Introduction to Central Nervous System Pharmacology

Introduction to Central Nervous System Pharmacology


The central nervous system (CNS) consists of the brain and spinal cord. Sensory information arrives to the CNS from the special senses and peripheral nerves and is integrated with memories and internal drive states to generate cognitive, emotional, and motor (behavioral) responses. This processing occurs because of the complex interplay of neurotransmitters and neuromodulators acting on their receptors to excite or inhibit CNS neurons. In persons with brain disorders, structural or functional disturbances of CNS processing produce aberrant cognitive, emotional, or motor responses. Brain disorders are seen in association with a variety of disease processes, including degenerative, ischemic, and psychological disturbances.

Most CNS drugs correct an imbalance in neurotransmitters or their receptors. Drugs are used to relieve the symptoms of brain dysfunction, but they usually do not correct the underlying disorder. Although short-term drug treatment may be effective in relieving acute symptoms such as pain and insomnia, drug therapy for many brain disorders is a lifelong process.

After reviewing pertinent concepts of CNS function and neurotransmission, this chapter explains the general mechanisms by which drugs alter CNS activities and processes.

Neurotransmission in the Central Nervous System

Principles of Neurotransmission

In the past century, great debates raged about the nature of neuronal communication in the CNS. The early physiologists believed that neurons communicated by electrical signals directly passing from neuron to neuron in a hard-wired fashion much like wires in a telegraph relay. The early pharmacologists argued for chemical transmission, with substances released into the synapse between communicating neurons. Modern research shows that both were right to some degree because most neuronal communication occurs by chemical neurotransmitters serving as messengers that enable neurons to communicate with one another. However, there is also evidence of direct voltage signaling between neurons at electrotonic or gap junctions.

The details of chemical neurotransmission undergo constant refinement as new mechanisms and neurotransmitters are discovered. An early statement by Sir Henry Dale, known as Dale’s principle, suggested that each neuron contained only one type of neurotransmitter. This principle was revised with the finding that neurons may release more than one neurotransmitter, as is the case with co-transmitters (see later). It was also thought that neurotransmitter action was limited to the single synapse where released. The neuroanatomic demonstration of diffuse neuronal systems with fine, widespread projections throughout the CNS, such as norepinephrine and serotonergic fibers arising from brain stem nuclei, led to the concept of the chemical soup or chemical milieu model of neurotransmission. Newer methods using in vitro brain slice preparations and other techniques show that neurotransmitters can diffuse far from the synapse and affect other neurons at other synapses. Identification of neuroactive substances both intrinsic and extrinsic to the CNS that exert generalized effects on neurons strengthened the concept of action at a distance. A neuromodulator is a general term for any substance that exerts an effect on neurotransmission among a set of neurons in the brain.

The action of drugs on the CNS is similar to the chemical milieu model of neurotransmission, because drug molecules are widely distributed throughout the brain and can simultaneously interact with receptors on neurons in several different neuronal tracts. This lack of specificity can lead to therapeutic effects and adverse effects at the same time. For this reason, the development of agents that are more selective for specific receptor types and subtypes is a useful approach to improving the therapeutic index of CNS drugs.

Neurotransmitter Synthesis and Metabolism

Neurotransmitters are synthesized in neuronal cell bodies or terminals, and they are stored in neuronal vesicles until they are released into a synapse (Fig. 18-1). The release of neurotransmitters is activated by membrane depolarization and calcium influx into the cell. Calcium evokes the interaction of storage vesicle proteins (synaptobrevin and synaptotagmin) and membrane-docking proteins (syntaxin and neurexin) and leads to vesicle fusion with the membrane and exocytosis of the neurotransmitter.

After exocytosis, the neurotransmitter may activate presynaptic and postsynaptic receptors. A neurotransmitter’s action is then terminated either by its reuptake into the presynaptic neuron or by its degradation to inactive compounds, with degradation catalyzed by enzymes located on presynaptic and postsynaptic neuronal membranes or within the cytoplasm.

