Neurotransmission in the CNS

Overview of neurotransmission in the CNS

PHR411: Pharmacology & Clinical Pharmacy-IV

Dr. Murad Hossain

Associate Professor
Department of Pharmaceutical Sciences
School of Life Sciences
University of North South
Email: murad.hossain@northsouth.edu
Forebrain (Prosencephalon):-
The fore (front)-brain is the largest part of the brain. The most obvious structure of the
forebrain is the cerebrum.
The forebrain plays a central role in the processing of information related to complex
cognitive activities, sensory and associative functions and voluntary motor activities.
The forebrain separates into the:
- Diencephalon; thalamus,
hypothalamus, epithalamus, and
subthalamus.
- Telencephalon which develops
into the cerebrum. The cerebrum
consists of the cerebral cortex,
limbic system and the basal
ganglia.
 Subdivision Functions
Cerebral - The cerebral cortex is essential for memory, attention, awareness, Cerebral thought,
Cortex language and consciousness
- It is commonly described as comprising three parts, sensory, motor and association
areas, the Cortex is connected to thalamus & basalganglia
Basal Ganglia - The basal ganglia are associated with a variety of functions including control of
voluntary motor movements, procedural learning, routine behaviours or "habits as
bruxism, eye movements, cognition & emotion
- It is nota separate system but a collection of structures
Limbic - There are several important structures within the limbic system: amygdala, Limbic
hippocampus, thalamus,
System - The limbic system supports a variety of functions including, epinephrine flow, emotion,
behavior, motivation, long-term memory and olfaction
Thalamus - The thalamus has multiple functions, some of its functions are sensory processing
and regulation of consciousness, sleep and alertness
- The hypothalamus is located below the thalamus, just above the brainstem and is part
of the limbic system
- It synthesizes and secretes certain neurohormones, often called releasing
Hypothalamus Hypothalamus hormones or hypothalamic hormones
-The hypothalamus controls body temperature, hunger, important aspects of
parenting and attachment behaviours, thirst, fatigue, sleep and circadian rhythms
Midbrain (Mesencephalon):-
The midbrain is an area of the brain that is in the middle of two other regions:
the forebrain and the hindbrain.
It is located within the brainstem and between the two other developmental
regions of the brain. the forebrain and the hindbrain.
Function; the midbrain serves
important functions in motor
movement and in auditory
and visual processing.
Hindbrain (Rhombencephalon) :-
- It includes the medulla, pons and cerebellum.
❑ Cerebellum;
- The cerebellum (Latin for "little brain") is a region of the brain that plays an important role in motor
control.
- The cerebellum coordinates voluntary movements such as posture, balance, coordination, and
speech, resulting in smooth and balanced muscular activity.
- It is also important for learning motor behaviours.
❑ Pons;
- In Latin, the word pons literally means bridge. - It helps relay messages from the forebrain to the
cerebellum.
- Regulation of respiration (there are two centers in the pons that affect respiration).
- Regulation of sleep and it has a role in dreaming.
❑ Medulla Oblongata;
- It is located in the lower portion of the brainstem.
- It is very important in heart rate and blood pressure control.
- It's responsible for multiple autonomic (involuntary) in the body such as vomiting. sneezing and
coughing.
-The basic functioning of neurons in the CNS is similar to that of the autonomic nervous system (ANS).
For example, transmission of information involves the release of neurotransmitters that diffuse across
the synaptic space to bind to specific receptors on the postsynaptic neuron.
-The circuitry of the CNS is much more complex than that of the ANS, and the number of synapses in
the CNS is far greater - The CNS, unlike the peripheral ANS, contains powerful networks of inhibitory
neurons that are constantly active in modulating the rate of neuronal transmission. In addition, the CNS
communicates through the use of multiple neurotransmitters, whereas the ANS uses only two primary
neurotransmitters, acetylcholine and norepinephrine.
➢Synaptic Potentials; Synaptic potential refers to the difference in voltage
