In general terms, neurons communicate with each other through chemical messengers called neurotransmitters. Given the complexity of the brain, it should not be surprising that there are more than 100 known neurotransmitters (Purves et al. 2008). Neurotransmitters are synthesized in nerve cells, sometimes using precursors from the diet (e.g. tyrosine; see Figure 5.8), and are released into the synapse where they bind to specific receptors located on the postsynaptic cell. As discussed in the present chapter, this simple view conceals the many fascinating ways in which neurons communicate with each other. This chapter focuses on the different categories of neurotransmitters, the synthesis, storage, transport and release of neurotransmitters, their action at receptors and their deactivation. The influence of drugs on neurotransmitter function will also be discussed. Chapter 6 examines the specific effects of neurotransmitters in the neuroendocrine system, and Chapter 10 covers the actions of neurotransmitters at their receptors on postsynaptic cells.

The neuron and the synapse

A typical neuron is shown in Figure 5.1. Neurons possess a cell body, which contains the nucleus, and the characteristic dendrites plus an axon. The dendrites receive messages from other cells onto their spines and shafts, while the axon transmits information to other cells. Although each nerve cell has only one axon, this axon may have a number of branches and the nerve terminals at the end of each branch can form synapses with other neurons.

Nerve cells communicate with each other by the release of neurotransmitters from the nerve terminals of the axon into the synapse, the space that separates the presynaptic and postsynaptic cells. Neurotransmitters released into the synapse then bind to their receptors on the postsynaptic cell. As shown in Figure 5.1, synapses can form between the axon of the presynaptic cell and a number of different sites on the postsynaptic cell, including the shafts and/or spines of dendrites (axodendritic synapses), the cell body (axosomatic synapses) and the axons (axoaxonic synapses).

Peptide hormones, neuropeptides, neurotransmitters and other non-steroid chemical messengers regulate cellular and biochemical activity by binding to receptors located in the plasma membranes of their target cells. These chemical messengers are generally polar and water soluble and so cannot readily enter their target cells to influence the cell nucleus in the manner described for steroid and thyroid hormones (Chapter 9). In order to induce biochemical changes within the target cell, they act as first messengers to activate a second messenger, such as cAMP, within the cytoplasm of the target cell. The transduction of information from the first to the second messenger is accomplished through the activation of membrane protein transducers (G proteins) and enzymes, such as adenylate cyclase. This chapter discusses membrane receptors for peptide hormones and neurotransmitters, the mechanisms by which signal transduction across the cell membrane occurs, the role of G proteins and receptor tyrosine kinases in this signal transduction, the second messenger systems activated, and the actions of the second messengers in the target cells, with special emphasis on neural target cells.

Some of this material was introduced in Chapter 5 and we will refer to relevant figures where appropriate.

Membrane receptors

Membrane receptors are complex proteins embedded in the cell membrane. The function of these receptors is to recognize specific ligands in the blood (e.g. peptide hormones, neuropeptides) or in the synapse (e.g. neurotransmitters) and bind to them. Once this binding occurs, signal transduction across the cell membrane occurs as described in section 10.2 below. As noted in the description of steroid hormone receptors, modern techniques of immunohistochemistry (using antibodies to receptor proteins) and in situ hybridization (allowing visualization of peptide mRNA) permit the ready localization of membrane receptors in any tissue of interest. Gene cloning and sequencing techniques enabled molecular biologists to develop three-dimensional models of many membrane receptors. There are three distinct types of membrane receptor: (1) ligand-gated ion channel receptors; (2) guanine nucleotide binding protein (G-protein-) coupled receptors; and (3) transmembrane-regulated tyrosine kinases.

Previous chapters have discussed the endocrine glands and their hormones (Chapter 2), the hormones of the pituitary gland (Chapter 3), the hypothalamic hormones (Chapter 4) and neurotransmitters (Chapter 5). This chapter will describe how neurotransmitters influence the release of hypothalamic and pituitary hormones and the hormones of the adrenal medulla, pancreas, thymus and gastrointestinal tract. It will also examine the electrophy-siological properties of neurosecretory cells and the effects of drugs on the release of neurohormones.

The cascade of chemical messengers

As shown in Figure 6.1, and using the adrenal gland as an example, there is a cascade of chemical messengers that regulate target tissue function from the brain to the endocrine glands. For example, neurons release a neurotransmitter that regulates the secretion of neurohormones (such as CRH) from hypothalamic neurosecretory cells. These hypothalamic hormones stimulate the cells of the adenohypophysis (anterior pituitary) to synthesize and release their hormones. Many pituitary hormones, such as ACTH, act on endocrine target cells, such as the adrenal cortex, causing them to synthesize and release their own hormones (e.g. cortisol) which then stimulate biochemical changes in target cells elsewhere in the body, including the brain. In each step of this pathway, the individual neurotransmitters and peptide hormones bind to membrane receptors that activate a second messenger, such as cAMP, within the target cell (see Chapter 10). Steroid hormones (such as cortisol) act on receptors located inside the target cells (see Chapter 9). This chapter describes the effects of neurotransmitters on hypothalamic neurosecretory cells.