Neurotransmitters can also diffuse from the synapse of their origin to affect neurons in the surrounding vicinity. In this way, different neurotransmitters released from different types of neurons form a chemical milieu, as described previously. The net influence of the chemical milieu on neurotransmission depends on the concentrations of the excitatory and inhibitory neurotransmitters acting at a particular synapse.

Excitatory and Inhibitory Neurotransmission

CNS neurotransmitters can evoke either an excitatory or an inhibitory synaptic membrane potential and trigger effects at presynaptic and postsynaptic sites on target neurons. If an excitatory postsynaptic membrane potential reaches firing threshold, an action potential is conducted along the dendritic and axonal membrane and evokes the release of a neurotransmitter from the nerve terminal. An inhibitory postsynaptic membrane potential hyperpolarizes the neuronal membrane and inhibits the firing of action potentials. Depending on whether a presynaptic membrane potential is excitatory or inhibitory, it will increase or decrease the release of a neurotransmitter from the neuron. Presynaptic receptors, also called autoreceptors, can also be coupled with cyclic adenosine monophosphate (cAMP) or other second messengers that modulate neurotransmitter release.

As shown in Box 18-1, the interaction of multiple neurotransmitters at a particular site in a neuronal tract enables the complex interplay of various neuronal systems and contributes to the wide range of functional expression exhibited in the CNS. For example, inhibition of the release of an inhibitory neurotransmitter will actually increase neurotransmission in the target neuron. Similarly, drugs can act in complex ways to affect neurotransmission. Ethanol (ethyl alcohol), for instance, can diminish the inhibitory influence of the cerebral cortex on certain human behaviors and thereby increase drug-induced behaviors, a phenomenon called behavioral disinhibition. Ethanol and other CNS depressants, initially or at low doses, exert their effects on the smaller and more numerous inhibitory neurons, creating disinhibition via excitation owing to removal of inhibitory neurotransmitters. At higher doses, larger excitatory neurons are inhibited and profound depression of CNS activity can occur.

Fast versus Slow Signals

Neurotransmitters in the CNS can be characterized as slow or fast, depending on the receptors that are activated and the persistence of signal transduction pathways. The best examples of fast neurotransmitters are γ-aminobutyric acid (GABA) and glutamate acting at ligand-gated ion channels. Binding of these amino acid neurotransmitters directly to subunits of the ion channel protein directly initiates ion flow with a signal that lasts for only a few milliseconds. Examples of slow neurotransmitters are norepinephrine and serotonin acting at G protein–coupled receptors. These activated G protein–coupled receptor proteins initiate a slower, multistep process with alterations in second messengers and membrane effects that can last from many milliseconds to as long as a second. A slow (long-acting) signal can influence the overall tone of a neuron because it can modulate the signals of several other fast neurotransmitters acting on the same neuron. For this reason, slow neurotransmitters can also be called neuromodulators.

Neurotransmitters and Receptors

Important neurotransmitters in the CNS include acetylcholine and several amino acids, biogenic amines, and neuropeptides. Table 18-1 lists the names, receptors, mechanisms of signal transduction, and functions of the major neurotransmitters.

