Victor J. Dzau, MD

• Professor of Medicine
• James B. Duke Distinguished Professor of Medicine
• Professor of Pathology

https://medicine.duke.edu/faculty/victor-j-dzau-md

A common scenario may be that the goal of a possible action is selected within the limbic or orbitofrontal circuit top rated erectile dysfunction pills buy viagra extra dosage with american express, passed on to the dorsolateral prefrontal circuit for selection of the implementation strategy erectile dysfunction doctors huntsville al buy viagra extra dosage mastercard, and finally passed to the skeletomotor loop for selection of a motor plan to execute the action goal of erectile dysfunction treatment viagra extra dosage 120mg low price. Although the basal ganglia loops operate in parallel erectile dysfunction drugs in the philippines purchase viagra extra dosage 120mg fast delivery, information can flow between loops through erectile dysfunction mayo clinic buy viagra extra dosage 150mg without prescription, for example erectile dysfunction endovascular treatment proven 130mg viagra extra dosage, promiscuous connections from thalamus to multiple areas of cortex. One illustration of this possibility is the projection from neurons in the ventral anterior nucleus of thalamus to cortical regions that participate in both executive function and movement execution loops. Since information may, but does not always, flow between basal ganglia loops, movement can proceed with or without an associated thought or feeling. One can readily discern the difference between a phone conversation with a friend who is reading email while talking to you and one with a friend focused entirely on conversing with you. To accomplish this variety of behaviors, the basal ganglia can, but does not always, couple action selection to emotions or thoughts. We can imagine that when all the loops engage in concert toward a common goal, we act with "heart," reflecting "singleminded" engagement. Perhaps when only the dorsolateral prefrontal and skeletomotor loops act in concert, we act methodically and deliberately, and when the skeletomotor loop operates solo, we "go through the motions. Some habitual actions may not need motivational or emotional support under most circumstances-a chef dices carrots at rapid speed while happily thinking about an enjoyable date the night before or an upcoming trip, a commuter drives home while thinking about the past day. However, there may be circumstances incompatible with successful completion of the same, normally automatic chunks-the same talented chef goes to work worried about a gravely ill mother and ends up cutting a finger instead of carrots, the commuter drives homeward after hearing bad news and crashes. Other actions clearly require motivational and emotional commitment for successful completion-an actor performing in a play, a parent trying to calm a child, an athlete competing in a championship game. In sum, between-loop crosstalk allows coupling of movement with emotion, intent, and focus. Neuropsychiatric disorders may result from deficits in one or more of the nonmotor basal ganglia loops. Basal ganglia dysfunction is implicated in neuropsychiatric diseases such as obsessive compulsive disorder and schizophrenia. Since the basal ganglia are involved in the selection of thoughts, strategies, perceptions, motivations, emotions, and goals, their heavy involvement in psychological function should come as no surprise. People with obsessive-compulsive disorder perseverate, continuing to select a single action (compulsion) or thought (obsession) over and over, long after the action or thought has outlived its utility. Both structures communicate indirectly with the motor hierarchy, only affecting motor neurons and motor interneurons through an indirect route. Both structures receive at least an order of magnitude more information than they send out to target structures, making them processing bottlenecks that reduce an overwhelming confusion of conflicting input to a concise and decisive winner-takes-all output. Furthermore, the basal ganglia are critical to , and the cerebellum may influence, many nonmotor functions, processing thoughts, emotions, and memories, all of which, of course, ultimately influence movements. Even the functions of the two, in sequencing movements and learning associations, overlap. In marked contrast to the case with the cerebellum, the basal ganglia do not receive peripheral or spinal input. Instead, input to the basal ganglia comes from virtually all areas of the cerebral cortex, as well as from subcortical regions that can themselves direct movement, such as the superior colliculus. Thus, the cerebellum receives information about muscle contractions, whereas the basal ganglia only receive input about movements and actions. Sensory input to the cerebellum comes from the spinal cord and represents the sensory consequences of movement. In contrast, neurons in cortical and brainstem regions interpret and then present sensory information about the world to the basal ganglia. Consider the sequential versions of an action, from motivation and selection of a goal in prefrontal cortex to action in motor cortex, to movement in the ventral horn interneurons, and muscle control in the -motoneurons. The basal ganglia receive motor information biased toward goal selection and action, whereas the cerebellum receives information biased toward movement and muscle contraction. The cerebellum smoothes out movements, important and trivial ones alike, whereas the skeletomotor loop of the basal ganglia ensures that salient actions take priority over automatic, mundane ones. The nonmotor functions of the cerebellum and basal ganglia may similarly diverge, with the cerebellum focusing on automatic associations and the basal ganglia on matching motivation, thought, emotion, strategy, and movement to urgency and circumstance. The cerebellum associates sensory input with motor output, so that a set of inputs related to the body and the outside world-an entire sensory gestalt-becomes associated with a particular movement. In contrast, the basal ganglia associate self-generated actions with their consequences, biasing present and future selection of actions toward previously rewarding ones. Ultimately, our actions are those dictated by the cerebellum and the basal ganglia, incorporating influences from the sensory world as well as from our cognitive, motivational, and emotional states. Complementary roles of basal ganglia and cerebellum in learning and motor control. The basal ganglia downstream control of brainstem motor centres-an evolutionarily conserved strategy. Pathophysiology of the basal ganglia and movement disorders: From animal models to human clinical applications. Evolution of the basal ganglia in tetrapods: A new perspective based on recent studies in amphibians. The striatum and subthalamic nucleus as independent and collaborative structures in motor control. Pushing typists back on the learning curve: Revealing chunking in skilled typewriting. What is exceptional about the nervous system is all that the brain does beyond simply sustaining life: perception, action, thought, emotion. We view the liver, skin, pancreas, heart, and so on through a single lens: how well do they support the life of the owner The nervous system, which also makes enormous contributions to sustaining life, is rarely viewed through this lens. Without a hypothalamus to drive food- and water-seeking and consumption, life ends. Without distributed thermoregulatory defenses, the body overheats during a summer walk around the block and life is over. In this section, we examine several ways in which the nervous system sustains life. As the modern epidemic of overweight makes