Homeostasis, Motivation, and Addictive States
Drinking Occurs Both in Response to and in Anticipation of Dehydration
Body Fluids in the Intracellular and Extracellular Compartments Are Regulated Differentially
The Intravascular Compartment Is Monitored by Parallel Endocrine and Neural Sensors
Motivational Systems Anticipate the Appearance and Disappearance of Error Signals
Energy Stores Are Precisely Regulated
Long-Term and Short-Term Signals Interact to Control Feeding
Motivational States Influence Goal-Directed Behavior
Both Internal and External Stimuli Contribute to Motivational States
Motivational States Serve Both Regulatory and Nonregulatory Needs
Brain Reward Circuitry May Provide a Common Logic for Goal Selection
Drug Abuse and Addiction Are Goal-Directed Behaviors
Addictive Drugs Alter the Long-Term Functioning of the Nervous System
THE TEMPERATURE OF THE AIR AT higher latitudes can fluctuate by 70°C (158°F) or more over the year, yet some birds and mammals live year round in such environments without hibernating or estivating. These animals keep their core temperatures within a narrow range, on the order of a few degrees, during both the fierce blizzards of winter and the sultry days of summer. This regulatory feat is just one of many that keep key physiological variables within limits favorable to vital processes of the body, such as cell division, energy metabolism, macromolecular synthesis, and cell signaling.
The active maintenance of a relatively constant internal environment is called homeostasis. Constancy of the internal environment is the basis of the freedom of action we and other animals enjoy because it partially decouples our physiology from immediate external conditions and greatly extends the range of available habitats. For example, salmon are able to live in both fresh and salt water because they can regulate the osmolality of their extracellular fluid. Hagfish, conversely, are confined to marine habitats because they cannot regulate the osmolality of their extracellular fluid, which reflects that of the external environment.
In climates with wide variation in temperature the budget-minded homeowner may set the thermostat to a lower value during the winter and a higher one during the summer; more sharply contrasting daytime and nighttime settings may be chosen when heating or air-conditioning costs are high. Similarly, in physiological systems the means and variances of regulated variables may be adjusted over the course of the day, the seasons, and the life cycle. For example, a dehydrated camel conserves water by letting its temperature increase above normal before beginning to sweat; at night it lets its temperature decrease below normal, thus starting the day cooler and delaying the onset of sweating. The zoologist Nicholas Mrosovsky has coined the term rheostasis to refer to the linkage of regulatory targets and ranges to chronobiological and life-cycle events.
Regulation is achieved through interlinked control systems with both physiological and behavioral outputs (Box 49-1). A key feature of these control systems is motivational states such as hunger and thirst. These states arise as responses to internal stimuli, such as signals from detectors of core temperature, and external stimuli, such as the sight of a shaded refuge from the sun. Motivational states influence the direction and vigor of behavior, steering the animal toward regions of the environment where conditions promote maintenance of normal body temperature and where resources essential to homeostasis, such as food and water, can be found. These states also influence the frequency and vigor of nonregulatory activities such as exploration and reproduction.
In this chapter we first look at homeostasis by focusing on the control systems responsible for the regulation of fluid and energy balance. We then explore motivational states, focusing on the brain’s reward circuitry. Finally, we examine how motivational states and related homeostatic processes are co-opted by drugs of abuse and result in addictive behavior.
A simple regulated system is illustrated in Figure 49-1A. Water pours into a reservoir from a supply pipe and leaks out through a drain pipe. A float provides information about the water level. A shaft links the float to two valves. One controls the inflow through the supply pipe. This linkage is called negative feedback because raising the water level decreases flow through the supply pipe, and the linkage extends back from the float to an upstream stage of the system. The other valve controls outflow through the drain pipe. Such a linkage is called positive feed-forward because raising the water level increases flow through the drain pipe, and the linkage extends forward from the float to a downstream stage of the system.
Figure 49-1A A simple regulated system. Changes in the position of the float alter the state of the valves in the supply and drain pipes so as to oppose changes in the water level. (Adapted, with permission, from Cabanac and Russek 2000.)
