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Glutamate is an amino acid that your brain uses as a neurotransmitter and it is almost always is excitatory. GABA is also an amino acid that your brain uses as a neurotransmitter and it is almost always inhibitory. These two neurotransmitters are widespread in your brain and tend to compete for turning your neurons on or off. Glutamate makes and breaks connections between neurons; this action allows your brain to learn. For example, if you consume a chemical that blocks the actions of glutamate you become amnestic, unable to remember anything new. The street drugs PCP and ketamine block glutamate receptors and depress the activity of your brain. Your brain makes its own PCP-like neurotransmitter called angeldustin. Chemicals that enhance the action of GABA, such as alcohol, barbiturates, or any of the popular drugs related to Valium and Librium, can make us sleepy, send us into a coma, or kill us by turning off too many neurons in the brain.

PET can be used to image neurotransmitter receptor ligands. Increased mu and delta, and probably decreased kappa opiate receptors have been demonstrated in patients with temporal lobe epilepsy (TLE). Ictal endogenous opiate release may occur in several seizure types. Increased MAO-B receptors in temporal lobe foci are consistent with focal gliosis. Reduced 5HT1A receptors have been found in TLE as well. The altered binding is correlated with depression, frequently associated with epilepsy, and may extend beyond the temporal lobe focus. Decreased dopamine receptor binding using a non-specific ligand was found in caudate and putamen in ring-chromosome 20 epilepsy and some patients with TLE. Reduced D2/D3 receptor binding was found in temporal lobe foci. Reduced NMDA receptor binding was reported in one TLE study. In autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), increased midbrain, pons and cerebellar, and decreased binding in dorsolateral prefrontal cortex nictotinic acetyl choline receptor binding was found. Patients with Rasmussen's encephalitis may have increased binding to the “peripheral benzodiazepine receptor,” also known as the “translocator protein 18 kilodalton.” The evidence in TLE is fragmentary. One study suggested increased p-glycoprotein transporter activity in TLE. Methodological problems include the fluctuating physiological state of patients with epilepsy, effects of antiepileptic drugs, and necessary partial volume correction for tissue loss in TLE and other anatomic lesions. However, PET has the potential to provide essential translational links between basic and clinical investigation of epilepsy.

The fatal crash of a private plane led to a lawsuit brought by the insurer against the manufacturer of the aircraft's engine. Investigators found no evidence of engine malfunction, so the insurer tried to place blame for the crash on the theory that the pilot was overcome by trimethylol propane phosphate (TMPP) gases leaking into the cockpit, causing him to have cognitive impairment such as disorientation, and to crash the plane, killing all aboard. No research exists concerning the effects of TMPP on humans, but because it is a GABA inhibitor that affects speech severely in diseases like Huntington's Disease, it seemed logical for the defense to analyze the recording of the pilot's speech from the time he departed until the time he crashed. The pilot's speech then was analyzed for syntax, word frequency, speech acts, pauses and pause fillers, pronunciation, and his use of the cooperative principle. No linguistic evidence of any type of aberration in the pilot's speech could be found in the recorded air-to-ground communications from the start of the flight to its fatal conclusion.

The cell body and dendrites of a motoneurone are covered with thousands of synaptic boutons, and the ultrastructure of the boutons is generally thought to be related to their functional characteristics (e.g., inhibitory vs excitatory). Most of the synapses are of types generating inward or outward ‘driving’ currents, important for directly modulating the spike-frequency of repetitive discharges. This includes excitatory glutaminergic and inhibitory glycinergic and/or GABA-ergic synapses with ionotropic postsynaptic receptors. A minor proportion of the boutons have a predominantly neurone-modifying function, e.g. changing the spike-threshold and/or repetitive spike-firing characteristics of the motoneurone. This concerns monoaminergic and several other types of boutons with metabotropic postsynaptic receptors, including also synapses with a facilitating effect on voltage-dependent ion channels for the generation of persistent inward currrent (PIC).

This chapter discusses the molecular biology of hippocampal cells with particular emphasis on synaptic function. It starts by describing the basis of all signal transmission processes, the release of the signaling transmitter from the presynaptic terminal. It then details the key glutamate and GABA receptors responsible for the “nuts and bolts” of hippocampal chemical transmission. As an example of modulatory transmission, it discusses how acetylcholine muscarinic and nicotinic receptors influence information flow in the hippocampal cell types.

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.