clear, rational, emotional, and perceptual factors strongly influence food acquisition and consumption. Effectors of thermoregulation such as sweating and cutaneous vasodilation do double duty as both defenders of core temperature and as emotional reactions. Cannon wrote a book titled the Wisdom of the Body, which popularized the idea that the body contains an organized system of defenses that maintain physiological variables such as body temperature and blood glucose within optimal ranges. Homeostasis is defined as the collection of physiological processes and behavioral actions that keep the internal milieu of the body steady or sufficiently so to support good health. On a daily time scale, the nervous system sets a circadian rhythm that organizes the timing of many physiological processes, such as ingestion, digestion, and hormone secretion. On a seasonal time scale, homeostatic limits are adjusted to the seasonal environment so that, for example, we feel chilly during the summer at an ambient temperature that is perceived as balmy in wintertime. Finally, our bodies continue to operate even as we move through our life cycle, growing, maturing, and aging from birth to death. Therefore, when a house door is opened on a cold wintry day, the heating system kicks in after room temperature has already dipped below the set temperature range. Small changes in core body temperature (dotted red line) that are quickly opposed may occur in very cold conditions. To take an example from thermoregulation, consider the core body temperature of a person (or pet) that leaves a heated house to walk into subfreezing temperatures. Deviations are prevented before they ever could happen through anticipatory thermoregulatory adjustments. Neural adjustments initiated by sensory input, circadian zeitgeist, or cognitive experience effectively prevent large deviations from homeostasis. For example, even as one moves from one temperature extreme to another, core body temperature does not change instantaneously; we are insulated beings after all. The lag in time allows for cutaneous thermoreceptors to send a message that elicits thermoregulatory adjustments before core temperature has a chance to budge. A circadian example of an anticipatory adjustment is the insulin release that precedes eating at roughly the same time as the day before. As a result of homeostatic mechanisms, physiology is remarkably steady across a wide variety of conditions. Continuing the example of thermoregulation, it is true that neurons within the hypothalamus are directly sensitive to temperature. Thermoreceptive neurons that innervate the skin sense ambient temperature changes and initiate physiological and behavioral reactions before the hypothalamus temperature ever changes. A second line of defense is a set of deep thermoreceptors surrounding internal organs including the spinal cord. Thus, peripheral sensory afferents serve as thermoregulatory sentries that, fortunately, prevent even small changes in brain temperature that can produce adverse effects such as extreme lethargy, confusion, and disorientation. The hypothalamus is certainly important to homeostasis and is a key site where hormones act to engage physiological adjustments. The hypothalamus also serves as an integrator for the coordination of different homeostatic systems so that, for example, a lower core body temperature is tolerated during sleep. Yet, the hypothalamus only achieves homeostasis by working in concert with neurons in the telencephalon, brainstem, spinal cord, and periphery. Another misconception, namely that homeostatic functions depend entirely on the autonomic nervous system, is so entrenched that many use autonomic and homeostatic as synonyms. The most obvious example that exposes the fallacious equivalency between autonomic and homeostatic is breathing. Breathing, absolutely critical to life, depends primarily on the diaphragm, which is skeletal musculature and under voluntary control. Most homeostatic function requires cooperation between skeletomotor and autonomic neurons. For example, micturition depends on the contraction of the detrusor muscle, a smooth muscle controlled by parasympathetic neurons, and the voluntary relaxation of the external urethral sphincter, a skeletal muscle controlled by sacral motoneurons. And this does not even speak to the need for an appropriate voiding posture that is entirely dependent on skeletomotor muscle control. In any case, a deviation outside of the acceptable range is not required for homeostatic adjustments to occur. The idea that homeostasis keeps the body in a constant, invariant state is rooted in its etymology because the Greek root homolos means "same" or "like. The pounding heart and dilated pupils that precede a bungee jumping adventure would not accommodate an afternoon nap on a rainy afternoon. Nor would the warm relaxed body that yields to an afternoon nap support bungee jumping. Each is simply appropriate for some sets of activities and entirely inappropriate for others. Allostasis is a term that acknowledges the changing nature of body physiology, with allo coming from the Greek root for "variable. The homeostatic approach to high blood pressure is to prescribe pharmacological drugs such as diuretics, -blockers, and the like. In contrast, the allostatic perspective holds that an elevation in blood pressure is the proper response to a brain state of heightened arousal, perceived danger, or the like. Exactly this response has evolved over thousands of years and has served humans and other mammals extraordinarily well through evolutionary time. Now consider that a person lives with a perception of danger, stemming from a military war, crime, poverty, social isolation, or the like. After a steady need for vigilance during the past stretch of time, the brain has learned to predict that vigilance will again be needed today, tomorrow, next week, and next month. According to this view, therapy should be directed toward a modification of the brain state that has essentially put an individual into a chronic state of heightened fight-or-flight readiness. It should not be directed at downstream players, such as peripheral sympathetic neurons or cardiac muscle, which are simply and correctly following orders. Taking the allostatic approach to disease necessarily widens the purview of medicine. It suggests that the conditions that put people into steady states of fear and danger are the true causes of at least some modern scourges. The allostatic lens further suggests that the cure for diseases such as hypertension and diabetes may be found in public parks, access to fresh food, and economic opportunities before it is found in molecular moieties. As introduced in Chapter 7, a group of neurons that controls hormone release is present in animals from worms to mammals. In vertebrates, hormone release is the core function of the hypothalamus around which many embellishments arose. Excessive voiding of dilute urine leads to insufficient hydration, marked by elevated plasma osmolarity and a feeling of thirst. This vicious cycle leads to high plasma osmolarity and low urine osmolarity, the cardinal signs of diabetes insipidus. The end result is greatly increased intake and output of fluid as though the affected person were a siphon, the Greek word for which is the root of the word "diabetes. Diabetes insipidus is distinct from diabetes mellitus, a condition in which glucose is not appropriately processed by insulin. A major difference between the two conditions is that the urine in patients with diabetes mellitus contains elevated levels of glucose (mellitus is derived from Greek words meaning "honey sweet"), whereas the urine in patients with diabetes insipidus does not.

