49: 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

  • The Intracellular Compartment Is Monitored by Osmoreceptors

  • Motivational Systems Anticipate the Appearance and Disappearance of Error Signals

• Energy Stores Are Precisely Regulated

  • Leptin and Insulin Contribute to Long-Term Energy Balance

  • 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 Recruit the Brain's Reward Circuitry

  • Addictive Drugs Alter the Long-Term Functioning of the Nervous System

  • Dopamine May Act As a Learning Signal

• An Overall View

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.

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).

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.

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 hyper volemia), 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 angio-tensinogen, which is cleaved by renin to produce a decapeptide, angiotensin I. In turn, the angiotensin-converting enzyme transforms angiotensin I into angio- tensin 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.

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.

So far we have reviewed physiological, neuroendocrine, and neuroanatomical components of the control systems for fluid and energy homeostasis. We now turn to another feature of homeostatic control systems: the motivational states governing the behaviors that provide the needed inputs, such as food and water.

A cheetah that has taken refuge from the mid-day sun in the shade of a tree greets the sight of a distant antelope with apparent indifference. In contrast, the sighting of an antelope toward the end of the afternoon provokes immediate orientation and stalking. The stimulus is the same, but the behavioral responses are very different. What has changed during the interval, separating the two sightings, is the motivational state of the animal.

Both Internal and External Stimuli Contribute to Motivational States

Motivational states influence attentiveness, goal selection, investment of effort in the pursuit of goals, and responsiveness to stimuli. The psychologist Dalbir Bindra proposed that motivational states arise from the interaction of internal and external inputs.

Internal inputs include physiological error signals and the circadian clock. For example, the frequency and duration of foraging varies with the time of day, the time since the cheetah has last eaten, and whether or not she is lactating. External inputs include incentive stimuli arising from the goal of the motivational state. For example, when a dehydrated cheetah comes across a water hole during a search for antelopes, the sight of the water may serve as an incentive stimulus, tipping the balance between hunger and thirst and driving the animal to interrupt its quest for food to drink.

There is positive feedback between incentive stimuli and motivational states; the more the animal interacts with the stimulus, the stronger the motivational state that promotes further contact. This positive feedback relationship helps ensure that complex behavioral sequences are completed. For example, the cheetah must stalk, chase, run down, and kill the antelope, and then drag the carcass to a refuge before beginning to feed.

Motivational States Serve Both Regulatory and Nonregulatory Needs

Feeding, drinking, and thermoregulatory behaviors and their underlying motivational states typically arise in response to or in anticipation of a physiological imbalance. In contrast, some motivational states such as sexual arousal serve biological imperatives other than homeostasis. Functionally, these non-regulatory states resemble those arising from physiological error signals. For example, some behaviors influenced by nonregulatory motivational states may be compensatory responses to deprivation, such as when a mammal that has been confined shows heightened motivation to explore once released from captivity.

Brain Reward Circuitry May Provide a Common Logic for Goal Selection

Goal-directed behaviors entail risks, costs, and benefits. Straying from the herd may offer an antelope better opportunities for foraging but at the risk of becoming an easier target for a lurking cheetah. Attacking the venturesome antelope offers the cheetah the promise of a meal with the risk that energetic and hydromineral resources will be depleted if the antelope gets away. Thus the neural mechanisms responsible for goal selection must weigh anticipated risks, costs, and benefits of behaviors that are likely to attain a specific goal.

Many studies of these neural mechanisms have used electrical brain stimulation as a goal. Rats and other vertebrates ranging from goldfish to humans will work for electrical stimulation of certain brain regions. The avidity and persistence of this self-stimulation is remarkable. For example, rats will cross electrified grids, run uphill while leaping over hurdles, or press a lever for hours on end in order to trigger the electrical stimulation. The phenomenon that leads the animal to work for the stimulation is called brain stimulation reward.

