The Basis of CNS Pharmacology

The nervous system, comprised of two major components, i.e., the peripheral nervous system (PNS) and the central nervous system (CNS), has three main functions: sensory input, integration of data, and motor output.4 The PNS is subdivided into sensory (afferent) and motor (efferent) divisions. Afferent sensory neurons conduct signals from the PNS to the CNS. Efferent motor neurons conduct signals from the CNS to the PNS.

The efferent motor division of the PNS is subdivided into somatic and autonomic systems. The somatic nervous system controls voluntary movements. The autonomic nervous system (ANS) controls involuntary responses. The sympathetic division of the ANS mobilizes body systems and is responsible for “fight or flight” responses. The parasympathetic division of the ANS conserves energy and is responsible for responses related to “calm and relaxation.”

The CNS has three functional levels: neocortical, limbic, and vegetative (Figure 1). The vegetative or lowest level consists of the brain stem and the reticular activation system that connect the brain to the spinal cord. The mid-level is the limbic system or the emotional center of the brain responsible for the biochemical events that constitute the stress response. The highest and most sophisticated level of the brain is the neocortex.

Figure 1.
Diagram showing the positions of the three functional levels of the CNS are such that a higher level can override a lower level of the brain.
The positions of the three functional levels of the CNS are such that a higher level can override a lower level of the brain.

The neocortex consists of grey matter surrounding the white matter of the cerebrum. The cerebral hemispheres, which contain the cerebral cortex and basal ganglia, are connected by a bundle of nerve fibers called the corpus callosum. The cerebral cortex is responsible for high-level functions, such as sensory perception, generation of motor commands, spatial reasoning, conscious thought, and in humans, language.

The basal ganglia consist of three deep nuclei of gray matter and include the caudate and putamen nuclei - known as the striatum, and the globus pallidus. They help initiate and control cortical functions. These actions include intended movement, behavior, and certain aspects of cognition. Regions of the basal ganglia responsible for movement ensure that intended actions are carried out and irrelevant movements are inhibited.

The cerebral cortex contains parts of, and interacts with, elements of the limbic system. Significant structures of the limbic system include the cingulate gyrus, amygdala, hippocampus, thalamus, and hypothalamus. The cingulate gyrus coordinates smells and sights with pleasant memories of previous emotions and participates in the emotional reaction to pain and the regulation of aggressive behavior.

The hippocampus is involved in learning memory, i.e., the conversion of temporary memories into permanent memories; helps to analyze and remember special relationships essential for accurate movements; and facilitates the use of memory to modify behavior. The amygdala connects with the hippocampus, the septal area, and the thalamus and mediates such feelings as friendship, affection, and expression of mood.

Various nuclei of the thalamus link sensory pathways from the periphery to the cortex and structures of the limbic system and is associated with changes in emotional activity. The hypothalamus controls mood (e.g., expression of emotions such as pleasure, rage, aversion, and displeasure); motivated behaviors such as sexuality and hunger; regulates thirst and body temperature; and via the pituitary gland, controls hormonal processes.

The cerebellum receives information related to spatial positioning; and sends signals to the motor areas of the cortex via the thalamus and down the spinal cord to regulate proprioception. The cerebellum coordinates skeletal muscle activity in space and time; maintains balance; controls eye movement; and influences motor learning (e.g., eye-hand coordination) and cognitive functions (e.g., timing of repetitive events and language).

The brainstem (medulla, pons and midbrain) connects the spinal cord to the thalamus and the cortex. The medulla and pons contain control centers that direct the autonomic nuclei that regulate heart rate, respiration, digestive functions, and reflex reactions (e.g., coughing and vomiting). In the midbrain, neurons in the periaqeaductal gray send descending projections to the spinal cord and modulate pain perception.

The spinal cord is organized into white and gray matter. White matter consists of fiber tracts that connect the periphery and spinal cord to more rostral areas of the CNS. Gray matter consists of dorsal and ventral horns. The dorsal horn relays sensory information from the periphery to the CNS. The ventral horn relays signals from central motor areas to skeletal muscle. Interneurons connect sensory and motor neurons and mediate reflexes.

Distant areas of the nervous system connect to one another and relay signals between the PNS and the CNS via long-tract neurons. Local circuit neurons maintain connectivity within a localized area of the CNS and modulate signal transmission. Single-source divergent neurons originate in various nuclei of the brainstem, hypothalamus, and basal forebrain and innervate broad areas of the CNS (Figures 2‑7).4,6-11