The routine laboratory evaluation for tremor should include thyroid function and other labs as clinically appropriate erectile dysfunction jackson ms buy viagra extra dosage 150mg. Proposed genetic mechanisms include potential polygenetic or epigenetic interactions or mitochondrial disorders buy generic erectile dysfunction drugs purchase 150 mg viagra extra dosage. It is typically symmetric in nature and involves the hands and arms erectile dysfunction prevents ejaculation in most cases purchase viagra extra dosage amex, becoming most apparent when holding arms in outstretched position erectile dysfunction ginseng buy cheap viagra extra dosage 120 mg online. Isolated head tremor may occur but must be distinguished from dystonic head tremor (which is usually due to cervical dystonia) erectile dysfunction treatment electrical cheap viagra extra dosage 200mg otc. Vocal tremor is best assessed by having the patient sustain a vowel sound such as "Ah erectile dysfunction over 50 120 mg viagra extra dosage mastercard," and listening for variance in the pitch and amplitude of the sound. If you would like a good example of what that sounds like, it is recommended that you watch a movie featuring Katherine Hepburn later in her career. If a leg tremor is suspected, then having the patient hold the leg with the knee extended in a seated position will often produce a tremor. If the tremor is difficult to elicit, an effective strategy is to ask the patient what activity generally produces the tremor, and try to reproduce that activity in the room. Sometimes this may be better done by having the patient send a video of this activity later, or reevaluating on a return visit where they bring the object that induces the tremor. In addition to the positive findings that suggest tremor, there are red flags that would make the diagnosis unlikely. Indeed, much of the evaluation of tremor is accomplished with a thorough history and physical examination. Common disorders associated with tremor will be described below to outline both salient clinical features along with basic evaluation and treatment options. There has been growing evidence as well that those patients with essential tremor for many years are much more likely to have mild to moderate cerebellar gait ataxia in addition to the tremor. They are equally efficacious for the treatment of tremor, each reducing tremor magnitude by approximately 50%. It is estimated that approximately 30% of individuals will not respond to these firstline agents. Sotalol and atenolol do have level B evidence as secondline agents, and metoprolol has not been sufficiently studied. Primidone can be sedating and caution should be used in elderly individuals as it is a barbiturate derivative and may cause confusion. Other second line agents, including gabapentin (monotherapy) and topiramate, were found to have level B evidence of effectiveness at treating limb tremor. Gabapentin is found to be effective in monotherapy, but not as an adjunct therapy for limb tremor. Benzodiazepines were considered potentially useful, but caution was recommended due to potential for abuse. Recent work has found that patients with essential tremor are much more likely to have mild gait ataxia in the later stages of the disease. These clinical findings have come at the same time as pathology showing changes within the cerebellum with loss of Purkinje cells. This suggests that the pathological 20 Non-Parkinsonian Movement Disorders Table 3. Leviteracetam, trazodone, and 3,4diaminopyridine were not effective, and the recommendation is that they should not be considered (level B evidence). For medically refractory tremor, botulinum toxin has Level C evidence for limb, head, and voice tremor. Medically refractory patients may also be considered for surgical options, which will be discussed below. A referral to occupational therapy is often useful in these patients as there are numerous products now available for tremor reduction. These include lowtech options such as adding weight to common household objects, and newer hightech options that use accelerometer data and robotic motors to sense and counteract tremor frequency movements. Mouse adapter to avoid multiple clicks or cursor tremor Utensils with accelerometers and pivot motors that can cancel tremor frequency Surgical treatment Surgical intervention is an option for those individuals whose tremor remains disabling despite adequate trials of optimal pharmacologic therapy. As with any surgical procedure, care should be used in selecting a surgeon who has adequate procedural volume to maintain skills in these stereotactic surgical techniques. Untreated essential tremor can be very disabling, so pharmacologic and, if needed, surgical intervention have very favorable outcomes that may justify risks of treatment. Druginduced tremor Some degree of tremor occurs in all human beings and is commonly referred to as physiologic tremor. In clinical practice, the term enhanced physiologic tremor is frequently used to refer to tremor exacerbated by drugs or circumstances that increase adrenergic activity. Differentiating druginduced tremor from other causes of tremor requires a thorough history and physical examination of the patient. A temporal relationship to the initiation of pharmacologic therapy is very useful in making the diagnosis. Tremor severity is typically dose dependent and improves with cessation of the drug. The exception is druginduced parkinsonian tremor that occurs at rest and can be asymmetric in onset. A list of substances and medications that are associated with tremor is provided in Table 3. Because valproate is commonly prescribed for various neurologic disorders, including epilepsy, migraine prophylaxis, and mood stabilization, tremor due to this drug is also common. Alcohol withdrawal classically has an associated postural tremor, and alcoholism can cause tremor as a downstream effect of chronic liver disease. Treatment of druginduced tremor may not be necessary, as the majority of patients do not feel that the tremor interferes with their daily activity. This is because most patients with druginduced tremor have lowamplitude postural tremor. Other important fiber tracts in tremor production include thalamocortical loops and tracts from the brainstem to the basal ganglia. It is likely that these loops set up oscillations in motor control at varying frequencies, and theoretically these oscillations reverberate to create tremor. It is important to note that dopamine blocking agents also include antiemetic drugs such as metoclopramide. If this is not an option clinically, then