Rewards are objects, stimuli, or activities that have positive value. Rewards can incite an animal to switch from one behavior to another or to resist interruption of ongoing action. For example, a rat that encounters a seed while scouting the environment may cease exploring to eat the food or carry it to a safe place; while nibbling the seed the rat will resist the efforts of another rat to steal the food from its paws. If seeds are made available only at a particular location and time, the rat will go to that location as the expected moment of reward delivery approaches. Much contemporary work in the neurosciences is directed at unraveling the neural mechanisms that mediate reward, how they shape behavior to meet physiological needs and environmental challenges and opportunities, and how they go awry in the case of behavioral pathologies such as drug addiction.

Although electrical stimulation is an artificial goal, it can mimic some of the rewarding properties of natural goal objects. For example, rewarding stimulation of the medial forebrain bundle can compete with, summate with, or substitute for hedonic stimuli such as sucrose solutions. The effectiveness of the reward produced by stimulating certain lateral hypothalamic sites is increased by weight loss and decreased by leptin, suggesting that the neural circuitry responsible for the rewarding effect plays a role in energy balance.

The circuitry that mediates brain stimulation reward is broadly distributed. Rewarding effects can be produced by electrical stimulation of sites at all levels of the brain, from the olfactory bulb to the nucleus of the solitary tract. Particularly effective sites lie along the course of the medial forebrain bundle and along longitudinally oriented fiber bundles coursing near the midline of the brain stem. Stimulation of both these pathways transsynaptically activates dopaminergic neurons in the ventral tegmental area of the midbrain; these neurons project to the nucleus accumbens (the major component of the ventral striatum), the ventromedial portion of the head of the caudate nucleus (in the dorsal striatum), the basal forebrain, and regions of the prefrontal cortex (Figure 49–4).

The midbrain dopaminergic neurons are activated by incentive stimuli and play a crucial role in brain stimulation reward. Pursuit of this reward is strengthened by increases in dopaminergic synaptic transmission and weakened by decreases. The dopaminergic neurons receive excitatory signals from cholinergic cells in the laterodorsal tegmental and pedunculopontine nuclei of the hindbrain. Stimulation of the medial forebrain bundle and caudal brain stem activates these cholinergic neurons. In turn, blockade of the cholinergic input to the midbrain dopaminergic neurons reduces the rewarding effects of the electrical stimulation.

Starving rats provided with brief daily access to food will forego eating to press a lever for brain stimulation. Such heedless pursuit of an artificial goal to the detriment of a biological need is one of many parallels between self-stimulation and drug abuse. More direct evidence comes from the fact that the animal will work even harder to self-stimulate when given a drug such as cocaine, amphetamine, heroin, and nicotine. As these results suggest, the midbrain dopaminergic neurons involved in the rewarding effect of brain stimulation also play a critical role in the rewarding effects of drugs.

Before humans began farming, our species foraged for safe and nutritious plants. Among the many plants that humans sampled, a small number produced changes in perception, mood, cognition, or arousal. Of these, a smaller subset—opium poppies, coca, tobacco, hemp, and products of fermented plant matter—contained substances that proved strongly rewarding, even though they lacked any nutritional value. Humans learned to purify these substances and later to synthesize related compounds for use as medicines.

For example, morphine, purified from the opium poppy, was chemically modified in attempts to produce compounds with greater specificity for analgesia. Among these was diacetylmorphine, or heroin, which was mistakenly marketed as a nonaddictive treatment for pain and cough. Other drugs, such as the amphetamines and sedative-hypnotics, are wholly synthetic compounds developed for a variety of medical indications.

Addictive drugs include some with approved medical uses (eg, morphine, amphetamines, and benzodiazepines), some that are legal but lacking in medical usefulness (eg, alcohol and tobacco), and some that are illegal in many countries (eg, marijuana). The term drug abuse refers to the use of drugs outside of medical supervision and in a manner that is potentially harmful or illegal. The addictive drugs listed in Table 49–1 produce reward; thus, individuals willingly use them and tend to take them repetitively. Herein lies the central danger of these drugs. When used repetitively they initiate molecular changes in the brain that promote continued drug-taking, behavior that becomes increasingly difficult to control. Individuals who regularly use these drugs impair their health and their ability to function.