The feedback and feed-forward linkages between the float and the valves regulate the water level. Even if the flow rate in the supply or drain pipe is altered by adding a booster pump or a partial blockage, the valves will compensate, and the water level will be confined to a narrow range. The two valves are called effectors because they bring about the adjustments that regulate the water level.
Physiological regulation is often achieved by means of a combination of negative feedback control over inputs and positive feed-forward control over outputs. For example, to maintain body weight after consuming a large meal, it is useful both to reduce subsequent food intake and to increase energy expenditure.
Figure 49-1B shows a control diagram of the regulated system in Figure 49-1A. The float is called a sensor because it monitors the regulated variable, the water level, within a regulated compartment, the reservoir. The output of the sensor is compared to a reference value or set point, a water level determined by the height on the float shaft at which the valve shaft is attached. Movement of the waterline away from the set point drives the two effectors to oppose the deviation, thus holding the water level close to the set point; the deviation of the regulated variable from the set point is called an error signal.
Some physiologists prefer the concept of a settling point to a set point. A settling point requires neither comparison to a fixed reference nor a physiological embodiment of the error signal. The settling point is simply the value of the regulated variable at which the input and output subsystems are balanced. For example, in the system in Figure 49-1A the settling point is the water level at which inflow equals outflow.
Drinking Occurs Both in Response to and in Anticipation of Dehydration
Severe dehydration generates an overwhelmingly powerful motivational state that focuses thought and action on procuring and consuming water while damping other needs and desires. A dehydrated animal will go to great extremes to find relief from the insistent discomfort of thirst. The behaviors associated with this tightly focused state are classified as primary drinking and can be construed as responses to an error signal (Figure 49-1B).
Figure 49-1B Control diagram of the simple regulated system. (Adapted, with permission, from Cabanac and Russek 2000.)
The control system underlying primary drinking enables the animal to respond to a physiological imbalance that would become life threatening if left uncorrected. But additional control over drinking is needed. If water were sought only when the animal was dehydrated, the animal could find itself in an inhospitable environment in which it would have to procure water while in a weakened and deteriorating state. Instead, behavior is programmed so as to avoid severe dehydration. When conditions allow, water is consumed in excess, even in the absence of an error signal, and the kidneys eliminate the surplus. Such secondary drinking often coincides with feeding.
In contrast to the simple system in Figure 49-1, physiological systems often comprise several compartmentalized subsystems that are separately regulated. A variety of sensors monitor these separate compartments, and different subsets of effectors are deployed to keep conditions constant within them. Fluid balance provides a case in point. Body water is partitioned between intracellular and extracellular compartments.
Body Fluids in the Intracellular and Extracellular Compartments Are Regulated Differentially
Intracellular and extracellular fluids must be separately regulated because of their different compositions. The principal extracellular cation is Na+, whereas the principal intracellular cation is K+. Fluctuation in the level of Na+ is generally more pronounced than that of K+. The fluctuations of these cations establish osmolality gradients that move water between the two compartments.
Loss of sodium and water from the extracellular compartment usually occurs with events that lead to decreased vascular volume (hypovolemia), such as hemorrhage or diarrhea. To offset the deficit, both water and sodium must be consumed. Thus primary drinking and sodium intake play essential roles in regulating vascular volume. These behaviors complement the physiological and endocrine mechanisms that maintain blood pressure while conserving water and sodium.
The Intravascular Compartment Is Monitored by Parallel Endocrine and Neural Sensors
Sensors for hypovolemia include detectors of arterial blood flow to the kidney that send information to the brain through two pathways: an endocrine signaling mechanism and a neural route. The neural pathway originates in vascular stretch receptors on the low-pressure side of the circulation, in the heart, great veins, and pulmonary circulation (baroreceptors). Visceral receptors monitoring the extracellular concentration of Na+, and arterial blood pressure are also thought to contribute to fluid homeostasis.
The brain circuitry that controls the behavioral, physiological, and endocrine responses to hypovolemia is distributed along the central nervous system and includes both local and long-loop pathways (Figure 49-2). Baroreceptors project primarily to the nucleus of the solitary tract. A decrease in stimulation of these receptors activates sympathetic output neurons in the caudal brain stem that maintain both blood pressure and cardiac output by increasing heart rate and triggering peripheral vasoconstriction.