treatment is often initiated with an anticholinergic medication such as benztropine or trihexyphenidyl. Parkinsonian tremor Classic parkinsonian tremor is asymmetric in onset, occurs at rest, and becomes less prominent with posture and action. It has been described as a "pill rolling" tremor as it typically affects the thumb and index finger, mimicking the action of rolling a pill between these two digits. Although usually rest tremor is predominant, tremor may be present with posture, and action; in this case, the clinician pays more attention to which tremor state has a greater degree of tremor than others. Clinically, this distinction can be difficult at times as, when a tremor becomes more severe, it can move from a more pure rest tremor to be present with posture and intention. One key clinical point here is that the tremor will typically be more severe with one of these positions. In 2011, the United States Food and Drug Administration approved the use of DaTscans to detect dopamine transporters (DaT) in individuals with parkinsonian syndromes. This imaging modality causing functional impairment, and it is a clinically viable option, the most efficacious response is generally to stop the causative medication. If this is not a viable option, and the medical condition requiring the tremorogenic drug requires treatment, switching to an equivalent nontremor causing agent would be reasonable. An example of this would be a patient on valproate or lithium for mood stabilization purposes, who could be switched to lamotrigine, which is much less likely to cause tremor but is still an effective agent. If none of these are options, then use of a tremorreducing agent such as propranolol or a benzodiazepine is a consideration. Although the majority of parkinsonian tremor cases will respond to dopaminergic medications, not all patients will respond; some parkinsonian tremors can be very resistant to treatment. In these cases, one option is to use an anticholinergic medication such as trihexyphendyl or benztropine. These must be used carefully in elderly patients due to the potential side effects of anticholinergic medications. Also included in this category are antiemetics like metoclopramide, promethazine, prochlorperazine. The diagnosis of functional tremor can be challenging, and often will require referral to a movement disorders specialist. Diagnosis is based on exclusion of organic causes of tremor and supported by acute onset and resistance to treatment. The diagnosis is also supported by variability of symptoms over time, and if the tremor comes and goes in discrete paroxysmal episodes that last for hours to days. In some cases, a precipitating event such as a personal life stressor, trauma, or major illness can be identified. On examination, functional tremor will vary in its appearance throughout the course of the clinic visit. The amplitude and the frequency of functional tremor are highly variable and diminish with mental distraction maneuvers. Another characteristic feature of functional movement disorders is "entrainment" and can be evaluated by having the patient tap his fingers with the contralateral (nonaffected) hand. If the tremor of the affected hand then shifts to match the frequency of tapping hand, this is entrainment and is suspicious of functional tremor. In general, clear communication that the tremor is not due to a lifethreatening disease, and that this may potentially resolve with time is essential. It is important to remain empathetic when expressing this information, and also to clarify that the functional movements are not considered to be under voluntary control of the affected individual. Pyschotherapy has been found to have a variable response, as has use of physical therapy. Specific medication treatment and ordering of diagnostic studies that are not absolutely necessary is not generally helpful. Decreases in size with distractibility Variable and will often move from one side of the body to the other Amplitude Location of tremor. The name rubral tremor comes from the fact that lesions of the red nucleus in the midbrain can cause this clinical sign. Cerebellar tremors can be associated with any fiber tracts or structures that send close connections to the cerebellum. The potential causes of a cerebellar tremor mirror the potential causes of cerebellar ataxia, which are described in a separate chapter. The common causes of cerebellar tremor include multiple sclerosis, cerebrovascular disease, autoimmune encephalitides, and a host of other potential etiologies. Wilson disease is caused by mutations in copper metabolism causing abnormal accumulation of copper. This disease is usually diagnosed by testing for serum ceruloplasmin, serum copper, and a 24 hour urine test for copper levels. A liver biopsy can be also diagnostic as there is copper accumulation in the liver. Once copper levels have been decreased, dietary copper restriction and treatment with zinc to compete with copper for gut absorption are also used. Dystonic tremor Tremor can often be a presenting symptom of dystonia of any part of the body. The tremor shares some common phenomenology with functional tremor, and this may delay diagnosis of a dystonic tremor. However, the dystonic tremor will be more predictable as to when it worsens in that it is always going to get worse with a consistent direction of the movement. For example, in a cervical dystonia, as the neck is turned away from the overactive muscle group, the tremor will increase in amplitude. Dystonic tremor may also reliably respond to a caution Dystonic tremor is often difficult to diagnose. The presence of a sensory trick, and the irregular nature of the tremor coupled with chronic pain complaints make some physicians call this a functional disorder. There is some controversy about tremors that primarily occur in a taskspecific manner. In this condition, there is a rhythmic tremor that only occurs when the patient writes. Interestingly, when the patient uses the same hand to do other activities, like typing, the tremor may not be present at all. Conclusion Tremor is the common movement disorder, and careful attention by the clinician can lead to a definitive diagnosis. Categorizing the tremor as rest, postural, or intention will aid in the differential diagnosis. Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. Some people are able to adequately treat the symptoms by simply bringing along with them a portable seat so that they can sit down any time they have to stand for a long time. Other treatment options include gabapentin, primidone, and dopaminergic medications.

