Neuroscience Chapter on Glial Cells and Neurons

Introduction to CNS Pharmacology and Basic Principles of Action of Drugs Affecting Neurotransmission

• Nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission.
• While some drugs have nonspecific effects on membranes, these usually still result in changes to synaptic transmission.
• A full understanding of drug effects on the CNS requires understanding brain organization from genes to circuits to behavior.

Organization of the CNS

• The CNS is composed of the brain and spinal cord.
• It integrates sensory information, generates motor output, and enables successful interactions with the environment.
• The human brain contains approximately 100 billion interconnected neurons supported by glial cells.
• Neurons are clustered into nuclei or organized in layered structures like the cerebellum or hippocampus.
• Connections between these clusters form intricate circuitry that regulates information flow.

Neurons

• Neurons are electrically excitable cells that process and transmit information via electrochemical signals.
• A typical neuron has a cell body (soma) and specialized processes called dendrites and axons.
• Dendrites receive inputs from other neurons and integrate this information.
• Axons carry output signals from the cell body, sometimes over long distances.
• Neurons communicate at specialized junctions called synapses.
• Neurotransmitters are released at synapses, interacting with receptors on other neurons.
• Axon initial segments have high concentrations of voltage gated sodium channels.

Neuroglia

• Glial cells (neuroglia) support neurons with multiple essential functions.
• Astrocytes are the most abundant glial cell, providing metabolic support, maintaining extracellular ion concentrations, and involved in synapse formation and function.
• Oligodendrocytes form the myelin sheath around axons in the CNS, speeding up signal propagation; damage to these cells contributes to multiple sclerosis.
• Microglia are specialized macrophages, acting as the primary immune defense in the CNS, and are involved in neuroinflammatory processes and synaptic pruning.

Blood-Brain Barrier (BBB)

• The BBB protects the CNS by limiting the passage of substances from the bloodstream.
• Tight junctions between capillary endothelial cells and surrounding astrocyte end-feet are crucial in maintaining the separation between circulating blood and the extracellular fluid in the CNS.
• Some substances, including certain drugs, are more readily transported across the BBB than others.
• Drugs must either be highly hydrophobic or use specific transport mechanisms to enter the CNS.
• Many nutrients have specific transporters for crossing the BBB.

Ion Channels & Neurotransmitter Receptors

• Neurons contain voltage-gated and ligand-gated channels.
• Voltage-gated channels respond to changes in the membrane potential.
• Ligand-gated channels respond to specific neurotransmitter binding, directly opening the channel.
• The opening of channels can initiate fast action potentials, or on a slower time scale alter the rate of neuron discharge.
• Metabotropic receptors activate G proteins that affect intracellular signaling, modulating other channels via different pathways.

Synapse & Synaptic Potentials

• The synapse is the junction between neurons where neurotransmitters are released to affect postsynaptic neuronal activity.
• Calcium channels are vital for neurotransmitter release.
• The time delay for postsynaptic responses is around 0.5 ms, mainly due to neurotransmitter release mechanisms and calcium channel activation.
• Synaptic potentials (EPSPs and IPSPs) summate to influence neuronal firing.
• Excitatory postsynaptic potentials (EPSPs) result from increases in cation permeability and result in depolarization.
• Inhibitory postsynaptic potentials (IPSPs) result from permeability changes leading to hyperpolarization.
• Metabotropic receptors can modulate voltage-gated channels.

Sites of Drug Action

• Drugs can affect various steps in neurotransmission, including synthesis, storage, release, reuptake, degradation, and interaction with receptors.
• Some drugs interfere with the intracellular storage of neurotransmitters, others affect neurotransmitter release, or block receptor function.
• Other drugs prevent the reuptake of neurotransmitters.
• Some drugs interfere with the degradation of neurotransmitters, prolonging their action.

Examples of Drug Action Sites

• Various drugs can interfere with neurotransmitter function in different ways affecting the synapse.

Retrograde Signaling

• Retrograde signaling involves signals that flow backward across the synapse, influencing transmitter release from the presynaptic neuron.
• Endocannabinoids are endogenous retrograde messengers commonly used and studied in this way.