between the inside and outside of a postsynaptic neuron. It is comes in three
forms;
A) Excitatory Post-Synaptic Potentials (EPSPs):
- The EPSPs (depolarize) are generated by the following:
1) Stimulation of an excitatory neuron causes the release of excitatory
neurotransmitter molecules, such as glutamate or acetylcholine, which bind to
receptors on the postsynaptic cell membrane. This causes a transient
increase in the permeability of sodium (Na+) ions.
2) The influx of Na+ causes a weak depolarization, or EPSP, that moves the
postsynaptic potential toward its firing threshold.
3) Stimulation of excitatory neurons increases, more excitatory neurotransmitter
is released.
B) Inhibitory Postsynaptic Potentials (IPSPs);
- The IPSPs (hyperpolarize) are generated by the following:
1) Stimulation of inhibitory neurons releases inhibitory neurotransmitter molecules,
such as γ-aminobutyric acid (GABA) or glycine, which bind to receptors on the
postsynaptic cell membrane. This causes a transient increase in the permeability
of specific ions, such as potassium (K+) and chloride (Cl-).
2) The influx of Cl- and efflux of K+ cause a weak hyperpolarization, or IPSP, that
moves the postsynaptic potential away from its firing threshold.
C) Combined effects of the EPSP and IPSP;
- Most neurons in the CNS receive both EPSP and IPSP input.
- Several different types of neurotransmitters may act on the same neuron, but each
binds to its own specific receptor. The overall action is the summation of the
individual actions of the various neurotransmitters on the neuron.
Brain (Central) Neurotransmitters:-
A) Amino Acid
1) Gamma (γ)-Aminobutyric Acid (GABA)
- GABA is the major inhibitory neurotransmitters (NTs) in the CNS, including the spinal cord.
- GABA receptors are divided into two main types: GABAA and GABAB.
- Inhibitory postsynaptic potentials in many areas of the brain have a fast and slow component.
The fast component is mediated by GABAA receptors and the slow component by GABAB
receptors.
- GABAA receptors are ionotropic receptors (ligand gated ion channel) that are selectively
permeable to Cl-. These receptors are selectively inhibited by Picrotoxin which cause
generalized convulsions.
- GABAB receptors are metabotropic receptors (G protein coupled receptors), depending on
their cellular location, either inhibit Ca+2 channels or activate K+ channels. These receptors
are selectively inhibited by Baclofen (antispasmodic drug). Inhibitory postsynaptic potential is
due to a selective increase in K+ conductance.
Brain (Central) Neurotransmitters:-
A) Amino Acid
2) Glycine
- Both GABA and Glycine are inhibitory neurotransmitters, which are typically
released from local interneurons. Interneurons that release glycine are restricted to the
spinal cord and brainstem.
- Glycine receptors (GlyR) that are selectively permeable to Cl-. These receptors are
selectively blocked by Strychnine, which is a potent spinal cord convulsant and has
been used in some rat poisons.
3) Glutamate and Aspartate
- Glutamate and Aspartate are the major excitatory neurotransmitter in the brain.
- This excitation is caused by the activation of both ionotropic and metabotropic
receptors.
- The ionotropic receptors can be further divided into three subtypes based on the
action of selective agonists: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
(AMPA), kainic acid (KA) and N-methyl-D-aspartate (NMDA).
- The metabotropic glutamate receptors are G protein-coupled receptors.
 B) Acetylcholine
- Acetylcholine was the first compound to be
identified pharmacologically as a transmitter
in the CNS.
- Most CNS responses to acetylcholine are
mediated by a large family of G protein-
coupled receptors.
- At a few sites, acetylcholine causes slow
inhibition of the neuron by activating the M2
receptor.
- A far more widespread muscarinic action in
response to acetylcholine is a slow
excitation that in is mediated by M1
receptors.
- Cholinergic pathways appear to play an
important role in cognitive functions, Simplified diagram of the acetylcholine pathways in the
especially memory. brain. PPT/LD, pedunculopontine and laterodorsal tegmental
nuclei;
 C) Monoamine
- Monoamines include the catecholamines (dopamine and norepinephrine) and serotonin.
- Although these compounds are present in very small amounts in the CNS.
1) Dopamine
- The major pathways containing dopamine are 1)