In people who are vulnerable as a result of genetic and nongenetic risk factors, drug use may progress to addiction, which is defined as compulsive drug use despite significantly negative consequences. The addicted person loses control over drug use—obtaining and using drugs come to dominate all other life goals. Addiction tends to persist despite attempts to limit drug use and despite serious negative consequences for the user, his family, and society.

Perhaps the most challenging and frustrating aspect of addiction is its persistence. Not only is it difficult to interrupt active drug use, but even when a person has successfully stopped using drugs the risk of relapse remains high for many years and in some cases for a lifetime. Even after long periods of abstinence, exposure to reminders (cues) of drug use, such as drug paraphernalia or people or places associated with prior drug use, may trigger intense drug urges and relapse into use. Cue-initiated relapses may occur even in individuals who have strongly resolved never to use drugs again, illustrating that addiction impairs the voluntary control of behavior.

In the laboratory, drug-associated cues elicit drug urges that correlate with physiologic responses, for example, activation of the sympathetic nervous system. Functional brain imaging has revealed that cue-conditioned drug responses activate medial regions of the prefrontal cortex; the amygdala, a structure that is thought to play a role in the consolidation of emotionally charged stimulus-reward associations (see Chapters 48 and 66); and the nucleus accumbens, a component of the brain reward circuitry (Figure 49–5).

Addictive Drugs Recruit the Brain's Reward Circuitry

As discussed above, the dopaminergic projections from the ventral tegmental area to the nucleus accumbens and other forebrain structures (Figure 49–4) are a central component of reward circuitry. The major dopamine receptor types in both the dorsal striatum and nucleus accumbens are the D₁ and D₂ G protein-coupled receptors. The D₁ receptors predominate in the prefrontal cortex. A dopamine transporter located on presynaptic neurons terminates the actions of the synaptically released dopamine by pumping it back into the presynaptic terminal (Figure 49–6).

Both pharmacological studies and analyses of lesions in animals confirm the importance of dopaminergic pathways in brain reward. Behavioral studies of the rewarding properties of drugs, using such paradigms as conditioned place preference or self-administration of drugs (Box 49–2), have found that drugs that block D₁ and D₂ dopamine receptors diminish the incentive properties of natural rewards and drugs. Similar conclusions have been reached in studies using other experimental disruptions of dopaminergic pathways.

Changes in extracellular dopamine levels within the nucleus accumbens and other brain structures can be measured in vivo using a microdialysis catheter. Although this method cannot measure dopamine within individual synapses, it can yield quantitative estimates that are thought to correlate with synaptic release of dopamine. This method demonstrates that all addictive drugs increase extracellular dopamine levels in the nucleus accumbens. Thus psychotropic drugs that do not produce significant dopamine release in the nucleus accumbens are not addictive.

There is one important caveat to what is often called the dopamine hypothesis of reward. Some drugs such as opiates also have receptors in reward pathways that are either parallel with or downstream of dopaminergic synapses. Thus opiates produce reward by both dopamine-dependent and dopamine-independent mechanisms. Mice that are genetically engineered to lack dopamine do not find cocaine to be rewarding but appear to gain significant residual reward from morphine.

Although the ability to increase synaptic dopamine is a shared property of all addictive drugs, they do so by different mechanisms. Psychostimulants, which include cocaine and amphetamines, act on the presynaptic terminals of dopaminergic neurons, and they do so in two different ways. Cocaine binds to and blocks the dopamine transporter on the membrane of presynaptic terminals, causing extracellular dopamine to accumulate to high levels following release. Amphetamines enter the presynaptic terminals of dopaminergic neurons through the dopamine transporter. Once in the cytoplasm they cause reverse transport of dopamine out of storage vesicles through the vesicular transporter and out of the neuron into the synapse through the membrane transporter. Thus the action of cocaine depends on normal vesicular release of dopamine by neurons of the ventral tegmental area, whereas the action of amphetamine does not.