In addition to principal cells, the cerebral cortex contains diverse classes of interneurons that selectively and discriminately innervate various parts of principal cells and each other. The hypothesized “goal” of the daunting connectionist schemes of interneurons is to provide maximum functional complexity. Without inhibition and dedicated interneurons, excitatory circuits cannot accomplish anything useful. Interneurons provide autonomy and independence to neighboring principal cells but at the same time also offer useful temporal coordination. The functional diversity of principal cells is enhanced by the domain-specific actions of GABAergic interneurons, which can dynamically alter the qualities of the principal cells. The balance between excitation and inhibition is often accomplished by oscillations. Connections among interneurons, including electrical gap junctions, are especially suitable for maintaining clocking actions. Thus, the cerebral cortex is not only a complex system with complicated interactions among identical constituents but also has developed a diverse system of components.

The nucleus of the solitary tract (NTS) is the first location within the central nervous system for the integration and modulation of cardiovascular afferent as well as other viscerosensory input. The NTS is therefore a pivotal structure for maintaining homeostasis. This chapter examines the fundamental cellular and molecular building blocks of NTS pathways. It discusses NTS neurotransmitters, (glutamate and γ-amino-butyric acid, GABA) and the baroreceptor reflex, the mechanisms regulating afferent information transfer to sites beyond the NTS and the mechanisms by which two major modulators, angiotensin II and nitric oxide, transform afferent information related to cardiovascular regulation. Particular consideration is given to emerging views on the nature and role of heterogeneity in afferents and NTS neurons and their projection targets outside the NTS. The chapter also considers the impact of new signaling molecules in the endothelial interface between the bloodstream and brain on neural control of the circulation.

Sympathetic preganglionic neurons in the lateral horn of the spinal cord are the source of sympathetic outflow to the periphery and the final site for integration of information that arises from central sympathetic premotor neurons. This chapter summarizes knowledge about sympathetic preganglionic neurons that has accumulated over the past twenty years. The first part of the chapter deals with the sympathetic preganglionic neurons themselves, describing their locations, morphologies, neurochemical phenotypes and electrophysiological properties. The second part of the chapter covers the neuronal circuitry that influences the activity of sympathetic preganglionic neurons, including the origin and neurotransmitter content of the synaptic inputs that these neurons receive. The chapter also highlights some of the questions that require answers in order to achieve a better understanding of how this important group of neurons contributes to the control of autonomic function.

This chapter discusses reflex autonomic regulation of the cardiovascular system by input from finely myelinated and unmyelinated sensory nerve fibers. The focus is on abdominal and cardiac visceral afferent activation during ischemia, somatic afferent stimulation with exercise and interactions between both afferent systems during electroacupuncture. Important mechanical and chemical stimuli are identified as well as interactions between chemical stimuli, that together provide input to cardiovascular regions in the central nervous system that process this information. For example, acupuncture-evoked modulation of visceral sympathoexcitatory reflex activity is processed in the spinal cord and hypothalamus [arcuate nucleus], midbrain [ventrolateral periaqueductal gray], and medulla [raphé nuclei and rostral ventrolateral medulla (RVLM)]. Both excitatory and inhibitory neurotransmitters, including among others, glutamate, opioids, endocannabinoids, GABA, nociceptin, and serotonin, are involved. The role of individual neurotransmitters varies by nucleus, but in concert they modulate reflex increases in blood pressure through their action on presympathetic RVLM neurons.

Krešimir Krnjević contributed to the identification of main neurotransmitters in the mammalian brain, notably the previously unsuspected transmitter functions of some amino acids – especially glutamate for excitation and GABA for inhibition; also the slower, muscarinic excitation - shown to be mediated by reduction in K conductance – exerted by acetylcholine and liberated in the cortex by ascending cholinergic fibres from the basal forebrain; as well as the opposite hyperpolarizing action of cytoplasmic Ca ions. These were viewed as possible mechanisms of consciousness and anaesthesia.

This chapter describes the subcellular distribution of glutamate and GABA receptors and voltage-activated channels on the neuronal surface, as detected with a variety of light and electron-microscopic techniques. Ionotropic glutamate and GABAA receptors are concentrated at glutamatergic and GABAergic synapses, respectively, on the somatodendritic domains of nerve cells. Different AMPA receptor subtypes are selectively targeted to functionally distinct glutamatergic synapses of a single cell. Furthermore, synaptic AMPA receptor number and density are also highly regulated at a single cell level.

Recent advances in cellular physiological techniques, particularly the development of in situ whole-cell patch-clamp recording, have permitted detailed physiological and pharmacological studies of proliferating cells in the ventricular and subventricular zones of embryonic neocortex. The results are beginning to shed light on the kinds of signals and cellular interactions that may underlie the regulation of cell-cycle events and gene expression in cortical progenitor cells. This chapter discusses the following topics: gap-junction channels provide an avenue for intracellular communication among cortical progenitors; uncoupling blocks DNA synthesis; the principal excitatory and inhibitory amino acid receptors are expressed before neuronal differentiation; cell-cycle events in the embryonic cortex are influenced by GABA and glutamate; GABA depolarizes ventricular zone cells because of high intracellular chloride concentration maintained by a chloride exchange pump; depolarization mediates the DNA synthesis inhibition induced by GABA and glutamate.