In addition alcohol and erectile dysfunction statistics purchase viagra extra dosage online, a number of mutations in uptake transporters are associated with personality traits such as impulsiveness or aggression erectile dysfunction venous leak viagra extra dosage 150mg discount. The modes of synthesis erectile dysfunction young adults treatment cheap viagra extra dosage express, packaging erectile dysfunction pills natural best viagra extra dosage 200mg, and release and the activated receptors and mechanisms of termination of neurotransmitter action for low-molecular-weight and peptide neurotransmitters are summarized in Table 12-1 erectile dysfunction doctor nashville cheap 130mg viagra extra dosage with visa. A common feature of low-molecular-weight neurotransmitters is that their production is tied to neuronal activity impotence bike riding order 120mg viagra extra dosage overnight delivery. As you recall from basic chemistry, enzymatic activity depends on the concentrations of substrate and product (termed the law of mass action). The dependence of enzyme activity on the concentrations of substrate and product is critical to understanding neurotransmitter synthesis in the nervous system. When neurotransmitter-the product-is abundant, the rate of neurotransmitter synthesis decreases, whereas when neurotransmitter supply is depleted, the rate of synthesis increases. Therefore, an important modulator of the activity of many neurotransmitter-synthesizing enzymes is neural activity. When neural activity changes for a sustained period of time, adaptive changes may occur. Persistent increases in neural activity can lead to increased production of neurotransmitter by any number of modifications, such as increasing the activity of the synthesizing enzymes or the affinity of the enzymes for a co-factor or by decreasing the affinity of an enzyme for an inhibitor. Regardless of the mechanism, short- and long-term mechanisms that link the rate of neurotransmitter synthesis to neurotransmitter release ensure that the supply of neurotransmitter remains in line with demand. After synthesis, low-molecular-weight neurotransmitters are transported into vesicles. This proton gradient-low in the cytosol to high in the vesicle-is then used by the vesicular transporters to "load" neurotransmitter into the vesicle. As mentioned earlier, we divide low-molecular-weight neurotransmitters into five categories based on the synaptic vesicle transporters. The correspondence between the five types of vesicular transporters and the five classes of low-molecular-weight neurotransmitters is shown in Table 12-2. In addition, acetylcholine is found in neurons in a restricted number of brain regions such as the basal forebrain. The small number of cholinergic, or acetylcholine-containing, neurons have widespread axonal projections that reach throughout the brain and spinal cord, playing a key role in facilitating learning and attention. For example, histaminergic (histamine-containing) neurons are only found in the tuberomammillary nucleus of the hypothalamus but reach all parts of the brain and spinal cord through widely projecting axons. A common misconception is that modulation is a code word for an unimportant contribution with only minor consequences. However, modulation is key to nervous functions that range from motor reflexes, thermoregulation, and walking to attention, learning, and cognition. Dysfunctions of modulatory pathways can lead to severe neurological diseases such as dementia (Box 12-1) or schizophrenia. However, they may delay symptoms in some people and improve function in fewer people. Aspartate, another amino acid, acts as an excitatory neurotransmitter in relatively few select regions of the brain. Adenosine, a purinergic nucleoside present in all cells, acts as an inhibitory neurotransmitter and may be important in promoting sleep. As most readers are personally aware, the adenosine receptor antagonist caffeine promotes wakefulness. Recall that it is the neurotransmitter used by all somatic motoneurons, preganglionic autonomic neurons, and postganglionic parasympathetic neurons. In the brain, acetylcholine plays a critical role in cognitive health through modulating attention, memory, arousal state, and the like (see Box 12-1). Under normal circumstances, dietary intake is the source of choline, the substrate for choline acetyltransferase. The choline transporter within the plasma membrane of cholinergic terminals transports choline from the extracellular space and into the synaptic terminal. The choline transporter has a high affinity for choline, meaning that it can act on choline that is present at very low concentrations. B: the synthesis, packaging, release, breakdown, and uptake mechanisms involved in cholinergic transmission are illustrated in situ. Production of acetylcholine follows the law of mass action, by which the rate of any reaction in dynamic equilibrium is proportional to the cytosolic concentrations of the substrate-choline in the case of the end-product acetylcholine. As acetylcholine is transported into recycling vesicles, free acetylcholine concentration decreases and production increases. Substrate availability also plays a role because a higher concentration of choline than of acetylcholine will favor acetylcholine production, whereas a higher concentration of acetylcholine than of choline favors acetylcholine degradation. Numerous esterases, enzymes that break acetylcholine down into choline and acetate, are present in the cytosol of the synaptic terminal. These esterases complicate the situation with neuronal production of acetylcholine because two enzymatic reactions are involved: choline acetyltransferase that produces acetylcholine and esterases that break it down. Acetylcholine is a substrate for esterases as well as the end-product of choline acetyltransferase, whereas choline is the substrate for choline acetyltransferase as well as the end-product of esterases. When acetylcholine builds up, choline acetyltransferase activity decreases and esterase activity increases, leading to a net breakdown of acetylcholine. In contrast, when choline builds up, choline acetyltransferase activity increases and esterase activity decreases, leading to a net synthesis of acetylcholine. In this way, large deviations in the concentration of acetylcholine away from equilibrium are prevented. Extracellular choline is taken up by a choline transporter in the synaptic terminal, providing substrate for further synthesis of acetylcholine. A large number of drugs and toxins ranging from efficacious therapeutics to insecticides to agents of biological warfare interfere with acetylcholinesterase function (see Box 12-2). Prolonging cholinergic signaling is therapeutic in conditions such as myasthenia gravis, in which cholinergic signaling is reduced. Myasthenic patients are weak because of a reduction in the number or clustering of acetylcholine receptors present on skeletal muscles (see Chapter 13). Edrophonium, a very short-acting anticholinesterase, is used as a diagnostic tool: a patient with myasthenia gravis can sustain a stronger muscle contraction for a longer time after edrophonium. Longer acting but still reversible anticholinesterases such as neostigmine provide effective treatment for patients with myasthenia gravis. Insecticides such as parathion are irreversible anticholinesterases and, at sufficient doses, can kill humans as well as insects. Finally, agents designed to kill humans, such as sarin, are, like insecticides, irreversible anticholinesterases. Customarily, Americans use norepinephrine and epinephrine, as I do in this book, whereas Europeans employ noradrenaline and adrenaline. Note that neurons that contain norepinephrine are referred to as noradrenergic and those that contain