Cocaine and amphetamines have analogous actions on the norepinephrine and serotonin transporters, causing increases in extracellular levels of those neurotransmitters as well. However, pharmacologic blockade and lesion experiments demonstrate that dopamine, not these other neurotransmitters, plays the key role in the rewarding properties of these drugs.

The effects of opiates on reward are more complex than those of the psychostimulants because opiates use both dopamine-dependent and dopamine-independent mechanisms. There are three classes of opioid receptors, μ, δ, and κ, and a structurally related receptor, ORL-1. The morphine-like opiates, including heroin (which is metabolized into morphine), methadone, and oxycodone, bind with highest affinity to μ receptors. The μ receptors are found in several regions of the brain and spinal cord where they serve different functions. In the brain stem and spinal cord they play a critical role in modulating pain information (Chapter 24). In other brain stem regions they play a role in controlling respiration, which is why opiates can cause respiratory arrest in overdose.

The μ receptors are also found throughout brain reward circuitry. In the ventral tegmental area they are found on GABA-ergic interneurons that tonically inhibit the dopaminergic neurons that project to the nucleus accumbens and prefrontal cortex. Opiate binding to these μ receptors inhibits the interneurons, resulting in disinhibition of the dopaminergic neurons and dopamine release. Because μ receptors are also expressed by nucleus accumbens neurons, opiates can also exert rewarding effects independent of dopamine inputs.

Microdialysis demonstrates that nicotine, ethyl alcohol, tetrahydrocannabinol, and phencyclidine all cause dopamine to be released in the nucleus accumbens. In addition to their shared effect—increasing synaptic dopamine in the nucleus accumbens—each family of addictive drugs has unique properties based on the receptors with which they interact (Table 49–1). For example, both morphine and cocaine are rewarding and addictive, morphine-like opiates are analgesic and sedating, and cocaine stimulates arousal.

Addictive Drugs Alter the Long-Term Functioning of the Nervous System

In addition to producing short-term reward and other acute pharmacologic effects, addictive drugs can produce long-term alterations in the functioning of the nervous system. Repeated use of addictive drugs can produce tolerance, dependence, withdrawal, and sensitization to differing degrees, as well as addiction. In humans tolerance, dependence, and withdrawal can all contribute to altered behavior. The behavioral consequences of sensitization, a phenomenon well established in animal models, are less clear for human drug users. None of these states is equivalent to addiction, which is defined as compulsive drug use despite significant negative consequences.

Tolerance refers to the diminishing effect of a drug after repeated ingestion of the drug at a constant dose, or alternatively the need to increase the dose to produce a constant effect. For example, the amount of alcohol needed to get drunk increases with regular use. Tolerance results from homeostatic responses of cells to excessive drug stimulation—molecular and cellular adaptations alter normal physiology to counterbalance the effects of the drug. One mechanism of tolerance is pharmacokinetic, in which induction of hepatic metabolic enzymes increase the rate of metabolic clearance of a drug. Pharmacokinetic adaptation plays almost no role in tolerance for addictive drugs other than alcohol. A second mechanism is pharmacodynamic: The action of a drug within the brain that produces habituation.

Dependence is inferred when withdrawal symptoms occur after drug use is curtailed. Whereas tolerance results from homeostatic mechanisms those associated with dependence alter the basal physiological state of cells and circuits. As long as drug use continues, this altered physiology is masked and symptoms do not occur. Cessation of drug use unmasks the abnormal physiological state, resulting in withdrawal symptoms.

When effects grow stronger with repeated drug use they are said to undergo sensitization. For example, the locomotor activity produced by amphetamine or cocaine increases with repeated use of the drug. In general the stimulant effects of a drug are more likely to increase (sensitization), whereas depressant effects tend to diminish (tolerance).

The mechanisms by which opiates produce tolerance, dependence, and a withdrawal syndrome have been elucidated in studies of the behavior of neurons in the locus ceruleus, the major noradrenergic nucleus in the brain. Acute administration of opiates to rats or mice slows the basal firing rate of locus ceruleus neurons because μ opioid receptors activate a K⁺ channel that reduces the firing rate. Over time, however, the neurons develop tolerance; their firing rate becomes more normal as the μ receptors become partly uncoupled from channel activation.

