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Drugs and foods can affect your brain and therefore your behavior. It is becoming increasingly difficult to define what is a drug (i.e., something that your brain wants or needs in order to function optimally) and what is a food (i.e., something that your body wants or needs in order to function optimally). The contents of your diet will only act upon your brain if in some way they chemically resemble an actual neurotransmitter within the brain, or if they are able to interact with an essential biochemical processes in your brain that influences the production, release, or inactivation of a neurotransmitter. Drugs and the contents of our diet often interact with these processes and alter how you think and feel. For example, the constant consumption of caffeine, nicotine, sugar, or heroin can produce changes within your brain that lead to craving with their absence from the diet. As far as your brain is concerned, everything you consume is a drug.

The action of neurotransmitters can be terminated by cleavage, diffusion, binding, or cellular uptake. In some cases, uptake is accomplished by glial cells localized at or near the synapse. Glial cells express a variety of neurotransmitter uptake systems, and these systems play a fundamental role in both normal brain function and disease states. All types of glial cells—astrocytes, oligodendrocytes, and microglia—can express transporters for neurotransmitter uptake. This chapter focuses on astrocyte glutamate uptake, which is the most fully characterized of the astrocyte neurotransmitter uptake systems.

Everything known about human behavior suggests it is regulated entirely by the human brain. Brain cells communicate with one another, and with other cells in the body, through small molecules called neurotransmitters (NT). NT are released by neurons, and are picked up by targeted cells through NT receptors (NTR). One place to look for a role of genes in human behavior is the genes controlling NT and NTR. Subtle changes in either of these molecules could have profound effects on behavior, and indeed scientists are beginning to correlate specific mutations in these genes with behavioral alterations. Knowledge of the pathways involved in NT function has allowed development of drugs that modulate these pathways up or down. The NT glutamate and its receptor are critical in learning and memory. A class of drugs called SSRIs (Prozac; Zoloft) can regulate the flow of the NT serotonin throughout the brain, affecting disorders such as depression and impulsivity.

This chapter discusses what has been learned from various approaches for investigating the functional properties of synapses. It focuses on synapses that use glutamate or γ-aminobutyric acid (GABA) as a transmitter, as these represent the vast majority of CNS synapses. It examines the evidence that neurotransmitter receptors are heterogeneous, can be differentially distributed through the dendritic tree, are highly dynamic, and contribute to various forms of synaptic scaling.

This chapter presents basic information related to functional systems of the brain. It describes the patterns of neural activity and the multiple neurotransmitter system. Disorders of the functional system and the effect of psychotropic drugs on the functional system are also discussed. Of great importance in the operation of the functional systems which determine behaviour is the fact that receptors for transmitters are diverse. There are several subtypes of receptor for each neurotransmitter, and the different subtypes mediate different effects.

This chapter discusses pruritus, which is a symptom of chronic cholestatic liver disease. Cholestasis is defined as a syndrome that arises as a consequence of impaired bile secretion and/or flow, which leads to the regurgitation of components of bile into plasma. A pathogenesis of pruritus of cholestasis is unknown. The chapter introduces the concept of pruritus of central origin, and then discusses the opioid neurotransmitter system. The next sections focus on the opioid system and the opioid antagonists.

With the acceptance of chemical neurotransmission came the recognition that synaptic transmission required a number of discrete processes: synthesis of the neurotransmitter, its storage, release, and interaction with receptors and termination of its actions. This chapter is concerned with synthesis, with metabolic degradation, and with two transport steps, one for storing the neurotransmitter in vesicles and one for terminating the responses to released neurotransmitter.

This chapter discusses the modalities of information transfer in the nervous system. The nervous system is organised around specialised cells called neurons, which work as integration units that transform all received information into new information. The neurons generate unitary electric pulses of invariant form and duration called action potentials or spikes. Neurons have an intrinsic firing frequency that is their frequency of producing spikes when they are not influenced. The chapter then considers the two major families of neurotransmitters. In general, a neuron releases only one type of neurotransmitter belonging to one of these two families. The first family is that of excitatory neurotransmitters; the neurons that release them are naturally called excitatory neurons. When they bind with postsynaptic receptors, they have a facilitating effect on the production of action potentials. Meanwhile, inhibitory neurons release neurotransmitters whose binding with postsynaptic receptors decreases the discharge frequency of the postsynaptic neuron. The chapter also describes a special family of neurotransmitters: the neuro-modulators.

The processes within a neuron that are subject to modulation include changes in amplitude or kinetics of the ion channels, the insertion or removal of ion channel proteins from the membrane, changes in the types of ion channels expressed or their localization within the neuron, and changes in release of neurotransmitter from the synaptic terminal. One relatively recently recognized feature of signaling pathways in neurons is that minute-to-minute variations in ion channel properties can be brought about by changing the physical association of the ion channel with its modulating elements. Finally, the activation of biochemical pathways that signal to the nucleus can produce long-term modulation of neuronal excitability by increasing or decreasing the synthesis of proteins required for ion channel expression and function. These mechanisms provide the means whereby one neuron can alter the properties of another neuron and are thus crucial for plasticity observed in the nervous system.

Buspirone's initial clinical development involved treatment of chronic anxiety in patients generally corresponding to the DSM-III. Dysfunction of central serotonergic neuronal systems is implicated in mood disorders, and treatment of these disorders has recently been focused on this neurotransmitter. The 5-HT_1A partial agonists possess a pharmacological profile predictive of both antidepressant and anxiolytic activity. Placebo-controlled studies with buspirone and gepirone in depressive disorders have shown that these agents produce significant therapeutic benefit. Buspirone and gepirone treatment resulted in global improvement of depressed patients, and specifically benefited symptoms of depressed mood, work and activity, anergia, diurnal variation, and other cardinal symptoms of depression.

