Neurotransmitters and CNS Functions

Introductory Neuropharmacology

• This presentation covers introductory neuropharmacology
• The presenter is Robert Peter Biney, PhD, from the School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Ghana
• The CNS is the most complex system
• Drug effects are difficult to understand
• There's a complex relationship between individual cellular behavior and whole-organ behavior

Learning Objectives

• Describe specific events at the neuronal synapse, relating to synthesis, storage, and release of neurotransmitters
• Identify major neurotransmitter types and receptors
• Explain the importance of specific neurotransmitters in health and disease.
• Describe how neurochemical imbalances may lead to neurological disorders.

Neuropharmacology

• Drugs affect behavior by influencing cellular function and neural mechanisms in the nervous system
• CNS drugs cross the blood-brain barrier (BBB) to affect brain function
• CNS drugs can selectively modify CNS function, and may stimulate or depress the CNS
• Drugs can alter mood, perception, consciousness, and behavior

Goals of Neuropharmacology

• Develop drugs to correct pathophysiological changes in the abnormal CNS
• Develop/use drugs as probe compounds to elucidate and manipulate the normal CNS

Neuropharmacology – Issues and Challenges

• The CNS is a very complex system
• Understanding drug effects is difficult
• The observed relationship between individual cellular behavior and whole-organ behavior is not direct.
• CNS-active drugs may act at multiple sites with disparate and opposing effects
• Many CNS disorders involve multiple brain regions and pathways, making a single therapeutic agent difficult

Classification of CNS Drugs – WHO ATC 1976

• An indication-based classification of CNS drugs that is primarily neurologically focused.
• Subdivided by indication, like analgesics (pain), anesthetics (surgery), etc.
• Detailed structure of the classification with specific types and categories of drugs, for example, antidepressants (N06A) to Anti-dementia drugs (N06D) are given.

Classification of CNS Drugs

• A table showing classes (e.g., general anesthetic agents), definitions (what the drugs do), and examples (specific types of drugs)
• Includes specific examples like opiates, benzodiazepines, and anti-depressants

Neurochemical Messengers

• Neurotransmitters: Cause changes in postsynaptic cells (excitation via depolarization or inhibition via hyperpolarization). Examples include acetylcholine.
• Neuromodulators: Affect a large population of neurons through slow synaptic actions. They can enhance or inhibit the effects of classical neurotransmitters. Example: Histamine.
• Neurohormones: Neuroendocrine cells release hormones into the bloodstream, acting at distant sites. Example: Oxytocin
• Neurotrophic factors: Assist neurons in repair, derived from neurons, astrocytes, microglia, or immune cells. Brain-derived neurotrophic factor is an example.

Neurotransmitters

• Endogenous chemicals in the brain that enable signaling across synapses
• Carry and modulate signals between neurons or other cell types
• Act on various targets to produce biological functions
• Cause electrical changes in postsynaptic cells, which can be excitation via depolarization or inhibition via hyperpolarization

History

• Otto Loewi and the discovery of chemical signaling in the nervous system (vagus stuff)
• Nobel Prize for this work in 1936, along with Henry Dale.

Neurotransmitters (Conventional vs. unconventional)

• Conventional: Stored in vesicles, released upon calcium influx, acting by binding to receptors on the postsynaptic cell membrane.
• Unconventional: Not stored in vesicles, can carry messages from postsynaptic to presynaptic neuron (retrograde), crossing the cell membrane to directly act inside the cell. Examples include endocannabinoids and nitric oxide.

Identification as a neurotransmitter

• Location within the presynaptic terminal of the neuronal pathway of interest.
• Release (in response to neuronal activity) must be calcium-dependent.
• Synaptic mimicry: The chemical should produce a response that mimics the transmitter released during nerve stimulation; this response should be blocked by a selective antagonist.
• Exceptions such as nitric oxide; not stored, synthesized on need, and diffuses across the membrane.