Figure 49-2 Components of the neural circuitry controlling fluid balance. The circuitry is shown in a stylized sagittal section through the rat brain. Information from baroreceptors in the circulatory system and from sensory receptors in the mouth, throat, and viscera is conveyed to the nucleus of the solitary tract and neighboring structures in the caudal brain stem through the glossopharyngeal (IX) and vagal (X) nerves (right side). The hormone angiotensin II (ANG II) provides the brain with an additional signal concerning low blood volume (left side). Circulating angiotensin II is sensed by receptors in the subfornical organ (SFO); SFO neurons project to and release angiotensin II in the median preoptic area (MePO), paraventricular nucleus of the hypothalamus (PVN), vascular organ of the lamina terminalis (OVLT), and adjacent lateral hypothalamic area (LHA). High arterial pressure is detected by baroreceptors that project to the caudal brain stem; when arterial pressure is too high, drinking is suppressed by an inhibitory input to the median preoptic area from the nucleus of the solitary tract. The osmolality of the blood is sensed by receptors in and near the OVLT that project to the median preoptic area and paraventricular nucleus of the hypothalamus. The latter nucleus is positioned to integrate inputs concerning both blood volume and osmolality and is believed to play a key role in triggering drinking. Neurosecretory cells in this nucleus (and in the supraoptic nucleus) trigger release of vasopressin from the neural lobe (NL) of the pituitary, thus decreasing urinary output. Input to the paraventricular nucleus from the suprachiasmatic nucleus (SCN) brings the fluid-regulatory system under the influence of the internal day/night clock (see Chapter 51). (Adapted, with permission, from Swanson 2000.)
Through connections between the caudal brain stem and the hypothalamus, decreased baroreceptor input also drives release of the peptide vasopressin from the posterior pituitary. Vasopressin increases blood pressure and increases reabsorption of water in the kidney (thus its alternate name, antidiuretic hormone). Because the kidneys filter an enormous volume of fluid each day—approximately 60 times the plasma volume—adjustment of urinary output has a large and rapid impact on the volume of fluid in the vascular system. This is an example of feed-forward control (Figure 49-1B).
Whereas a decrease of cardiopulmonary baroreceptor firing may stimulate primary drinking, the high-pressure side of the circulation exerts an opposing influence. The nucleus of the solitary tract receives input from peripheral detectors of arterial blood pressure. As the arterial blood pressure increases (eg, during hypervolemia), noradrenergic projections from this nucleus to the median preoptic area, a small midline nucleus in the basal forebrain, reduce drinking. This is an example of negative feedback control (Figure 49-1B).
The endocrine signaling mechanism that monitors arterial blood flow functions in parallel with the neural pathway. The reduction in arterial blood flow to the kidneys during hypovolemia causes the release of the protease renin into the circulation. The substrate for this protease is the circulating prohormone angiotensinogen, which is cleaved by renin to produce a decapeptide, angiotensin I. In turn, the angiotensin-converting enzyme transforms angiotensin I into angiotensin II, its active octapeptide derivative. The potent vasoconstricting effect of angiotensin II helps maintain blood pressure in the face of decreased vascular volume. Angiotensin II also stimulates aldosterone release from the adrenal cortex. Aldosterone increases reabsorption of Na+ in the kidney while favoring K+ excretion; these complementary effects shift fluid from the capacious intracellular compartment to the depleted intravascular compartment.
Peptide hormones, such as angiotensin II, do not cross the blood–brain barrier freely. However, the brain is able to monitor the circulation directly through specialized, densely vascularized structures, the circumventricular organs, which lack a normal blood–brain barrier and thus provide circulating peptides access to receptors on central neurons. In two of these circumventricular organs, the subfornical organ and vascular organ of the lamina terminalis, angiotensin II acts as a powerful stimulus of drinking and vasopressin release.
Neurons in the subfornical organ project to the median preoptic area and the paraventricular nucleus of the hypothalamus where they release angiotensin II. Injection of angiotensin II into these two nuclei elicits vigorous drinking, whereas cutting the input from the subfornical organ blocks the drinking response to circulating angiotensin II. Thus angiotensin II acts first as a hormone (in the subfornical organ) and then as a neurotransmitter (in the median preoptic area and paraventricular nucleus of the hypothalamus).