Neural control of hypothalamic neurosecretory cells

6.2.1 Neural input to the endocrine hypothalamus

Figure 4.1 illustrates the different nuclei of the hypothalamus, many of which have neurons, or nerve terminals, which release a variety of neurotransmitters including GABA, glutamate, kisspeptin, opioids, dopamine, norepinephrine and serotonin. These neurotransmitters all bind to receptors on hypothalamic neurosecretory cells. This chapter describes the magnocellular hypothalamic neurosecretory cells of the paraventricular and supraoptic nuclei (PVN and SON), whose axons terminate in the posterior pituitary, and the parvicellular hypothalamic neurosecretory cells, whose axons terminate in the median eminence (see Figure 3.1).

The aim of this book

The aim of this book is to introduce students to the language and concepts of neuroendocrinology, including how the neuroendocrine system influences behavior. It began with a consideration of the many chemical messengers in the body, classified as “true” hormones, neurohormones, neurotransmitters, pheromones, parahormones, prohormones, growth factors, cytokines, adipokines, vitamins and neuropeptides. As more became known about the neuroendocrine system, it became clear that these classifications are not unambiguous and a single chemical might fit into two or more classes of messenger and perform different functions. This means that while the classification of chemical messengers is useful to begin the study of neuroendocrinology, by the end it provides little help in understanding the different actions of peptides, steroids, neuropeptides and neurotransmitters on different target cells, even within the same tissue.

The hormones of the endocrine and pituitary glands are generally accepted as the major components of the neuroendocrine system. However, the traditional endocrine function of hormones being released into the bloodstream to act on peripheral target cells represents only a small part of the neuroendocrine activity of hormones such as testosterone, cholecystokinin or somatostatin. These hormones also have significant effects in the brain, via specific receptors, and can alter neural regulation of autonomic reflexes, behavior and emotional states. The hypothalamus provides the link between the brain and the traditional endocrine system and provides the locus for external factors, such as environmental influences, to regulate endocrine target organs. Thus, while the endocrine system consists of a number of closed-loop feedback systems that maintain homeostatic control over the synthesis, storage, release and deactivation of hormones, external stimuli can alter these systems. For example, environmental stimuli, social interactions and cognitive factors can greatly alter the functioning of the endocrine system by altering the neurotransmitter/neuropeptide pathways that regulate the release of hypothalamic hormones.

As illustrated in Figures 6.5 and 6.11, pituitary (LH, FSH and ACTH) and steroid (cortisol) hormone levels in the bloodstream fluctuate dramatically over short periods of time (minutes to hours). In addition, hormones such as GH, ACTH and melatonin show marked circadian variations in their secretion patterns (Figure 6.5). These patterns are physiologically important; for example, we saw in the case of LH secretion, a continuous release, rather than a pulsatile secretion, will not stimulate the ovaries or testes correctly (Figure 7.4). In other words, fertility is dependent on an appropriate pulsatile LH signal reaching the gonads. This principle might be generally applicable to all pituitary hormone secretions. The measurement, or assay, of hormone levels is therefore an important clinical goal, as well as a crucial aid in understanding how hormone levels in blood are regulated and how the neuroendocrine system functions in health and disease. This chapter thus begins with an examination of the methods for measuring hormone levels in the circulation.

Analysis of hormone levels

The level of a circulating hormone can be measured directly in blood samples or estimated by measuring hormone levels in the saliva, urine or feces, measuring urinary metabolites, or by using bioassays. The determination of glucocorticoids levels in hair, for example, is a way to detect long-term exposure to stress.

8.1.1 Direct measurement of circulating hormones

In the past 20 years, there have been striking changes in the analytical techniques used to estimate hormone levels. Until recently, the benchmark in determination of hormone levels was the radioimmunoassay. However, this method, employing antibodies specific to each hormone, and radioactively labeled hormones, is slow, labor-intensive and raised safety problems in the use and disposal of radioactive materials. It is now routine to analyze hormone levels using rapid and automated chemiluminescent or immunometric assays that produce data in a matter of hours, rather than days.

A widely used assay is the Enzyme-linked Immunosorbent Assay (ELISA).

The pituitary gland

The pituitary gland, which is also called the hypophysis, is attached to the hypothalamus at the base of the brain (Figure 3.1). Secretion of the hormones of the pituitary gland is regulated by the hypothalamus and it is through the hypothalamic-pituitary connection that external and internal stimuli can influence the release of the pituitary hormones, thus producing the neural-endocrine interaction. The pituitary has been called the body's “master gland” because its hormonal secretions stimulate a variety of endocrine glands to synthesize and secrete their own hormones. However, it is really the hypothalamus that is the master gland, because it controls the pituitary.

