hyperpolarization of the membrane, which
constitutes an IPSP.
 Increased permeability to K+
. Because the K+
gradient is directed out of the cell, hyperpolarization and stabilization of the membrane
potential occur (an IPSP).

20.  Electric potential changes associated with the EPSP and IPSP at most sites are the results of passive fluxes of ions down their concentration
gradients. The changes in channel permeability that cause these potential changes are specifically regulated by the specialized postjunctional
receptors for the neurotransmitter that initiates the response.
 These receptors may be clustered on the effector cell surface, as seen at the NMJs of skeletal muscle and other discrete synapses, or
distributed more uniformly, as observed in smooth muscle. These high-conductance, ligand-gated ion channels usually permit passage of Na+
or Cl–
; K+
and Ca2+
are involved less frequently.
 In the presence of an appropriate neurotransmitter, the channel opens rapidly to a high-conductance state, remains open for about a
millisecond, and then closes. A short square-wave pulse of current is observed as a result of the channel’s opening and closing. The
summation of these events gives rise to the EPSP.
 The ligand-gated channels belong to a superfamily of ionotropic receptor proteins that includes the nicotinic, glutamate, and certain 5HT3
and purine receptors, which conduct primarily Na+
, cause depolarization, and are excitatory; and GABA acid and glycine receptors, which
conduct Cl–
, cause hyperpolarization, and are inhibitory.
 Neurotransmitters also can modulate the permeability of K+
and Ca2+
channels indirectly. In these cases, the receptor and channel are
separate proteins, and information is conveyed between them by G proteins.
3. Initiation of postjunctional activity: -
 If an EPSP exceeds a certain threshold value, it initiates a propagated action potential in a postsynaptic neuron or a muscle action potential in
skeletal or cardiac muscle by activating voltage-sensitive channels in the immediate vicinity.
 In certain smooth muscle types in which propagated impulses are minimal, an EPSP may increase the rate of spontaneous depolarization,
cause Ca2+
release, and enhance muscle tone; in gland cells, the EPSP initiates secretion through Ca2+
mobilization.
 An IPSP, which is found in neurons and smooth muscle but not in skeletal muscle, will oppose excitatory potentials.

21. 4. Destruction or dissipation of the transmitter: -
 When impulses can be transmitted across junctions at frequencies up to several hundred per second, there must be an efficient means of
disposing of the transmitter following each impulse.
 At cholinergic synapses involved in rapid neurotransmission, high and localized concentrations of AChE are available for this purpose. When
AChE activity is inhibited, removal of the transmitter is accomplished principally by diffusion. Under these circumstances, the effects of
released ACh are potentiated and prolonged.
 Rapid termination of NE occurs by a combination of simple diffusion and reuptake by the axonal terminals of most of the released NE.
Termination of the action of amino acid transmitters results from their active transport into neurons and surrounding glia. Peptide
neurotransmitters are hydrolysed by various peptidases and dissipated by diffusion.
 Cotransmission:
i. Cotransmission is defined as control of a single target cell by two or more substances released from one neuron in response to the same neuronal event.
ii. In the ANS besides the primary transmitters like ACh and NA, neurones also release purines (ATP, adenosine), peptides (vasoactive intestinal peptide
(VIP), neuropeptide-Y (NPY), substance P, enkephalins, somatostatin, etc.), nitric oxide and prostaglandins as cotransmitters.
iii. In most autonomic cholinergic neurons’ VIP is associated with ACh, while ATP is associated with both ACh and NA. The transmitter at some
parasympathetic sites is N0. and these are called nitrergic nerves.
iv. Vascular adrenergic nerves contain NPY which causes long lasting vasoconstriction.
v. The cotransmitter is stored in the same neurone but in distinct synaptic vesicles or locations. However, ATP is stored with NA in the same vesicle. On
being released by nerve impulse the cotransmitter may serve to regulate the presynaptic release of the primary transmitter and/or postsynaptic sensitivity
to it (neuromodulator role).

22. vi. The time-course of action of the primary transmitter and the cotransmitter is usually different. The cotransmitter VIP of parasympathetic neurones
produces a slow and long-lasting response, while another one (NO) has an intermediate time-course of action between VIP and ACh (fast acting).
Similarly, in sympathetic neurones, the cotransmitter PY is slower acting and ATP faster ac ting than NA.