The Intracellular Compartment Is Monitored by Osmoreceptors
An increase in extracellular osmolality draws water out of cells, causing the cells to shrink. Changes in cell volume are monitored by specialized neurons called osmoreceptors, which translate cell shrinkage or swelling into changes in membrane potential.
A population of central osmoreceptive sensory neurons in the vascular organ of the lamina terminalis projects to neuroendocrine cells in the paraventricular and supraoptic nuclei of the hypothalamus to drive vasopressin release, thus decreasing urinary output (Figure 49-2). Additional projections from these primary sensory neurons to the median preoptic area carry signals that drive drinking in response to cellular dehydration. These latter signals are relayed to the paraventricular nucleus of the hypothalamus, where they converge with inputs from the system that regulates the intravascular compartment.
Motivational Systems Anticipate the Appearance and Disappearance of Error Signals
Changes in intake or expenditure are not immediately registered in physiological systems. For example, water that has been swallowed by an animal undergoing cellular dehydration must be absorbed from the gut and distributed before osmoreceptors of the brain can detect a return toward homeostasis. If consumption continued until the error signal disappeared, the system would overshoot its target. Wastefulness and instability are avoided by terminating drinking well before plasma osmolality is restored.
Thus the regulatory system acts as if it anticipates the cellular rehydration that will eventually follow fluid ingestion, perhaps by using information supplied by peripheral osmoreceptors or visceral Na+ receptors. Such anticipatory control is a common feature of motivational systems. For example, migratory birds and whales gain prodigious amounts of weight prior to setting off on their journeys. Unlike the simple regulatory system shown in Box 49-1, the input and output subsystems of motivational systems can be adjusted in anticipation of the appearance and disappearance of error signals.
Energy Stores Are Precisely Regulated
Dieters need little convincing that long-term energy stores are regulated, for they have learned how difficult it is to maintain hard-won weight losses. If we are plump when we are young, we usually remain so. That is, our adiposity relative to the norm for our age tends to remain stable throughout our lives. Recent research on the neural, endocrine, and autonomic mechanisms controlling food intake and energy expenditure is beginning to reveal how energy stores are regulated so precisely.
Leptin and Insulin Contribute to Long-Term Energy Balance
Fat constitutes the long-term energy depot of the body and the brain monitors its state. Elegant experiments in mice first showed that a humoral signal is involved. The circulatory systems of pairs of mice were joined surgically (parabiosis). A normal mouse was paired with a mutant one carrying a recessive homozygous mutation of a gene called obesity (ob), which produces morbid obesity and hypothermia. This surgical linkage normalized the body weight and temperature of the mutant mouse. The ob/ob mouse lacks a circulating signal from energy stores that produces feedback control over food intake and feed-forward control over energy expenditure; the normal partner supplies this signal, correcting the deficits.
Mice with homozygous mutation of the diabetes (db) gene also are obese. Linking the circulatory system of these mice to that of a normal or ob/ob mouse not only failed to correct the diabetes and hypoglycemia, it also caused emaciation and death of the normal or ob/ob partner. In contrast to the ob/ob mouse, the db/db mouse produces the circulating signal but lacks a functional receptor. The signal is elevated in the obese db/db mouse, thus decreasing the food intake and increasing the energy expenditures of its unfortunate surgically joined partner.
Some 25 years after the first parabiosis studies, the circulating signal, the mutated receptor, and their genes were identified. The circulating signal was identified by Jeffrey Friedman and his colleagues as a peptide hormone called leptin. It is produced principally by white adipocytes (fat-storing cells) in amounts positively correlated with the level of stored fat. Leptin is transported across the blood–brain barrier and acts in the brain and in the periphery at receptors that are members of the cytokine-receptor superfamily.
In normal-weight individuals leptin reduces food intake while increasing energy expenditure, lipolysis, and thermogenesis. Most obese humans have very high levels of leptin, suggesting that they have become insensitive to this key hormone. The rare humans who lack leptin because of mutation of the ob gene are morbidly obese and hypothermic; the body weight and temperature of such individuals can be normalized by exogenous administration of leptin.