The pituitary gland consists of two primary organs: the anterior pituitary (adenohypophysis or pars distalis) which is a true endocrine gland, and the posterior pituitary (neurohypophysis) which is formed from neural tissue and is an extension of the hypothalamus (Figure 3.1). The pituitary gland is attached to the hypothalamus by the pituitary (hypophyseal) stalk. Further details of the anatomy and physiology of the pituitary gland can be found elsewhere (Norman and Litwack 1997; Amar and Weiss 2003; Boron and Boulpaep 2005; Gardner and Shoback 2011).

The neurohypophysis (posterior pituitary)

The neurohypophysis consists of neural tissue and contains the nerve terminals (about 100,000) of axons whose cell bodies are located in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. The axons of these large magnocellular neurosecretory cells project down from the hypothalamus through the part of the pituitary stalk called the infundibulum and terminate in the posterior pituitary gland (Figure 3.2). The neurosecretory cells of the PVN and SON manufacture the hormones oxytocin and vasopressin (also called antidiuretic hormone, ADH), which are transported down the axons and stored in nerve terminals in the posterior pituitary. The axon terminals in the posterior pituitary are surrounded by supporting cells called pituicytes.

In this second edition of An Introduction to Neuroendocrinology, we have rewritten and greatly extended the original content. The revised text includes entirely new reference lists and a complete new set of illustrations. The book reflects the many advances that have occurred in the study of neuroendocrinology during the past 20 years. Nevertheless, and although the text is based largely on modern references, our primary aim is to provide an introductory description of mammalian neuroendocrine control systems. Several books are available that cover this topical and clinically relevant field, but, although valuable, these tend to be advanced texts of the edited, multi-author type. Our book is designed to provide the basic principles necessary to understand how the brain controls, and responds to, the endocrine hormones. It will be suitable for a variety of different students and especially those who might not have been previously exposed to a focused course in neuroendocrinology. Thus, students in psychology, biology and science should be able to master much of the basic material. However, the book is also highly appropriate for honors students and first-year graduate students in physiology, anatomy, neuroscience and medicine. This book is therefore designed for students in two levels of classes: introductory classes, in which all of the material will be new to the student, and more advanced classes, in which the students will be familiar with many of the terms and concepts through courses in biology, physiology, psychology or neuroscience, but who have not studied neuroendocrinology as an integrated discipline.

This book offers an overall outline of the neuroendocrine system and will provide the vocabulary necessary to understand the interaction between hormones and the brain. In addition, we provide a concise description of those topics that must underpin any attempt to learn, and to teach, neuroendocrinology. For example, there are chapters on basic neuroscience (neurotransmitters and neuropeptides), the physiology of the endocrine glands (hormones), receptors and receptor signaling mechanisms (e.g. G proteins; nuclear receptors), hormone assay and gene expression techniques (e.g. ELISA; in situ hybridization) and a description of the immune system, with particular emphasis on the integration of immune and neuroendocrine pathways.

The endocrine glands

The location of the human endocrine glands is shown in Figure 2.1. The pineal gland is a small gland lying deep between the cerebral cortex and the cerebellum at the posterior end of the third ventricle in the middle of the brain. The hypothalamus exerts some degree of control over most of the endocrine glands through the release of neurohormones, neuropeptides and neurotransmitters. The pituitary gland hangs from the bottom of the hypothalamus at the base of the brain and sits in a small cavity of bone above the roof of the mouth.

The thyroid gland is located in the neck and the small parathyroid glands are embedded in the surface of the thyroid. In the chest is the thymus gland, which is very important for the production of T lymphocytes that play a critical role in the immune response. The heart and lungs also act as endocrine glands that secrete hormones. The gastrointestinal (GI) tract, consisting of the stomach and intestines, is also an important source of hormones. The liver secretes several hormones such as somatomedin (also called IGF-1), important for growth. The adrenal glands are complex endocrine glands situated on top of the kidneys. The pancreas secretes hormones involved in regulating blood sugar levels and the kidney also produces hormone-like chemicals. The testes and ovaries produce gonadal hormones, or sex hormones, which, in addition to the maintenance of fertility and sex characteristics, have important effects on behavior. During pregnancy, the placenta acts as an endocrine gland. The endocrine glands occur in similar locations in all vertebrates. A large endocrine gland is fat (adipose tissue) which can be found beneath the skin (subcutaneous), in the abdominal cavity surrounding the heart and GI tract (see Figure 2.1), and within tissues such as liver and muscle. Fat secretes a variety of hormones called adipokines. Finally, two of the largest tissues in the body – skeletal muscle and bone – secrete factors that act in an endocrine fashion.