Introduction
Most drugs that impact the central nervous system (CNS) function by altering some aspect of the neurotransmission process. CNS drugs can act presynaptically, affecting neurotransmitter production, storage, release, or termination, or postsynaptically by activating or blocking receptors. This chapter outlines CNS neurotransmission with an emphasis on neurotransmitters involved in the action of clinically useful CNS drugs. Understanding these concepts is key to grasping the etiology and treatment strategies for neurodegenerative disorders responsive to drug therapy, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (Figure 8.1).
Neurotransmission in the CNS
The basic functioning of CNS neurons is similar to that of the autonomic nervous system (ANS), as discussed in Chapter 3. In both systems, information transmission involves neurotransmitters that cross the synaptic cleft and bind to receptors on the postsynaptic neuron, causing intracellular changes. However, several significant differences exist between peripheral ANS and CNS processes. The CNS is more complex, with more intricate circuitry and a greater number of neurotransmitters than the ANS, which primarily relies on acetylcholine and norepinephrine. Additionally, neuronal communication in the CNS is modulated by a greater variety of neurotransmitters.
Synaptic Potentials
In the CNS, most synapse receptors are linked to ion channels. Neurotransmitter binding to postsynaptic membrane receptors causes rapid but temporary ion channel openings, allowing specific ions to flow according to their concentration gradients. This ionic movement changes the postsynaptic membrane potential, leading to depolarization or hyperpolarization, depending on the ions involved and their direction of movement.
A. Excitatory Pathways
Neurotransmitters are classified as excitatory or inhibitory based on their effects. Excitatory neuron stimulation causes ion movement that depolarizes the postsynaptic membrane. This process, called excitatory postsynaptic potentials (EPSP), involves the following steps:
1. Excitatory neurotransmitters, such as glutamate or acetylcholine, are released and bind to postsynaptic cell receptors, increasing sodium (Na+) ion permeability.
2. Sodium influx causes a weak depolarization or EPSP, moving the postsynaptic potential toward its firing threshold.
3. If more excitatory neurons are stimulated, more neurotransmitter is released, potentially causing the EPSP to surpass the threshold and trigger an all-or-none action potential. Nerve impulses typically reflect synaptic receptor activation by thousands of excitatory neurotransmitter molecules from many nerve fibers (Figure 8.2).
B. Inhibitory Pathways
Inhibitory neuron stimulation causes ion movement that hyperpolarizes the postsynaptic membrane, generating inhibitory postsynaptic potentials (IPSP). This involves:
1. Inhibitory neurotransmitters, like γ-aminobutyric acid (GABA) or glycine, are released and bind to postsynaptic cell receptors, increasing the permeability of specific ions, such as potassium (K+).
2. Potassium influx causes hyperpolarization, moving the postsynaptic potential away from its firing threshold and reducing action potential generation .
Combined Effects of EPSP and IPSP
Most CNS neurons receive both EPSP and IPSP, with multiple neurotransmitters acting on the same neuron but binding to specific receptors. The overall effect is the sum of individual neurotransmitter actions on the neuron. Neurotransmitters are not uniformly distributed in the CNS but are localized in specific neuron clusters that synapse with particular brain regions. This chemical coding of neuronal tracts may allow for selective pharmacological modulation of certain pathways.
IV. Neurodegenerative Diseases
Neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, MS, and ALS, are characterized by the progressive loss of specific neurons in distinct brain areas, resulting in movement, cognitive, or both types of disorders.
V. Overview of Parkinson’s Disease
Parkinsonism is a progressive neurological disorder characterized by tremors, muscular rigidity, bradykinesia, and postural and gait abnormalities, primarily affecting individuals over 65, with an incidence of about 1 in 100.
A. Etiology
The cause of Parkinson’s disease is largely unknown. The disease is associated with the destruction of dopaminergic neurons in the substantia nigra, leading to reduced dopamine action in the corpus striatum, which is involved in motor control.