epinephrine are referred to as adrenergic in America and Europe alike. Receptors that bind norepinephrine or epinephrine are universally referred to as adrenergic receptors. The five different monoamines depend on different synthetic pathways, and their actions are terminated by different mechanisms. All of these reactions except the conversion of dopamine into norepinephrine take place in the cytoplasm, and this exceptional reaction takes place within the synaptic vesicle. B: In dopaminergic, or dopamine-containing, terminals, the vesicular monoamine transporter transports dopamine, made in the cytoplasm, into synaptic vesicles. Cytosolic epinephrine is transported back into the synaptic vesicle by the vesicular monoamine transporter. Note that adrenergic, or epinephrine-containing, terminals contain all of the catecholaminergic enzymes. In dopaminergic terminals (B), only dopamine is synthesized and transported into vesicles. However, in noradrenergic terminals (C), norepinephrine predominates but lesser amounts of dopamine are present. Similarly, in adrenergic vesicles (D), some dopamine and norepinephrine are present along with mostly epinephrine. A second similarity among monoamines is the paucity of classical synapses involving a presynaptic element and a postsynaptic element separated by a narrow synaptic cleft. Instead, monoamines appear to depend primarily on volume, also termed paracrine, transmission meaning that monoamine neurotransmitters may act at some distance from the site where they are released. Thus, the presynaptic monoaminergic release site is often simply a varicosity at some distance from the postsynaptic receptors where a released monoamine binds. By current estimates, monoamines can travel up to 20 microns, a staggering distance, before decreasing to an ineffective concentration. Considering that a typical synaptic cleft is on the order of 30 nanometers across, the extracellular distance potentially traveled by monoamines is almost 1,000 times greater than the distance traversed by a neurotransmitter at a classical synapse. The upshot of volume transmission is that monoamines released from one site act on a large number and variety of cells located anywhere within a large radius from the site of release. Epinephrine-containing neurons are contained in both the brainstem and hypothalamus and appear to be important for cardiovascular regulation as well as for other homeostatic functions. Although brain epinephrine systems are not as well studied as dopaminergic and noradrenergic ones, they may nonetheless play as of yet unheralded and critical roles. Because pharmacological manipulations of these transmitters consistently alter affect and mood, drugs that affect the synthesis and uptake of serotonin, dopamine, and norepinephrine are typically termed psychotropic. Psychotropic drugs affect our psychological functioning and are used to treat a number of disorders that are typically classified as psychiatric. Although many think that a decrease in serotonergic transmission leads to depression, an excess of serotonin to aggression, and so on, precise alignments between particular monoamine deficits and particular psychiatric disorders have eluded investigators to date. One reason for this difficulty is that many psychotropic drugs, such as those used to treat depression, must be taken for weeks before providing any relief, presumably because long-term changes in transmitter metabolism and receptor responsiveness are necessary for clinical efficacy. Furthermore, although one monoamine may play a primary role in any given psychiatric disorder, serotonin, dopamine, and norepinephrine are all likely to contribute. The two-step process from tyrosine to dopamine occurs entirely in the cytosol of synaptic terminals. It may seem strange that norepinephrine is made in the vesicle rather than the cytosol. In fact, norepinephrinecontaining vesicles also contain a small amount of dopamine. As with acetylcholine, the law of mass action applies to catecholaminergic synthesis. The more catecholamine product present, the less is synthesized; the more substrate present, the more catecholamine is synthesized. Clinicians noticed that treated patients appeared happier although their tuberculosis remained problematic. Men in this family exhibit a pathological and explosive form of aggression and impulsive destructive behavior. This is because, normally, phenylalanine hydroxylase converts phenylalanine, an essential amino acid, into tyrosine. Different mutations give rise to different degrees of phenylalanine hydroxylase dysfunction from less efficient catalysis to no activity in the case of null or missense mutations. Since virtually every natural source of protein, including eggs, meat, fish, eggs, cheese, nuts, flour, and soy contains phenylalanine and should be avoided, amino acid supplements are necessary. The goal of the diet is simple: to keep phenylalanine below levels that cause neurological damage. The challenge arises because any slip-up in following the diet during the formative years can have severely adverse effects on brain function that undo the protection achieved by years of strict adherence. However, gestational exposure to high phenylalanine levels results in stunted brain growth and severe intellectual disability in babies that come to term. Furthermore, phenylalanine and other amino acids are actively transported across the placenta, resulting in far higher concentrations of phenylalanine in the fetal circulation than in maternal blood. Use of a plant enzyme, phenylalanine ammonia lyase, to degrade phenylalanine within the digestive tract is under development. Eating meals rich in carbohydrates and proteins increases serum tryptophan levels, which in turn increases brain tryptophan levels and may underlie a postprandial serotonin surge within the brain following a large meal of both carbohydrates and fish or meat. Tryptophan hydroxylase is thought to have arisen by gene duplication of its close relative, tyrosine hydroxylase. Serotonin is transported into vesicles by the vesicular monoamine transporter, the same transporter that carries catecholamines into vesicles. As in the case of catecholamines, the first enzymatic reaction in the synthesis of serotonin is rate-limiting. In contrast to catecholamines, however, the supply of the initial amino acid substrate, in this case, tryptophan, is also a key determinant in how much serotonin is made. Dietary restriction of tryptophan intake impacts serotonin levels and alters brain function, whereas tryptophan loading increases serotonin synthesis, and, when excessive, can cause the serotonin syndrome. The serotonin syndrome involves symptoms secondary to massive autonomic activation such as sweating, hyperthermia, nausea and vomiting, and palpitations along with muscle contractions and cognitive symptoms such as confusion and agitation. The symptoms of the serotonin syndrome are a dramatic reminder that serotonin plays a modulatory role in virtually every function of the nervous system. The incidence of serotonin syndrome is increasing as the psychotropic use of serotonin-boosting drugs increases and the lack of widespread recognition of the serotonin syndrome fuels a dangerous level of underdiagnosis for this potentially lethal condition. Tricyclic antidepressants are minimally selective monoamine reuptake inhibitors that inhibit the transport of both norepinephrine and serotonin through actions at the respective reuptake transporters. Inhibiting norepinephrine and serotonin reuptake results in elevated extracellular concentrations of norepinephrine and serotonin. However, the efficacy of tricyclic antidepressants in relieving depression is due to longer term effects rather than to the acute increase in monoamine neurotransmitter levels.