Chronic opiate administration also produces dependence that sets the stage for withdrawal. Following chronic opiate administration, blockade of μ receptors by the opioid receptor antagonist naloxone produces a dramatic withdrawal syndrome. (This is observed in laboratory rats, which exhibit such withdrawal symptoms as "wet dog" shakes, as well as in opiate-dependent humans given naloxone to reverse respiratory arrest.) One mechanism that contributes to dependence is the strengthening of a Na⁺ conductance in locus ceruleus neurons; this adaptation can act to balance the efflux of K⁺ produced by μ receptor stimulation. The relative excess of Na⁺ influx following naloxone inhibition of μ receptor-mediated K⁺ efflux renders the neurons hyperexcitable. This results in burst firing that correlates with withdrawal behaviors.

Historically, dependence and physical withdrawal were thought to be cardinal features of addiction. We now know that they are neither necessary nor sufficient. First, some drugs such as cocaine and amphetamines that readily cause compulsive, "out of control" use may produce little or no dependence and do not produce physical withdrawal. More importantly, the risk of relapse into drugs that can produce physical withdrawal, such as opiates and alcohol, can persist for years after drug use has stopped and withdrawal symptoms have resolved.

If dependence and withdrawal were the central mechanisms of addiction, we could successfully treat addicted people by sequestering them until they were well past the period of withdrawal. Unfortunately this is not the case, as stress or drug-related cues can readily cause relapse. Based on the important role of drug-associated cues in drug-seeking and relapse, some clinical investigators have emphasized the need to consider the neural mechanisms of associative learning as central to addiction.

Dopamine May Act As a Learning Signal

An earlier view of the function of dopamine was that it conveyed "hedonic signals" in the brain and that in humans it was directly responsible for subjective pleasure. From this point of view addiction would reflect the habitual choice of short-term pleasure despite a host of long-term life problems. However, the hedonic principle cannot easily explain the persistence of drug use by addicted persons as negative consequences mount.

In fact, the effects of dopamine have proven to be far more complex than was first thought. Dopamine can be released by stressful as well as by rewarding stimuli. Moreover, rodents lacking dopamine—rats in which dopamine is depleted by 6-hydroxydopamine and mice genetically engineered so that they cannot produce dopamine—continue to exhibit hedonic responses to sucrose.

Wolfram Schultz and his colleagues discovered that dopaminergic neurons have a complex and changing pattern of responses to rewards during learning. In one experiment Schultz trained monkeys to expect juice at a fixed interval after a visual or auditory cue. Before the monkeys learned the predictive cues, the appearance of the juice was unexpected and produced a transient increase above basal levels of firing in dopaminergic neurons. As the monkeys learned that certain cues predict the juice, the timing of the firing changed. The neurons no longer fired in response to presentation of the juice—the reward—but earlier, in response to the predictive visual or auditory cue. If a cue was presented but the reward was withheld, firing paused at the time the reward would have been presented. In contrast, if a reward exceeded expectation or was unexpected, because it appeared without a prior cue, firing was enhanced (Figure 49–7).

These observations suggest that dopamine release in the forebrain serves not as a pleasure signal but as a prediction-error signal. A burst of dopamine would signify a reward or reward-related stimulus that had not been predicted; pauses would signify that the predicted reward is less than expected or absent. If a reward is just as expected based on environmental cues, dopaminergic neurons would maintain their tonic (baseline) firing rates. Alterations in dopamine release are thought to modify future responses to stimuli to maximize the likelihood of obtaining rewards and to minimize fruitless pursuits. For natural rewards, like the sweet juice consumed by the monkeys in Schultz's experiments, once the environmental cues for a reward are learned, dopaminergic neuron firing returns toward baseline levels. Schultz has interpreted this to mean that as long as nothing changes in the environment, there is nothing more to learn and therefore no need to alter behavioral responses.