Figure 2.
Diagram showing Glutamatergic neurons are found throughout the brain - most densely concentrated in the cerebral cortex, the hippocampus, the amygdala, the basal ganglia, the brain stem, and the spinal cord.
Glutamatergic neurons are found throughout the brain - most densely concentrated in the cerebral cortex, the hippocampus, the amygdala, the basal ganglia, the brain stem, and the spinal cord.
Figure 3.
Diagram showing  GABAergic neurons are found throughout the brain - most highly concentrated in the substantia nigra and globus pallidus of the basal ganglia, the cerebellum, the hypothalamus, interneurons throughout the brain, the periaqueductal gray, and the spinal cord.
GABAergic neurons are found throughout the brain - most highly concentrated in the substantia nigra and globus pallidus of the basal ganglia, the cerebellum, the hypothalamus, interneurons throughout the brain, the periaqueductal gray, and the spinal cord.
Figure 4.
Diagram showing Dopaminergic neurons arise in the substantia nigra and the ventral tegmental area and project to the striatum and the cerebral cortex, and to the amygdala and the hippocampus of the limbic system.
Dopaminergic neurons arise in the substantia nigra and the ventral tegmental area and project to the striatum and the cerebral cortex, and to the amygdala and the hippocampus of the limbic system.
Figure 5.
Diagram showing Cholinergic neurons arise in the pedunculopontine nucleus, the nucleus basalis, and the medial septal nuclei and project widely throughout the brain (hippocampus), and the spinal cord.
Cholinergic neurons arise in the pedunculopontine nucleus, the nucleus basalis, and the medial septal nuclei and project widely throughout the brain (hippocampus), and the spinal cord.
Figure 6.
Diagram showing Serotonergic neurons arise in the raphe nuclei and project to the limbic system, the basal ganglia; and via the basal forebrain, to the cerebral hemispheres as well as the cerebellum and the spinal cord.
Serotonergic neurons arise in the raphe nuclei and project to the limbic system, the basal ganglia; and via the basal forebrain, to the cerebral hemispheres as well as the cerebellum and the spinal cord.
Figure 7.
Diagram showing Noradrenergic neurons arise in the locus coeruleus and the lateral tegmental area.
Noradrenergic neurons arise in the locus coeruleus and the lateral tegmental area and project widely throughout the cerebral cortex, the hypothalamus, the brain stem, cerebellum, and the spinal cord.

Neurons communicate with one another and with other cells through the release of neurotransmitters.5 Neurotransmitters are synthesized by cytoplasmic enzymes and are stored in neuronal vesicles. When a nerve is stimulated its resting potential changes and the action potential generated causes an influx of Ca2+ ions into the presynaptic nerve terminal and the content of neurotransmitter-filled vesicles exocytose into the synaptic cleft.

The released neurotransmitter diffuses across the synaptic cleft and on the postsynaptic axonal membrane binds either to a neurotransmitter-gated ionotropic receptor and/or to a metabotropic receptor (e.g., a G protein-coupled receptor). Ionotropic receptor activation modulates ion channel function directly, while metabotropic receptor activation leads mainly to cAMP-dependent modulation of other ion channels.

A neurotransmitter may be excitatory or inhibitory and in some cases both (as a function of receptor subtypes). Excitatory neurotransmitters induce a net inward current by opening cation-specific ion channels, e.g., Na+ and Ca2+ ion channels; or by closing K+ ion “leak channels.” The net influx of Na+ and Ca2+ ions and the reduced outward flow of K+ ions across the neuronal membrane results in axonal membrane depolarization.

Inhibitory neurotransmitters induce a net outward current by opening K+ ion channels or Cl ion channels and induce K+ efflux or Cl influx, respectively. The loss of intracellular cations (i.e., K+ ions) and the gain of intracellular anions (i.e., Cl ions) moves the membrane potential away from its threshold value, reduces the ability of inward current to depolarize the membrane, and results in neuronal membrane hyperpolarization.

Termination of ionotropic neurotransmission at postsynaptic neurons is accomplished by two mechanisms: (1) degradation of the neurotransmitter by enzymes in the synaptic cleft and/or by (2) neurotransmitter uptake into the presynaptic terminal by specific transporters allowing the neurotransmitter to be recycled into synaptic vesicles for storage. Termination of signaling by a G protein-coupled neurotransmitter also involves intracellular enzymes.

Neurotransmitters in the CNS include acetylcholine, amino acids, monoamines, and a number of neuroactive peptides and purines (Table 1). Major amino acids neurotransmitters include glutamate, gamma-aminobutyric acid (GABA), and others such as glycine and aspartate. Major monoamine neurotransmitters include the catecholamines dopamine and norepinephrine; and the indoleamine serotonin.4,6-11

Table 1. Major neurotransmitters in the CNS.4,6-11
Neurotransmitter SystemReceptor TypesFunctional ClassMajor Actions
Glutamate
    See Figure 2
Ionotropic
    AMPA
    Kainate
    NMDA
Excitatory (major)Memory, learning
Metabotropic
    mGlu1 and mGlu5
Excitatory
mGlu2-4 and mGlu6-8Inhibitory
GABA
    See Figure 3
Ionotropic
    GABAA
Metabotropic
    GABAB
Inhibitory (major)Sleep, muscle tone, source of well-being
Dopamine
    See Figure 4
Metabotropic
    D1 and D5
ExcitatoryEnables intended movement, attention, learning, emotional regulation, memory, motivation (reward system), executive functions
D2, D3, and D4Inhibitory
Norepinephrine
    See Figure 5
Metabotropic
    α1, β1, β2, and β3
ExcitatoryVigilance, alertness, responsiveness to unexpected stimuli, source of well-being, sleep-wakefulness, learning, memory, attention, consciousness, regulates temperature and pituitary function, reduced digestion, increased heartbeat
α2Inhibitory
Serotonin
    See Figure 6
Ionotropic
    5-HT3
ExcitatoryMood, arousal, modulates eating (appetite), pain perception, behavior, regulates body temperature, sexual behavior
Metabotropic
    5-HT1
Inhibitory
5-HT2 and 5-HT4-7Excitatory
Acetylcholine
    See Figure 7
Ionotropic
    Nicotinic NN
ExcitatoryAlertness, sleep-wakefulness, skeletal muscle contraction, memory formation, learning and general intellectual functioning, sensory responses
Metabotropic
    Muscarinic M1 and M5
Excitatory
Muscarinic M4Inhibitory