We saw that information is supported by graded potentials in the dendrites and soma and by action potentials in axons erectile dysfunction video 130 mg viagra extra dosage. For neural communication to occur impotence lack of sleep order 200 mg viagra extra dosage with visa, the ultimate target of intracellular signaling is the synaptic terminal erectile dysfunction medication covered by insurance discount viagra extra dosage 200mg mastercard. As will be explored in the next chapter erectile dysfunction pills order cheapest viagra extra dosage and viagra extra dosage, information is once again carried by graded potentials in the synaptic terminal erectile dysfunction tulsa generic viagra extra dosage 120 mg free shipping. Cells that lack an axon erectile dysfunction due to drug use purchase viagra extra dosage paypal, such as retinal neurons and non-neuronal sensory hair cells of the inner ear employ graded potentials exclusively. However, for cells with an axon, the all-or-none language of spike trains is translated back into a graded potential within the synaptic terminal. The graded potential of the synaptic terminal in turn drives neurotransmitter release, the central topic explored in the next chapter. Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis. Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore. State-dependent inhibition of sodium channels by local anesthetics: A 40-year evolution. The crux of the challenge here is to ensure a tight correspondence between neuronal activity and the synchronous release of neurotransmitter. In the moments between being activated, a cell may "mutter" but not loudly enough that nearby neurons mistake the utterances for an intentional communication. By tying neural communication to neuronal activity, messages are meaningful and easily distinguished from background noise. In this chapter, we examine the biochemical processes by which neurons send a chemical message to a postsynaptic cell. As explored in the next chapter, the chemical used in neural communication is a neurotransmitter. Synaptic vesicles are released from the active zone, a stretch of synaptic membrane that faces a postsynaptic cell across the divide of the synaptic cleft. A minority of synaptic vesicles are docked at the active zone and then primed for release by protein complexes that bring them into extreme proximity to the plasma membrane. Release results when the membrane of a synaptic vesicle fuses with the plasma membrane so that neurotransmitter from the inside of the synaptic vesicle is now in the synaptic cleft. Molecules of neurotransmitter then passively diffuse across the synaptic cleft to reach a postsynaptic cell where they have effects as described in Chapter 13. Because of the fusion of synaptic vesicle membranes into the plasma membrane, the active zone membrane of working synapses is rich in valuable membrane proteins. This active zone membrane is endocytosed, and synaptic vesicle proteins are then reassembled into recycled synaptic vesicles, allowing for more rounds of neurotransmitter release. Yet membrane fusion is a ubiquitous process required for all living cells-from yeast to plant to human-to survive. Constitutive membrane fusion serves basic cell biological functions such as the synthesis and trafficking of proteins through the endoplasmic reticulum and Golgi apparatus, the insertion of proteins into the plasma membrane, the construction of internal organelles, and cell division. Because membrane fusion events occur constitutively throughout all cells, it is not surprising that few, if any, inherited or autoimmune diseases involve a primary defect in membrane fusion machinery. It is equally unsurprising that bacteria and predatory animals have evolved the ability to synthesize, accumulate, and use toxins and venoms that specifically disable membrane fusion associated with neurotransmitter release. Unlike constitutive membrane fusion, membrane fusion associated with the release of neurotransmitters must be tightly controlled so that it occurs synchronously when triggered by neuronal activity. Thus, the challenge to neurons is not membrane fusion per se but rather gaining complete control over the timing of membrane fusion. Neurons must yoke membrane fusion between synaptic vesicle and plasma membranes to an intended neural message. More accurately, spontaneous release is not prevented but rather minimized, sufficient to avert a multitude of neuronal "whispers," born of spontaneous and asynchronous release, from accumulating into a crescendo that a postsynaptic cell mistakenly interprets as an intentional message. Tying synchronous release to neuronal activity is the essence of neural communication. Neurons have optimized the connection between message and neurotransmitter release by using a sharp rise in the concentration of calcium ions at the active zone as the requisite trigger for the vast majority of synaptic release. Synaptic vesicles dock at the active zone, are primed, and, when triggered by a sharp increase in local calcium ion concentration, fuse to the membrane (red insets). When an action potential arrives in the synaptic terminal, calcium ion influx is triggered, and a high concentration of calcium ions is reached at the active zone. Neurotransmitter may leak out through the fusion pore, but free diffusion of neurotransmitter into the synaptic cleft requires an expanded pore. The insets show cartoons of docked and primed vesicles along with the initial fusion pore and the expanded "omega" fusion pore. Membrane from the active zone is endocytosed, and recycled vesicles are formed anew from the functional vesicle proteins. Synaptic vesicle recycling can occur either through endocytosis of just enough membrane to form a single synaptic vesicle (cartoons inside of circle) or through bulk endocytosis followed by budding off of single vesicles (cartoons outside of circle). In both cases, vesicle proteins (blue) must be sorted from plasma membrane proteins (red) and nonfunctional proteins (not shown), which are degraded. After a recycled vesicle is formed, it is filled with neurotransmitter and becomes part of the recycling pool. In sum, substantial neurotransmitter release should reliably accompany every neuronal message and should not occur in the absence of a neuronal message. This ideal one-to-one relationship between neuronal activity and synchronous neurotransmitter release is accomplished by an exquisite dance of biochemical interactions between a large number of proteins. Before examining the details of the neurotransmitter release dance step by step, we consider an overview of what is currently understood about the release process. It should be noted that work in this field is intense, and, although our understanding is evolving rapidly, complete agreement on all steps currently evades us. Although we are most interested in neurotransmitter release per se, the actual release of neurotransmitter is relatively trivial-transmitter simply diffuses from a vesicle into the synaptic cleft through an opening or pore-compared to the complex process of membrane fusion triggered by neuronal activity. There are two fundamentally different types of synaptic vesicles and, consequently, two processes of neurotransmitter release. The release of low-molecular-weight neurotransmitters from small synaptic vesicles is tightly regulated so that release accompanies