Addictive drugs differ from natural rewards in that they cause dopamine release in the reward circuitry no matter how often they are consumed. Dopamine is released even when these drugs do not produce subjective pleasure. To the brain, consumption of addictive drugs would thus always signal "better than expected" and in this way would continue to influence behavior to maximize drug-seeking and drug-taking. If this idea is correct, it might explain why drug- seeking and consumption become compulsive and why the life of the addicted person becomes focused on drug-taking at the expense of all other pursuits.

These experiments, combined with the importance of cues in promoting drug taking, have suggested that learning and memory might play a central role in addiction. For example, drug-seeking is often initiated by drug-related cues—the people, paraphernalia, bodily sensations, and smells associated with prior drug use. Such cues must, of course, be stored in memory and associated with specific behaviors. Interestingly, dopamine has been implicated in the formation of long-term memories in hippocampal and cerebral cortical circuits (Chapters 66 and 67).

These considerations have led to the idea that when someone uses addictive drugs the release of dopamine strengthens the associative memories that bind drug-related cues to drug urges and drug-seeking. The brain reward circuitry that normally reinforces the pursuit of goals with positive survival value is usurped by drug-related goals.

If dopamine-dependent associative memory processes are involved in the pathogenesis of addiction, what cellular and molecular mechanisms might be involved? Long-term change in synaptic function is a fundamental property of neural circuits involved in learning. The best characterized physiologic mechanisms of such long-term changes in the mammalian brain are long-term potentiation and long-term depression (Chapters 66 and 67). These mechanisms are thought to underlie many different types of learning and memory. Indeed, drug use can lead to synaptic changes similar to long-term potentiation and depression in the striatum and nucleus accumbens, as well as in the midbrain dopaminergic neurons themselves.

Activation of the dopaminergic pathways also resembles learning in that these pathways are capable of initiating many changes in gene expression. Relating these changes to learning-related alterations in synaptic connections and circuit function remains an important challenge. For example, dopamine action at the D₁ receptors leads to the activation of the transcription factor cyclic AMP response element binding protein (CREB). CREB has been implicated in diverse memory processes in a variety of species, including the Drosophila fly, the marine snail Aplysia, and mice (Figure 49–8, and see Chapters 66 and 67). In the dorsal striatum and nucleus accumbens, psychostimulants produce phosphorylation of CREB through activation of the D₁ receptors and the second messenger cyclic AMP. This leads to activation of the cAMP-dependent protein kinase, which then phosphorylates CREB, leading to its activation. A large number of CREB-regulated genes are thus induced by dopamine and psychostimulants.

The ability of cells, organs, and organisms to survive and function in the face of changing conditions such as alterations in temperature or nutrient availability depends on mechanisms that maintain a relatively constant internal milieu. Complex brain circuits orchestrate the physiological processes that redistribute and transform internal resources such as water, electrolytes, and energy stores to correct and anticipate deviations from homeostasis. Tightly integrated with these circuits are the neural systems mediating behaviors that procure vital resources from the environment and help to conserve scarce supplies or expend surpluses.

Motivational states adjust the vigor and incidence of these behaviors according to biological needs, both those stemming from regulatory imperatives such as the maintenance of blood volume and those stemming from nonregulatory imperatives such as reproduction. The strength of a motivational state depends not only on internal conditions but also on external incentive stimuli such as food or estrus odors.

Choosing between competing incentives requires that the current and predicted benefit of each incentive be assessed, a task attributed to brain reward circuitry. Activation of this circuitry creates resistance to interruption of ongoing actions and promotes behaviors that anticipate or procure rewards.

The dopaminergic projection from the ventral tegmental area to the nucleus accumbens powerfully influences goal-directed behavior. All addictive drugs increase synaptic dopaminergic transmission in this pathway, an effect that may mimic and ultimately overwhelm the influence of natural stimuli and motivational states. Dopamine facilitates the cellular and molecular mechanisms of learning and memory. In vulnerable individuals drug-associated cues may be transformed into powerful incentive stimuli. Thus reminders of prior drug use may precipitate relapses to drug-seeking despite the disastrous consequences that a return to drug use might bring. Such a state of addiction is not easily abolished, and relapse remains a serious risk even after many years of abstinence.