This chapter compares the effect of some selected drugs on food intake, their effects on taste preferences, and their effects on taste reactivity measures. It aims to determine the extent to which it can be inferred that the effects of drugs on hedonic processes contribute to their effects on food ingestion. The findings reveal that the clearest example of drugs that affect palatability are those that act as agonists at benzodiazepine receptors linked to gamma-Aminobutyric acid (GABA)_A receptors.

This chapter describes further experiments in identifying neurotransmitters in the central nervous system. After decades of concentration on acetylcholine and adrenaline/noradrenaline, new studies shifted the focus. Glutamate turned out to be the major excitatory neurotransmitter in the brain as well as the sensory neurotransmitter of dorsal root ganglion cells. GABA turned out to be the major inhibitory neurotransmitter in the brain, with glycine a prominent inhibitory neurotransmitter in the spinal cord. Furthermore, considerations of pathologies and therapeutics fostered an interest in many of the more newly established neurotransmitters, notably dopamine, serotonin, GABA, and enkephalin.

The neurotransmitter γ-aminobutyric acid (GABA) confers neural inhibition in the central nervous system primarily by acting at GABA-gated chloride channels named GABAA and GABAc receptors. Structurally and functionally distinct receptor subtypes are assembled from multiple homologous subunits. Receptor heterogeneity is, however, limited by only partial overlap in the expression pattern of the different subunits and by the rules that govern receptor assembly. GABAc receptors are homo- or heteromers composed of ρl–3 subunits. Formation of GABAA receptors involves initial assembly of α and β subunits followed by the addition of a third type of subunit, most commonly the γ2 subunit.

This chapter integrates and organizes pharmacological studies of memory by searching for generalizations or “rules” about the roles of hormonal and neurotransmitter systems in the regulation of learning and memory processes. In doing so, it is important to examine carefully the extent to which these generalizations are similar and different for results obtained with systemic injections and those obtained with direct brain injections. Consistently, systemic injections of epinephrine or of glucose, which may contribute to epinephrine effects on memory, enhance memory when administered near the time of training. Similarly, systemically administered drugs that promote the functions of central cholinergic, glutaminergic, or noradrenergic systems enhance memory on later tests. Moreover, diminished release of the neurotransmitters or pharmacological blockade of their receptors can impair memory. There also appear to be some neurochemical systems, for example, opioid and GABA, for which activation impairs, and inactivation enhances, learning and memory.

Tuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disorder that can cause circumscribed, benign, noninvasive lesions in any organ (Curatolo 2003; Gomez 1999). It affects about 1 newborn in every 6000 (Osborne, Fryer et al. 1991). The term tuberous sclerosis of the cerebral convolutions was used more than a century ago to describe the distinctive findings at autopsy in some patients with seizures and mental subnormality; the term tuberous describes the potato-like consistency of gyri with hypertrophic sclerosis (Bourneville 1880). The wide range of organs affected by the disease implies an important role for the TSC1 and TSC2 genes encoding hamartin and tuberin in the regulation of cell proliferation and differentiation. Tuberous sclerosis complex is a protean disease: the random distribution, number, size, and location of lesions cause varied clinical manifestations, involving the brain, skin, eyes, heart, kidney, lung (Curatolo et al. 2008). Some lesions, such as renal angiomyolipomas, do not occur until a certain age; by contrast, cardiac rhabdomyomas appear in the fetus and almost always regress spontaneously in infancy (Sosunov et al. 2008). About 85% of children and adolescents with TSC have central nervous system (CNS) manifestations, including epilepsy, learning difficulties, mental retardation, challenging behavioral problems, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), which can be associated with the structural CNS features generally seen in TSC (Curatolo et al. 1991; Gillberg et al. 1994). Abnormalities of neuronal migration and cellular differentiation, and excessive cell proliferation, all contribute to the formation of the various TSC brain lesions including cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), and widespread gray and white matter abnormalities, these latter being identified even in patients with average intelligence (Ridler et al. 2001; de Vries et al. 2005; Ridler et al. 2007). Further characterization of these typical lesions has been provided by progress in structural and functional imaging (DiMario 2004; Luat et al. 2007). Major and minor criteria exist to diagnose TSC (Table 32.1). The diagnosis is made when two major features, or one major and two minor ones, can be detected.