neuronal activity, whereas release from inactive neurons is rare. The illustrated synapses are characterized by a large number of clear synaptic vesicles in the synaptic terminals (At1, At2) and by the electron-dense (therefore dark in an electron micrograph) membranes of both the active zone and the postsynaptic density. The presynaptic density marking the active zone is crowded with calcium channels, and the postsynaptic density is crowded with receptors. A: One presynaptic terminal (At1) contains concentrations of synaptic vesicles at each of two active zones (arrows). The terminal is synapsing onto a spinehead (sp) that emerges from a dendrite (Den). That same dendrite also receives a synapse from an additional terminal (At2) at the upper left. B: As in A, one presynaptic terminal (At1) has two active zones, whereas a second presynaptic terminal (At2) has a single active zone. Both terminals are synapsing onto Purkinje cell spines (sp1, sp2) in the cerebellum. In the final section of this chapter, we consider the release of a different class of neurotransmitter, the neuropeptides, from large, dense-core vesicles. The type of neuronal activity that triggers release from large vesicles, as well as the molecular details of this release, differs substantially from the process of release from small synaptic vesicles. Thus, the calculated Nernst potential for calcium ions is a potential of hundreds of millivolts, far more positive than even the peak of the action potential. The enormously steep gradient in free calcium ions dictates that when calcium-permeable channels on the plasma membrane are open, calcium ions will always enter the cell and will do so with a great deal of driving force. Unlike other ions, most calcium ions within a cell are sequestered in intracellular stores or deposits rather than existing freely within the cytosol. Within the cytosol, calcium ions act as critical second-messengers that can modify enzyme activity and change ion channel properties (see Chapter 13). However, for our purposes of understanding the role of calcium ions in triggering synaptic vesicle release, we now focus our attention solely on voltage-gated calcium channels in the plasma membrane at the active zone. However, unlike sodium channels, calcium channels do not rapidly inactivate but instead remain open for as long as the membrane is sufficiently depolarized. Consequently, the total amount of calcium ion influx increases as the time that a synaptic terminal is sufficiently depolarized increases. Since the waveform of the all-or-none action potential can vary, the calcium ion influx accompanying action potentials varies as well. Remember that the time course of an action potential can vary with differences in membrane capacitance so that unmyelinated axons fire slower action potentials than do myelinated axons. The amount of calcium ion influx in turn determines the amount of transmitter released, so that as more calcium ions enter the cell, more neurotransmitter is released. Consequently, the end result of the action potential-the amount of neurotransmitter released-varies between action potentials with different time courses. Finally, it is important to remember that the depolarization needed to open calcium channels can arise from an action potential invading the synaptic terminal, as is the case for most neurons, or from a graded depolarization in the case of nonspiking neurons and sensory cells. As a result, fewer calcium channels open, fewer calcium ions enter the cell, and less neurotransmitter release results. Calcium channels are located at the active zone immediately adjacent to sites where docked synaptic vesicles are primed and where membrane fusion occurs. Because of this architecture, calcium ions achieve a very high concentration at the active zone. Thus, neurotransmitter release is triggered by a very high but very localized concentration of calcium ions. As a consequence, the vesicular and plasma membranes fuse, opening a small pore through which neurotransmitter may leak out. The importance of calcium channels to release is exemplified by Lambert-Eaton syndrome, a rare (<5 cases per million) autoimmune disease in which antibodies are directed against a subset of voltage-gated calcium channels. As mentioned in Chapter 2, paraneoplastic Lambert-Eaton syndrome arises from antibodies made in response to a malignancy, typically a small-cell lung carcinoma. In up to half of the patients with Lambert-Eaton syndrome, there is no malignancy and the disease is not paraneoplastic. Regardless of etiology, Lambert-Eaton syndrome causes a loss of voltage-gated calcium channels critical to triggering synaptic release of neurotransmitter. This loss greatly impairs the synchronous release of neurotransmitter triggered by neuronal activity. Due to a decrease in the number of functional voltage-gated calcium channels within motoneuronal synaptic terminals, patients typically present with motor weakness as their chief complaint. With fewer calcium channels, each action potential results in less neurotransmitter release and therefore less muscle contraction. Diagnostic of Lambert-Eaton syndrome is an increasing or incremental response to repeated stimulation. The increasing response occurs because calcium ions, entering through the remaining voltage-gated calcium channels, progressively build up in the motoneuron terminal, eventually reaching levels that are sufficient for vesicle fusion with the plasma membrane. Thus, repeated stimulation circumvents the primary defect in Lambert-Eaton syndrome. Treating patients with diaminopyridine, a potassium channel blocker, is an effective therapeutic because it increases calcium ion influx by blocking repolarization of the action potential and thereby prolonging spike duration. Ensuring the proximity of these key active zone elements requires a number of proteins. Finally, a close association between synaptic vesicles and the plasma membrane is insufficient for triggered release. V oltage-gated calcium channels must also be in close proximity to the other two active zone elements. Within relatively inactive synaptic terminals that release only one or a few vesicles rarely, the number of docked vesicles is far less than the number in highly active synaptic terminals. Accordingly, the structure of the active zone varies to accommodate the docking of anywhere from a few to many vesicles. In a number of specialized sensory cells with high rates of neurotransmitter release, a proteinaceous "ribbon" extends into the cytosol, with synaptic vesicles docked on all sides of the ribbon. Ribbon-containing synapses are present in sound- and light-sensing cells, as well as in vestibular sensory cells that respond to accelerating forces. Because of their molecularly distant attachments, these proteins only overlap at their untethered ends. Thus, the association is loose initially and the complexed proteins are in the trans- conformation. Vesicle and plasma membranes would fuse if it were not for two interacting molecules, complexin and synaptotagmin. Recall that synaptotagmin is the calcium ion sensor that links release to calcium ion influx. In the absence of a high calcium ion concentration, complexin and synaptotagmin act together to prevent fusion of primed vesicles, thereby "clamping" down on spontaneous synaptic release.

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