Levels of the pancreatic hormone insulin are also positively correlated with fat mass. Like leptin, insulin reduces food intake and increases thermogenesis. During fasting leptin and insulin levels decrease before the fat stores fall, and thus fat stores are rapidly replenished once eating is resumed.
Circulating leptin and insulin bind to receptors on two populations of neurons in the arcuate nucleus of the medial hypothalamus. These two populations have opposite responses to leptin and insulin and opposite influences on energy balance.
One population of arcuate neurons secretes two anabolic signaling molecules (signals that promote energy storage): neuropeptide Y and agouti-related peptide. The second population secretes two catabolic signaling molecules (signals that promote use of energy stores): α-melanocyte–stimulating hormone and cocaine-and amphetamine-related transcript (Figure 49-3B).
The antagonism between anabolic and catabolic signals from the arcuate nucleus is illustrated by the action of agouti-related peptide. This molecule is an endogenous antagonist of the melanocortin receptors MC3 and MC4. The endogenous agonist at these receptors is the α-melanocyte-stimulating hormone released from arcuate neurons when the organism is in a catabolic state. Agouti-related peptide blocks the ability of the hormone to reduce food intake, increase energy expenditure, and decrease fat storage. Injection of neuropeptide Y into the hypothalamus triggers feeding and promotes lipogenesis while decreasing energy expenditure. Thus release of either peptide produces anabolic feedback and feed-forward effects that promote weight gain while suppressing signaling in the antagonistic catabolic pathway.
Projections from the arcuate nucleus to the paraventricular and lateral regions of the hypothalamus relay signals carried by circulating leptin and insulin (Figure 49-3C). Neurons in these areas have long been implicated in energy balance. For example, bilateral lesions of the paraventricular nucleus increase food intake and body weight, whereas lesions in the lateral hypothalamic area produce opposite effects. Neuropeptides that decrease food intake or increase energy expenditure are released by different subgroups of neurons in the paraventricular nucleus. Neuropeptides that increase food intake are found in separate subgroups of neurons in the lateral and perifornical regions of the hypothalamus.
As with fluid balance, the neural circuitry responsible for energy balance is broadly distributed. This circuitry includes important components in the dorsal vagal complex of the caudal brain stem in addition to the hypothalamic cell groups described above.
Long-Term and Short-Term Signals Interact to Control Feeding
The gastrointestinal tract plays a role in short-term control of ingestive behavior. Two of the gastrointestinal hormones that inform the brain about the state of the gut are cholecystokinin and ghrelin (Figure 49-3A). Cholecystokinin is secreted from the gut during meals. It promotes the termination of the meal by slowing gastric emptying and by stimulating vagal inputs to the lower brain stem circuitry involved in the patterning of meals.
Ghrelin is implicated in the initiation rather than the termination of meals. In contrast to cholecystokinin, release of ghrelin from the stomach peaks prior to a meal, when the stomach is still empty. Ghrelin receptors are found in numerous brain sites; eating has been elicited by direct administration of ghrelin into the arcuate and paraventricular hypothalamic nuclei and the dorsal vagal complex.
To alter food intake, signals such as leptin and insulin, which reflect the state of long-term energy stores, must interact with the short-term signals that determine the composition and patterning of meals. These interactions occur at many levels. For example, leptin promotes the release of cholecystokinin from the duodenum; leptin and ghrelin exert opposing influences on arcuate neurons containing neuropeptide Y and agouti-related peptide. Leptin, insulin, and ghrelin all interact with the 5’-adenosine monophosphate-activated protein kinase (AMPK), a molecular sensor of short-term energy status. To fuel vital physiological processes, cells must maintain a high ratio of adenosine triphosphate (ATP) to 5’-adenosine monophosphate (AMP); AMPK is activated when this ratio falls below a critical threshold. Activation of AMPK stimulates catabolism while suppressing anabolism, thus restoring the ATP/AMP ratio. In hypothalamic neurons implicated in energy balance, leptin, insulin, and high glucose levels all inhibit AMPK activity whereas fasting and ghrelin activate it.
Motivational States Influence Goal-Directed Behavior
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