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This chapter reviews a number of early hypotheses about the role of neurotransmitters in depression. These hypotheses had some potential, but never had the impact one might have hoped for in the effort to shed light on the problems faced in personalized medicine in psychiatry. Psychiatry is hampered by its inherent inability to physically access the brain. Biopsies are not routinely performed to study illnesses such as depression, and, until recently, imaging the central nervous system was at best crude and at times painful for the patient. Recent advances in understanding genetics and depression, as well as results from brain imaging studies, provide opportunities for developing more targeted tests that hopefully are less affected by extraneous events. Still, the earlier experiences do provide some context, and lessons that can be used to develop more effectively personalized medicine for psychiatry.

This chapter details early studies on signal molecules between nerve cells that mediate behavior. The key signal molecules for these functions are neurotransmitters, neuropeptides, internal second messengers, hormones, and pheromones. Apart from the sex hormones, most of these major types of components were first identified and their significance recognized in and around the 1950s. Before the 1950s, the biochemistry and pharmacology of the brain were essentially nonexistent. By the end of the decade, all the major categories of signaling agents had begun to emerge and the first textbook of brain biochemistry had appeared. Second messengers were discovered in 1957 and have been an essential motif in neurobiology since the 1970s. Neuropeptides were also first discovered in the 1950s and became a major theme in the 1970s, linked to second messengers. Pheromones were identified and named in the 1950s, and are recognized to control the social behaviors of most animals, including significant roles in humans.

Nervous systems are directional signalling systems. Several components of nervous systems are present in non-metazoan organisms, and sponges are able to use electrical signals without having a nervous system. Nervous systems evolved within Eumetazoa, first as a nerve net, but there were numerous tendencies to create heterogeneity within this system by the emphasis of particular regions or pathways. This can be seen in cnidarians, and particularly occurs within bilaterians. A brain and an orthogon (the regular arrangement of longitudinal and circular nerves) are characteristic bilaterian features, and their exact evolution is discussed in this chapter. The tendency to concentrate and specialize the nervous system is very common among bilaterians. A variety of neurotransmitters are used in nervous systems, most of which are broadly distributed, while only few are of phylogenetic importance.

This chapter examines the components of the impaired neural networks that might underlie the presentation of autistic symptoms. Topics covered include the neural network models of autism, central nervous system ontology, candidate regions in autism, trouble at the cellular level, trouble with neurotransmitters, trouble with circuitry in autism, and trouble with myelination of neural networks. It is shown that the autistic syndromes may be considered as one extensive set of impaired final common circuits presenting with dysfunctional information processing of behavior and cognition in very young children. Deficits in pragmatics, linguistic abilities, mindreading, executive functions, episodic memory, self-awareness, central coherence, and affective processing have been documented. These deficits are caused by many disease entities whose shared symptoms likely occur owing to malfunction of certain distributed neural networks.

Parasympathetic preganglionic neurons, which have cell bodies in the brainstem and spinal cord, are the source of all parasympathetic outflow. Consequently, these neurons are important sites for central autonomic integration and modulation. This chapter describes the properties of preganglionic neurons of the different parasympathetic outflows, including their location, anatomical organization, synaptic inputs, and properties. The chapter focuses on vagal preganglionic neurons, highlighting the aspects of their organization that are likely to be common to other parasympathetic outflows and emphasizing major developments since 1990. The chapter also discusses data showing that central regulation of parasympathetic preganglionic outflows is highly complex and organized so that the overall autonomic output is appropriate for the response required in any particular situation. It also presents evidence that parallel systems mediate autonomic behavioral and endocrine responses.

This chapter presents an autobiography of Solomon H. Snyder. Snyder identified receptors for opiates and neurotransmitters and elucidated mechanisms of drug action. He characterized messenger systems including IP3 receptors and inositol pyrophosphates, and identified novel neurotransmitters including nitric oxide, carbon monoxide and D-serine. His early years, career, and achievements are discussed.

This chapter discusses modern concepts in neurotransmitter release, and learning and synapses. Fusion and re-uptake of specialized membrane is involved in a number of processes which affect neuronal morphology and function including, intracellular vesicle trafficking, neurotransmitter release, and membrane expansion. We are only beginning to understand the molecular mechanisms of exocytosis/endocytosis which occur at synapses and the role of regulation of these steps on complex cellular behaviors. A better understanding of these phenomena will have considerable implications for the molecular basis of synaptic adaptation.

The neurotransmitter glutamate mediates the majority of excitatory synaptic transmission in the brain. Excitatory glutamatergic synapses feature a prominent thickening at the cytoplasmic surface of the postsynaptic membrane at sites of close opposition to the presynaptic terminal for which the term Post Synaptic Density (PSD) was coined. This chapter discusses the structural features and components of the excitatory PSD, functional interactions between PSD components, proposed functions of the PSD, and PSD structure and pathophysiology of the CNS.

Fast synaptic transmission is crucial for real-time functioning of the brain. All the receptor molecules that mediate fast transmission events are also ligand-gated ion channels, i.e., they are ion channels that undergo allosteric structural changes on binding a particular neurotransmitter molecule, resulting in the opening of the channel, the entry of selected ions into the neuron and subsequent signalling events. Their primary function is to receive signal input at postsynaptic membranes, where some also play central roles in synaptic plasticity. However, they are also found in postsynaptic membranes outside synapses, and in presynaptic terminals, where they are involved in the control of transmitter release. This chapter presents an overview of current knowledge of the molecular biology of these receptors.