Synthesis and Storage

• Two main categories of neurotransmitters:
• Small molecule transmitters: Synthesized and stored in the terminal–fast release
• Neuropeptides: Synthesized in the cell body transported to the terminal-slower release.
• A neuron typically synthesizes and releases only one type of small molecule, while releasing multiple neuropeptides

Release

• Translocation/mobilization: Calcium influx phosphorylates synapsin, promoting translocation.
• Fusion and release: SNARE proteins guide and promote fusion with the cell membrane. Synaptobrevin, SNAP-25, Syntaxin, and Synaptotagmin.
• Target for neurotoxins.

Neurotransmitter Actions

• Ionotropic receptors: Ligand-gated channels
• Metabotropic receptors: G-protein coupled receptors (GPCRs)

Neurotransmitter Clearance

• Necessary for appropriate neural signalling, achieved through:
• Neuronal transport
• Degradation by enzymes

Learning Objectives (revisited)

• Appreciate how neurochemical imbalance leads to neurological disorders

Small Molecule Neurotransmitters

• Two classes: Amino Acids (e.g., glutamate, GABA, glycine, acetylcholine.)
• Biogenic Amines (e.g., dopamine, noradrenaline, serotonin, histamine)

Glutamate

• Primary excitatory neurotransmitter in the CNS
• Excitatory synaptic transmission is mediated by glutamate binding to ionotropic receptors.

Glutamate

• Acts on 3 ionotropic receptors subtypes (AMPA, Kainate, NMDA).
• Also acts on 8 metabotropic receptor subtypes.
• Effects may be excitatory or inhibitory.

AMPA and NMDA Receptors

• Synaptic plasticity
• Excitotoxicity

Glutamate (metabotropic receptors)

• 8 metabotropic receptors (mGlu1-8)
• Regulate cell excitability and synaptic transmission
• Group I—typically located postsynaptically, is largely excitatory
• Group II and III—typically located presynaptically, tend to reduce synaptic transmission and neuronal excitability

GABA

• Primary inhibitory neurotransmitter in the CNS
• Release from local interneurons
• Ubiquitous

GABA Receptor

• Ionotropic receptors (GABAA) : Gates Cl–, fast IPSP, and are blocked by picrotoxin and bicuculline, these are convulsants
• Metabotropic receptors
• Localized to perisynaptic regions
• Inhibits Ca2+ channels
• Also inhibits adenylyl cyclase
• Selectively inhibited by baclofen and is a spasmolytic

Acetylcholine

• First compound identified pharmacologically as a transmitter in the CNS
• Primary role in autonomic nervous system
• Important neurotransmitter at neuromuscular junction
• Important in memory
• Degeneration of cholinergic pathways is a hallmark of Alzheimer's disease
• Acts on two receptor subtypes: Nicotinic (ionotropic), and Muscarinic (metabotropic)

Dopamine

• Generally exerts a slow inhibitory action
• Four main dopaminergic pathways: Nigrostriatal, Mesolimbic, Mesocortical, and Tuberoinfundibular.
• Acts on 5 receptor subtypes (all metabotropic)

Serotonin

• 5-HT is involved in neurological responses, including behavioral responses, feeding behavior, mood, sleep, and vomiting
• Antidepressants (SSRIs, triptans) affect serotonin transmission

Noradrenaline

• Noradrenaline transmission is critical to the arousal system and control of mood
• Involved in functional deficiency contributing to depression
• Key psychotropic and antihypertensive drugs

Cannabinoids

• Endocannabinoids act as retrograde synaptic messengers
• Synthesized and secreted in response to intracellular Ca²⁺ increase
• Two receptor types (CB₁ and CB₂), linked to G-protein and inhibition of adenylate cyclase activity
• CB₁ primarily in CNS; CB₂ primarily in periphery
• Therapeutic potential for vomiting, pain, muscle spasms, and multiple sclerosis.

One minute papers

• Several different one minute papers appear to be presented covering various topics within neuropharmacology.

Note that some slides are visually engaging, but lack direct, substantive information; this summary is highly condensed and assumes essential details and relationships are easily understood from the illustrations and organization.