1. Substantia Nigra: Part of the extrapyramidal system, the substantia nigra is the source of dopaminergic neurons (Figure 8.4). These neurons make numerous synaptic contacts within the neostriatum, modulating many cells’ activities. The dopaminergic system provides a tonic, sustaining influence on motor activity rather than responding to specific movements.
2. Neostriatum: Normally, the neostriatum is linked to the substantia nigra by neurons that secrete GABA. In turn, the substantia nigra sends neurons back to the neostriatum, secreting dopamine. This mutual inhibition maintains a degree of inhibition in both areas. In Parkinson’s, the destruction of substantia nigra cells leads to a decrease in dopamine secretion in the neostriatum, reducing dopamine’s inhibitory influence on cholinergic neurons and resulting in overactive acetylcholine production, disrupting muscle control.
3. Secondary Parkinsonism: Certain drugs, like phenothiazines and haloperidol, which block dopamine receptors, can induce parkinsonian symptoms (pseudoparkinsonism) and should be used cautiously in Parkinson’s patients.
B. Treatment Strategy
The neostriatum has an abundance of excitatory cholinergic neurons opposing dopaminergic action. Parkinson’s symptoms result from an imbalance between excitatory cholinergic and reduced inhibitory dopaminergic neurons. Treatment aims to restore dopamine in the basal ganglia and counteract cholinergic neuron activity to reestablish the dopamine/acetylcholine balance.
Central nervous system (CNS) drugs primarily work by modifying neurotransmission processes. These modifications can occur presynaptically by influencing neurotransmitter production, storage, release, or termination, or postsynaptically by interacting with receptors. Understanding neurotransmission in the CNS is crucial for comprehending the treatment of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).
Neurotransmission in the CNS shares similarities with the autonomic nervous system but is more complex due to a greater diversity of neurotransmitters and more intricate neural circuitry. Synaptic potentials in the CNS involve neurotransmitter binding to postsynaptic receptors, leading to rapid ion channel openings that result in depolarization (excitatory) or hyperpolarization (inhibitory) effects.
Neurodegenerative diseases are marked by the progressive loss of specific neurons, causing characteristic motor and cognitive disorders. Parkinson’s disease, in particular, results from the degeneration of dopaminergic neurons in the substantia nigra, leading to reduced dopamine levels in the corpus striatum and an imbalance with excitatory cholinergic activity. Treatment strategies for Parkinson’s aim to restore dopamine levels and counteract excessive cholinergic activity to rebalance neural signals and improve motor control.
In summary, CNS drugs and treatments for neurodegenerative diseases rely on a detailed understanding of neurotransmission processes and the specific roles of various neurotransmitters in maintaining neural function and balance.
CONCLUSION
Central nervous system (CNS) drugs primarily work by modifying neurotransmission processes. These modifications can occur presynaptically by influencing neurotransmitter production, storage, release, or termination, or postsynaptically by interacting with receptors. Understanding neurotransmission in the CNS is crucial for comprehending the treatment of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).
Neurotransmission in the CNS shares similarities with the autonomic nervous system but is more complex due to a greater diversity of neurotransmitters and more intricate neural circuitry. Synaptic potentials in the CNS involve neurotransmitter binding to postsynaptic receptors, leading to rapid ion channel openings that result in depolarization (excitatory) or hyperpolarization (inhibitory) effects.
Neurodegenerative diseases are marked by the progressive loss of specific neurons, causing characteristic motor and cognitive disorders. Parkinson’s disease, in particular, results from the degeneration of dopaminergic neurons in the substantia nigra, leading to reduced dopamine levels in the corpus striatum and an imbalance with excitatory cholinergic activity. Treatment strategies for Parkinson’s aim to restore dopamine levels and counteract excessive cholinergic activity to rebalance neural signals and improve motor control.
In summary, CNS drugs and treatments for neurodegenerative diseases rely on a detailed understanding of neurotransmission processes and the specific roles of various neurotransmitters in maintaining neural function and balance.