TABLE 18-1

Major Neurotransmitters and Their Receptors in the Central Nervous System

Acetylcholine Muscarinic    
  M1, M3, M5 ↑IP3, ↑DAG, ↑iCa2+ Excitatory; role in arousal and consciousness, memory consolidation
  M2, M4 ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; autoreceptor and heteroreceptor, decreases NT release
  Nicotinic ↑gNa+, ↑gCa2+ Excitatory; increases NT release, role in nicotine dependence
Amino Acids      
GABA GABAA ↑gCl Inhibitory (major); ligand-gated ion channel site of action of sedative-hypnotics, alcohol, general anesthetics
  GABAB ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; modulates motor neuron excitability
Glutamate NMDA, AMPA, KA ↑gNa+, ↑gCa2+ Excitatory (major); roles in LTP (memory), excitotoxicity of neurons
  mGlu1, mGlu5 ↑IP3, ↑DAG, ↑iCa2+ Excitatory; memory consolidation, neuronal excitation
  mGlu2-mGlu4, mGlu6-mGlu8 ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; role in thalamic sensory processing
Glycine Strychnine-sensitive ↑gCl Inhibitory; highest levels in spinal cord
  Strychnine-insensitive Co-agonist at NMDA receptor Excitatory; obligate coagonist for function of NMDA receptor
Biogenic Amines      
Dopamine D1, D5 ↑cAMP, ↑PKA Excitatory; basal ganglia function, memory and performance
  D2, D3, D4 ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; decreases dopamine release, reduces firing of neurons
Norepinephrine α1 ↑IP3, ↑DAG, ↑iCa2+ Excitatory; autonomic nuclei in brain stem
  α2 ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; sympathetic outflow from CNS; decreases pain transmission
  β1, β2 ↑cAMP, ↑PKA Excitatory; cortex, limbic system, nucleus accumbens
Serotonin (5-HT)* 5-HT1 ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; role in anxiety and depression
  5-HT2 ↑IP3, ↑DAG, ↑iCa2+ Excitatory; widespread distribution, role in antipsychotic action
  5-HT3 ↑gNa+, ↑gCa2+ Excitatory; mediate fast neuronal transmission in neocortex; presynaptic modulation of NT release
  5-HT4 ↑cAMP, ↑PKA Excitatory; role in cognitive processes, anxiety
Histamine H1 ↑IP3, ↑DAG, ↑iCa2+ Excitatory; increases NT release, role in arousal, anxiety
  H2 ↑cAMP, ↑PKA Excitatory; located in hippocampus, amygdala, and basal ganglia
  H3 ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; autoreceptor and heteroreceptor, decreases NT release
Opioid peptides Mu, delta, kappa ↓cAMP, ↑gK+, ↓gCa2+ Inhibitory; analgesic role in sensory processing, role in drug dependence for opioids and other substances
Tachykinins NK1, NK2, NK3 ↑IP3, ↑DAG, ↑iCa2+ Excitatory; role in pain processing, autonomic regulation


AMPA, α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate; cAMP, cyclic adenosine monophosphate; CNS, central nervous system; DAG, diacylglycerol; 5-HT, 5-hydroxytryptamine (serotonin); g, ion channel conductance; GABA, γ-aminobutyric acid; i, intracellular; IP3, inositol triphosphate; KA, kainate; LTP, long-term potentiation; NK, neurokinin; NMDA, N-methyl-D-aspartate; NT, neurotransmitter; PKA, cAMP-dependent protein kinase.

*Over a dozen types of serotonin receptors are cloned; the four given here are the main types.

The receptors can be divided into two basic groups: ionotropic receptors, also called ligand-gated ion channels, which are directly associated with ion channels, and metabotropic receptors, which are typical G protein–coupled receptors (see Chapter 3). Although this terminology is most frequently applied to receptors for amino acid neurotransmitters (e.g., GABA and glutamate), it is equally appropriate for other classes of neurotransmitter receptors.

The mechanisms of signal transduction for neurotransmitters in the CNS are similar to those for neurotransmitters in the autonomic nervous system. The activation of ionotropic receptors alters chloride, sodium, potassium, or calcium influx and thereby evokes excitatory or inhibitory membrane potentials. The linkage of metabotropic receptors with G proteins leads to activation or inhibition of adenylyl cyclase and alteration in the levels of intracellular cAMP, or activation of phospholipase C and the formation of inositol triphosphate and diacylglycerol. Metabotropic receptor activity can also modulate ion channel activity via second messengers (most notably calcium) that activate protein kinases responsible for the phosphorylation of ion channels. Signal transduction for other receptors in the CNS is discussed in Chapter 3.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Introduction to Central Nervous System Pharmacology

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