Cellular Organization of the Brain

• Neurons and their networks in the CNS can be categorized into hierarchical and diffuse neuronal systems.
• Hierarchical systems are pathways involved in sensory perception and motor control.
• These involve relay or projection neurons and local circuit neurons connected in pathways.
• Diffuse systems involve neurons with widespread projections that affect global brain functions such as sleep, wakefulness, appetite, and attention.

Neurotransmitters

• Many molecules serve as neurotransmitters, mediating communication between neurons.
• Key neurotransmitters include amino acids, monoamines, neuropeptides, endocannabinoids, purines, and nitric oxide.
• Neurotransmitter receptors may be ionotropic (directly influencing ion channels) or metabotropic (indirectly influencing ion channels via signaling cascades).

Specific Neurotransmitters, Receptors, and Mechanisms

• Further detail on the action of specific CNS neurotransmitters, receptors subtypes, mechanisms of action, and impact on physiological systems.

GABA and Glycine

• GABA and Glycine are inhibitory neurotransmitters primarily located in different areas of the brain and spinal cord, respectively
• Both are involved in inhibitory postsynaptic potentials (IPSPs)
• GABA receptors are divided into GABAA and GABAB types, both affecting postsynaptic ion channels with different actions and mechanisms.

Acetylcholine

• Acetylcholine is a critical neurotransmitter in the CNS.
• It has both ionotropic (nicotinic) and metabotropic (muscarinic) receptors.
• Acetylcholine plays important, widespread roles in cognitive functions especially memory.

Dopamine

• Dopamine is a neurotransmitter with diverse functions in the CNS.
• Key pathways include the nigrostriatal pathway (crucial for motor control) and the mesolimbic pathway (linked to reward and motivational processes).
• Dopamine receptors are primarily metabotropic, affecting neuronal activity through second-messenger systems.

Norepinephrine

• Norepinephrine is a neurotransmitter with significant effects throughout the CNS.
• Its primary location is in the locus coeruleus and projects widely.
• Norepinephrine primarily acts on metabotropic receptors, influencing mood, attention, arousal, and cognitive processing.

5-Hydroxytryptamine (Serotonin)

• Serotonin is a major neurotransmitter with diverse functions in the brain.
• It has a variety of receptor subtypes and acts both excitatoryly and inhibitorily in most areas.
• Its different receptor subtypes can exert varying effects (excitatory or inhibitory) throughout the different parts of the CNS.

Histamine

• Histamine is produced by neurons in the tuberomammillary nucleus primarily in the posterior hypothalamus.
• Primarily metabotropic, histamine actions influence arousal, attention, and cognitive functions, and is associated with sleep-wake regulation and other cognitive functions

Neuropeptides

• Neuropeptides act as neurotransmitters, frequently in conjunction with other neurotransmitters like glutamate.
• They often have multiple roles in the nervous system impacting a variety of processes.
• Because of their widespread activities, neuropeptides often play a greater modulatory role as opposed to a primarily direct excitatory or inhibitory one.

Orexins (Hypocretins)

• Orexins, produced in the hypothalamus, are excitatory neuropeptides involved in regulating sleep-wake cycles, appetite, and other functions.
• The mechanism of action is primarily through activating G-protein coupled receptors.

Endocannabinoids

• Endocannabinoids are lipid-based retrograde messengers.
• They influence synaptic function via receptors on adjacent neurons.
• Cannabinoids have diverse effects on numerous processes, including memory, cognition, and pain perception. This diverse role points toward multiple and complex actions involving CNS transmission.
• Some effects are similar to that of marijuana.

Nitric Oxide (NO)

• NO is a gaseous neurotransmitter primarily produced in response to calcium-dependent signaling.
• It is a retrograde messenger, diffusing readily between neurons and influencing synaptic transmission across different synapses.
• NO may regulate long-term changes in synaptic strength through its impacts on neuronal activity.

Purines (Adenosine, ATP, etc.)

• ATP and related molecules like adenosine act as neurotransmitters.
• Their actions are generally slow, impacting various neural processes, including memory and arousal, through distinct receptor pathways