This chapter provides a general overview of neuronal currents known to exist in brain cells, how they may be modulated by neurotransmitters, and how the interplay between the two can result in complicated patterns of activity in synaptic circuits.

This chapter focuses on astrocytes. In the last fifteen years, the status of astrocytes has changed profoundly from a cell scaffold and metabolic-trophic reservoir offering neurons a necessary, yet only passive, support to a full actor, working in collaboration with other glial cells and with the surrounding neurons by the continuous exchange of chemical messengers including glutamate, a classical neurotransmitter. Astrocytes as neurosecretory cells, stimulus-secretion coupling in astrocytes, and the role of regulated secretion from astrocytes in brain physiology are discussed.

This chapter presents an autobiography of Leslie L. Iversen. Iversen has been at the forefront of research on neurotransmitters and neuropeptides and understanding the mode of action of CNS drugs. He was among the first to describe the detailed properties and pharmacological specificity of the noradrenaline transporter (NAT) in sympathetic nerves and brain, and he helped to strengthen the concept of antipsychotic drugs as dopamine receptor antagonists. He participated in the first demonstration of the release of GABA on activation of an inhibitory synapse, and was the first to describe GABA uptake into inhibitory nerve endings in mammalian brain. His early years, career and achievements are discussed.

This chapter focuses on the structure and function of the microcircuits of the neocortex and their components. Topics covered include embryonic development, neuronal elements, synaptic connections, basic circuit, synaptic actions, neurotransmitters, dendrites, spines, and functional operations.

This chapter describes the neuroanatomy and neurotransmitters of frontal-subcortical circuits and the clinical behavioral syndromes associated with the specific focal lesions within the circuits. It reviews the neuropsychological and behavioral consequences of posterior pallidotomy and of deep-brain stimulation in the pallidum and subthalamic nucleus in patients with Parkinson's disease. Thus, both “naturally occurring” and intentional lesions or interruption of the circuit are considered.

Cell proliferation is the earliest step in the protracted process of mammalian brain development. Various genetic and environmental factors modulate the pace of cell proliferation and the number and type of cells produced. This chapter describes the spatiotemporal features of cell proliferation and the effect of neurotransmitters, major constituents of the chemical environment of the developing brain that modulate the process of precursor cell formation. It focuses on three neurotransmitters that are the most abundant in the developing brain: dopamine, γ-aminobutyric acid (GABA), and glutamate. The goal is to present an overview of the organization and activity of precursor cell populations and discuss the potential for modulation of precursor cell activity by neurotransmitters.

L-Glutamate (Glu) is the most prevalent neurotransmitter in the mammalian central nervous system (CNS) and is responsible for mediating the majority of its excitatory signaling. From the start, glutamate characterization as an excitatory transmitter was complicated considerably by its almost universal presence in CNS cells, as well as by its many roles in intermediary metabolism. This chapter discusses the basic principles of glutamate as an excitatory amino acid (EAA) neurotransmitter in the context of their historical roots, along with the effect of glutamate on CNS neurons, demonstrations of calcium-dependent glutamate release, identification of agonists and antagonists with which to delineate the three ionotropic receptor classes, participation of EAA ionotropic receptors in excitotoxicity, role of N-methyl-D-aspartate (NMDA) receptors in long-term potentiation, cloning of the ionotropic glutamate receptors, delineation of metabotropic glutamate receptors, postsynaptic molecular organization at the excitatory synapse, and structural changes underlying gating of ionotropic glutamate receptor channels and activation of metabotropic glutamate receptors.

This chapter explores the organic basis of eating disorders, and discusses whether eating disorders are a form of addiction. Gene variations seem to be involved in both anorexia and bulimia nervosa. However, it is unclear what these variations are and how they may interact with environmental stressors to determine the onset of the disorders. Moreover, though there is clear evidence that physiological abnormalities are linked to eating disorders, variations are generally corrected as abnormal eating patterns are abandoned. The relationship between these abnormalities and the onset of eating disorders is thus unclear. This has important ethical implications: it cannot be claimed that eating disorders are caused by organic causes, or that organic dysfunctions diminish the sufferers’ autonomy.

Salicylate induced tinnitus, either following a single high dose or following repeated administration of low dose. Salicylate interacts with the auditory system both in the cochlea and in the central auditory system. In the cochlea it down-regulates the action of prestin in the wall of the outer hair cells and thereby causes a temporary hearing loss. In addition salicylate interacts with the arachidonic acid cycle causing an increase in NMDA receptor activity and increased spontaneous firing rates in auditory nerve fibers. Centrally, salicylate down-regulates serotonin and GABA activity. This makes searching for neural substrates of tinnitus difficult at the least. Salicylate also increases the gain of the more central parts of the auditory system for sound, reflected in increased startle responses and potentially inducing hyperacusis. High levels of salicylate presents variable tend to decrease spontaneous firing rates in primary auditory cortex.

The primary targets of noise trauma (and ototoxic drugs) are the cochlear hair cells. Even if the result of noise exposure is just a temporary threshold shift, this may result in permanent loss of the ganglion cells that innervate the inner hair cells. Central nerve degeneration may ensue. The trauma generally causes a reduction in spontaneous firing rates of auditory nerve fibers. This typically causes an imbalance between neural excitation and inhibition in the central auditory system. This results in hyperactivity in the DCN, and can result in tonotopic map reorganization, likely only in cortical areas, accompanied by increased SFR and increased neural synchrony. This trio of changes is considered to comprise potential neural substrates of tinnitus. Shortly after the trauma restoration of the excitatory-inhibitory balance can prevent the occurrence of these substrates and likely also tinnitus.