The plasticity of the adult nervous system allows it to learn new things and remember them, to adapt to change and to recover from injury. This chapter describes a developmental approach to tackle the technical problem faced in identifying molecular changes underlying plasticity based on the premise that the maturational events of normal brain development offer an experimental model for the study of synaptic plasticity. The many events involved in normal synaptogenesis can be divided into two broad phases: synapse formation and synapse maturation. The postsynaptic density is a protein-rich specialization on the cytoplasmic surface of the postsynaptic membrane at most synapses, irrespective of neurotransmitter type. There is clear evidence from biochemical and morphological studies that, in the forebrain as a whole, synapse formation is still occurring rapidly at hatching and is not complete until about 1–2 weeks post-hatch.

Animals acquire information about the world through the process of learning, and store that information as memory. Central as the storage process is to adaptive behaviour, progress in understanding its neural bases have recently shown clear signs of being successful. Young chicks approach a wide range of conspicuous objects. If the chicks continue to be exposed to a particular object, they learn its characteristics. If their preferences are subsequently tested the chicks selectively approach the training or imprinting object and may not approach, or may actively avoid a novel object. When neurotransmitter molecules are liberated from the presynaptic bouton, they diffuse into the synaptic cleft and bind to receptors present in the postsynaptic density. Learning leads to changes in the connections made between neurons, representing specific memories. There is evidence that some of the changes are closely tied to learning.

Many events can alter the neurotransmitter phenotype of central nervous system (CNS) neurones. For instance, most neurones down-regulate their neurotransmitters and the enzymes that make them after axotomy or other forms of damage. Neurotrophins tend to cause neurons to upregulate their neurotransmitter phenotype or even change it, and neurotrophins often prevent the downregulation of neurotransmitter phenotype after damage. There are so many examples of these types of behaviour that it would not be sensible in this book to try and detail them all. However, there are two particular experimental models in which neuroplasticity of this type has been analysed in detail, and this chapter describes them.

Constipation is common among older adults, in general. However, it is very common among people with Lewy body disorders, and the reason is dysautonomia. Lewy body disorders tend to impair control of gut motility by the autonomic nervous system. At the stomach level, bloating may develop when the stomach fails to empty into the upper small intestine. At the other end, constipation is the consequence of Lewy processes affecting motility in the colon. Colon motility (peristalsis) is what moves the remnants of digested food (stool) to the rectum for expulsion. These regions are shown in Figure 15.1. Drugs that block the neurotransmitter acetylcholine are notorious for worsening constipation; these include medications used to treat urinary urgency (overactive bladder). All of the anticholinergic drugs for bladder overactivity that were listed in Table 12.1 cause constipation, as does another bladder drug, trospium (Sanctura). The tricyclic drugs for depression shown in Table 12.1 have variable anticholinergic properties and also tend to be constipating. One needs to balance benefits against the side effect of constipation if considering these medications. In the setting of DLB or PDD, constipation is typically due to autonomic nervous system dysfunction, often exacerbated by medication side effects. However, there are exceptions and the primary care clinician or internist should consider whether colonoscopy is appropriate. This procedure involves inserting a scope into the anus and then advancing the instrument to visualize the entire colon. In this way hidden colon cancers are detected before they become deadly. It is common knowledge that several natural remedies help prevent constipation: fruits, vegetables, fluids, and fiber. Individuals with constipation should make sure that their diet includes adequate fruits, which make a good snack. Meals should include vegetables, such as green beans, peas, and squash; catsup and potatoes do not count as vegetables. Intake of six to eight tall glasses of water, juice, or other fluids may help maintain moisture in the stool, making it easier to pass. Finally, fiber needs to be included in the diet in order to give the stool bulk. These strategies are often insufficient for persons with Lewy disorders, and additional measures are often necessary.

This chapter focuses on the basics of brain anatomy and function. We begin with individual neurons and principles of neural signaling, and then move on to gross brain structure to help orient the reader to the parts of the brain often implicated in neuroscience work that may have legal relevance. The rest of the chapter is devoted to introducing the functional subsystems in the brain that mediate higher cognitive functions. We discuss executive functions that may be important to law, including memory, cognitive control, attention, and moral cognition. In the concluding section we identify common errors that are made in interpreting neuroscience information.

Affective disorders are described with respect to a model of positive and negative affect, which suggests that clinical depression may result both from an impairment of reward anticipation and experience as well as from an increase in negative affect, which correlates with increased activation of limbic circuits associated with fear and anxiety. Dopamine and serotonin dysfunction interacting with such functional alterations are described, and stress effects on these neurotransmitter systems are discussed. The dimensional approach to affective disorders is explained with respect to different syndrome clusters reflecting negative affect and clinical depression.

ADHD is usually due to a depletion of certain chemical messengers in the front part of the brain. The major cause of this depletion relates to a number of defective genes. ADHD shares some of its causative genes with certain other conditions, so having ADHD makes also having these other conditions more likely. To help many children with learning and behavioural difficulties, we need to treat an impairment in their brain function. This chapter discusses impairment in brain function as a cause of ADHD, including executive function deficits, frontal lobe underactivity, neurotransmitter depletion, gene defects, and non-genetic factors. It also describes the mechanism of comorbidity.