substantia nigra to the neostriatum, 2) ventral
tegmental to limbic structures, particularly the limbic
cortex, 3) hypothalamus to pituitary gland.
- Dopamine generally exerts a slow inhibitory action
on CNS neurons (D2).
- Five dopamine receptors have been identified, and
they fall into two categories: D1-like: D1 & D5 (G.) and
D2-like, D2, D3 & D4 (Gi). All dopamine receptors are
metabotropic.
- Parkinson's disease; caused by a loss of
dopamine- (2) Mesolimbic & Mesocortical secreting
neurons in an area of the substantia nigra.
- Schizophrenia involves altered levels of dopamine
activity. Fig. Simplified diagram of the dopamine pathways in the brai. The pituitary
gland (P) is shown, innervated with dopaminergic fibres from the
hypothalamus. Ac, nucleus accumbens; SN, substantia nigra; VTA, ventral
 2) Norepinephrine (NE)
- Most noradrenergic neurons are located in the locus
coeruleus (LC) (is a nucleus in the pons involved with
physiological responses to stress and panic).
- AII noradrenergic receptor subtypes are
metabotropic and it has both inhibitory & excitatory
effects.
- Inhibitory Effects: Norepinephrine can hyperpolarize
neurons by increasing potassium conductance. This
effect is mediated by α2 receptors.
- Excitatory Effects. In many regions of the CNS,
norepinephrine actually enhances excitatory inputs
by both indirect and direct mechanisms:
- The indirect mechanism involves dis-inhibition:
that is, inhibitory local circuit neurons are inhibited.
- The direct mechanism involves blockade of
potassium conductance, this effect is mediated by
either α1 or ß receptors.
- Facilitation of excitatory noradrenergic synaptic
transmission play an important role in behavioral
processes e.g. attention and arousal.
 3) 5-Hydroxytryptamine (5-HT, Serotonin)
- Most serotonin pathways originate from
neurons in the raphe (midline regions
of the pons and upper brainstem).
- 5-HT acts on more than a dozen
receptor subtypes.
- All 5-HT receptors are metabotropic,
except for the 5-HT3 receptor.
- Excitatory Effects: The 5-HT3
receptor (ionotropic) exerts a rapid
excitatory action at a very limited
number of sites Basal Forebrain in
the CNS.
- Inhibitory Effects: In most
Hippocampus areas of the CNS, 5-
HT has a strong inhibitory action.
Median Raphe This action is
mediated by 5HT1A recèptors.
- Both excitatory and inhibitory actions can occur on the same neuron. - Other proposed regulatory
functions of 5-HT-containing neurons include sleep, temperature, appetite and neuroendocrine
control.
 D) Neuropeptide
- Neuropeptides are a peptides used by neurons to communicate with each other.
- Neuropeptides modulate neuronal communication by acting on cell surface receptors.
- Many neuropeptides are co-released with other small-molecule neurotransmitters.
- Generally, peptides act at metabotropic receptors. Neurotransmitters generally affect the excitability
of other neurons, by depolarising them or by hyperpolarising them.
- Neuropeptides include:
- Opioid peptides; e.g., Enkephalins, Endorphins and Dynorphins
- Non-opioid peptides; e.g., Neurotensin, Substance P, Somatostatin, Cholecystokinin, Vasoactive
intestinal polypeptide, Neuropeptide Y, and Thyrotropin-releasing hormone.
- For example; Substance P released from small sensory neurons in the spinal cord and brainstem and
causes a slow excitatory postsynaptic potential in target neurons. Glutamate, which is released with
substance P from these synapses, presumably plays an important role in transmitting pain stimuli.
Substance P is certainly involved in many other functions because it is found in many areas of the CNS
that are unrelated to pain pathways.
 E) Nitric Oxide
- The CNS contains a substantial amount of nitric oxide synthase (NOS) enzyme within certain classes of
neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA
receptors, which increases intracellular calcium, results in the generation of nitric oxide.
- Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its
role in synaptic transmission and synaptic plasticity remains controversial.

F) Endocannabinoids
- The endogenous cannabinoids are involved in a variety of physiological processes including appetite,
pain-sensation, mood and memory and in mediating the psychoactive effects of cannabis.
- Two primary endocannabinoid receptors have been identified: CB1 and CB2.