Advances in the neurobiological bases for food 'liking' versus 'wanting'.

The neural basis of food sensory pleasure has become an increasingly studied topic in neuroscience and psychology. Progress has been aided by the discovery of localized brain subregions called hedonic hotspots in the early 2000s, which are able to causally amplify positive affective reactions to palatable tastes ('liking') in response to particular neurochemical or neurobiological stimulations. Those hedonic mechanisms are at least partly distinct from larger mesocorticolimbic circuitry that generates the incentive motivation to eat ('wanting'). In this review, we aim to describe findings on these brain hedonic hotspots, especially in the nucleus accumbens and ventral pallidum, and discuss their role in generating food pleasure and appetite.

Incentive sensitization by previous amphetamine exposure: increased cue-triggered "wanting" for sucrose reward.

We reported previously that an amphetamine microinjection into the nucleus accumbens enables Pavlovian reward cues in a conditioned incentive paradigm to trigger excessive instrumental pursuit. Here we show that sensitization caused by previous amphetamine administration also causes reward cues to trigger excessive pursuit of their associated reward, even when sensitized rats are tested in a drug-free state. Rats learned to lever press for sucrose pellets, and they separately learned to associate sucrose pellets with Pavlovian cues (30 sec auditory cues). Amphetamine sensitization was induced by six daily injections of amphetamine (3 mg/kg, i.p.; controls received saline). Rats were tested for lever pressing under extinction conditions 10 d later, after a bilateral microinjection of intra-accumbens vehicle or amphetamine (5 microg/0.5 microl per side). Cue-triggered pursuit of sucrose reward was assessed by increases in pressing on the sucrose-associated lever during intermittent presentations of a free conditioned stimulus (CS+) sucrose cue. Sensitized rats pressed at normal levels during baseline and during the CS-, but the CS+ triggered 100% greater increases in pressing from sensitized rats than from control rats after vehicle microinjection. Sensitization therefore enhanced the incentive salience attributed to the CS+ even when rats were tested while drug-free. For control rats, a microinjection of intra-accumbens amphetamine was needed to produce the same enhancement of cue-triggered reward "wanting." The amphetamine microinjection also interacted synergistically in sensitized rats to produce intrusive cue-triggered pursuit behaviors (e.g., investigatory sniffing) that interfered with goal-directed lever pressing. These results support the incentive-sensitization theory postulate that sensitization causes excessive cue-triggered "wanting" for an associated reward.

Fear and feeding in the nucleus accumbens shell: rostrocaudal segregation of GABA-elicited defensive behavior versus eating behavior.

This study examined localization of positive versus negative motivational functions mediated by GABA circuits within the accumbens shell. Microinjections of a GABA(A) agonist (0, 25, 75, and 225 ng/0.5 microl muscimol) in rostral shell sites elicited appetitive increases in eating behavior. In contrast, microinjections in caudal shell sites elicited defensive burying or paw-treading behavior. Rats whose microinjections landed bilaterally outside of the accumbens shell did not display either behavior. Defensive treading elicited by caudal shell muscimol microinjection appeared to be a negative motivated response to threat (similar in parameters and orientation to normal defensive burying of a threatening electrified shock prod). The nucleus accumbens shell thus appears functionally heterogeneous in coding motivational valence. The demonstration that muscimol elicits positive eating behavior from rostral shell versus negative defensive behavior from caudal shell suggests in particular that GABAergic substrates of positive and negative types of motivated behavior in the nucleus accumbens shell are segregated along a rostrocaudal gradient.

Incentive-sensitization and addiction.

The question of addiction concerns the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities, and the inability to cease drug-taking, that is, the problem of relapse. In this paper we summarize one view of this process, the "incentive-sensitization" view, which we first proposed in 1993. Four major tenets of the incentive-sensitization view are discussed. These are: (1) potentially addictive drugs share the ability to alter brain organization; (2) the brain systems that are altered include those normally involved in the process of incentive motivation and reward; (3) the critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli; and (4) the brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting").

Comparative expression of hedonic impact: affective reactions to taste by human infants and other primates.

This study examines behavioral affective reactions elicited by tastes from eight newborn human infants, and from 27 other infant or adult primates. Non-human primates belonged to 11 species: three great apes (chimpanzee, orangutan, gorilla), three Old World monkeys (rhesus monkey, greater spot-nosed monkey, and red-capped mangabey), four New World monkeys (golden-handed tamarin, cotton-top tamarin, white tufted-ear marmoset, and Humboldt's night monkey), and one lemur (mongoose lemur). The taste of sucrose elicited homologous positive hedonic patterns of facial affective reactions from humans and other primates, whereas quinine elicited homologous aversive or negative affective patterns. The degree of similarity between human and other primate affective reaction patterns appeared to be strongly indicative of their phylogenetic relatedness. For example, affective reaction patterns of human infants and great apes were more similar to each other than either were to Old World monkeys or New World monkeys. Certain affective reaction components were found to be shared by humans and all primates, whereas other components were restricted to particular taxonomic groups. Finally, allometric timing parameters for the duration of components indicated that the 'same' affective reaction could have different durations in species of different size. These results show that both positive/negative valence and intensity of affective reaction may be quantitatively assessed in human and non-human primates, and indicate that taste-elicited affective reaction patterns of human infants are related systematically to those of other primate species.

Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward "wanting" without enhanced "liking" or response reinforcement.

Amphetamine microinjection into the nucleus accumbens shell enhanced the ability of a Pavlovian reward cue to trigger increased instrumental performance for sucrose reward in a pure conditioned incentive paradigm. Rats were first trained to press one of two levers to obtain sucrose pellets. They were separately conditioned to associate a Pavlovian cue (30 sec light) with free sucrose pellets. On test days, the rats received bilateral microinjection of intra-accumbens vehicle or amphetamine (0.0, 2.0, 10.0, or 20.0 microgram/0.5 microliter), and lever pressing was tested in the absence of any reinforcement contingency, while the Pavlovian cue alone was freely presented at intervals throughout the session. Amphetamine microinjection selectively potentiated the cue-elicited increase in sucrose-associated lever pressing, although instrumental responding was not reinforced by either sucrose or the cue during the test. Intra-accumbens amphetamine can therefore potentiate cue-triggered incentive motivation for reward in the absence of primary or secondary reinforcement. Using the taste reactivity measure of hedonic impact, it was shown that intra-accumbens amphetamine failed to increase positive hedonic reaction patterns elicited by sucrose (i.e., sucrose "liking") at doses that effectively increase sucrose "wanting." We conclude that nucleus accumbens dopamine specifically mediates the ability of reward cues to trigger "wanting" (incentive salience) for their associated rewards, independent of both hedonic impact and response reinforcement.

Do California ground squirrels (Spermophilus beecheyi) use ritualized syntactic cephalocaudal grooming as an agonistic signal?

Animal communication theory holds that many signals have evolved from nonsignal precursors. This field and laboratory study of California ground squirrels (Spermophilus beecheyi) provides evidence for the coexistence of such a precursor with its derived display. The precursor is an ancient, endogenously sequenced (syntactic) pattern of cephalocaudal grooming movements (CCGs) shared by all rodent suborders. The following evidence supports the hypothesis that a supernormal version of this pattern has been selected for signal function. Syntactic CCGs in the field (a) were more rigidly stereotyped than ordinary syntactic CCGs in the laboratory; (b) differed from laboratory syntactic CCGs in other ways that enhanced their conspicuousness, in part through exaggeration of the syntactic cephalocaudal pattern; (c) were associated with scent marking and social staring; and (d) were associated with intrasexual agonistic encounters that did not escalate to fighting.

The psychology and neurobiology of addiction: an incentive-sensitization view.

The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentive-sensitization theory of addiction", which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting"). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.

The hedonic impact and intake of food are increased by midazolam microinjection in the parabrachial nucleus.

Benzodiazepines have been reported to induce eating when administered into the brainstem of rats (either the fourth ventricle or the parabrachial nucleus). Benzodiazepines in the brainstem also have been reported to enhance the hedonic impact of taste, as measured by hedonic/aversive taste reactivity patterns, when administered to the fourth ventricle. The present study examined whether the parabrachial nucleus in particular is a brainstem site of the benzodiazepine-produced enhancement of eating and palatability. Food intake (cereal mash) was measured after brainstem microinjections of midazolam or vehicle (0.0, 7.5, and 15.0 microg) into the parabrachial nucleus, the nucleus of the solitary tract, the pedunculopontine tegmental nucleus, or the fourth ventricle (60 microg). We used the taste reactivity paradigm to measure hedonic/aversive affective reactions elicited from rats by oral infusions of a bittersweet solution (7% sucrose-0.01% quinine). Positive hedonic reactions and negative aversive reactions to sucrose-quinine were also measured after microinjections of midazolam (0.0, 7.5, and 15 microg) into the parabrachial nucleus. Midazolam increased food intake and selectively enhanced positive hedonic taste reactivity patterns to the bittersweet solution when microinjections were delivered to the parabrachial nucleus. When administered to the other brainstem sites at the same doses, however, midazolam had no effect. We therefore conclude that the parabrachial nucleus can mediate the benzodiazepine-induced enhancement of the hedonic impact of taste as well as mediating the enhancement of eating behavior.

Super-stereotypy I: enhancement of a complex movement sequence by systemic dopamine D1 agonists.

Peripheral administration of D1 dopamine agonists elicits grooming behavior from rodents. The present study examined grooming behavior and the relative probability and stereotypy of a natural sequence of grooming movements (called a syntactic grooming chain) that follows a predictable fixed pattern of serial order. We compared the amount of grooming behavior vs. the stereotypy of sequential patterns after peripheral administration of either a partial D1 agonist (SKF 38393; 2.5, 5.0, 10, 20 mg/kg), a full D1 agonist (SKF 82958; 0.1, 0.2, 0.5, 1.0 mg/kg; i.p.), a D2 agonist (quinpirole; 5.0, 10 mg/kg), or ACTH (2.0, 5.0 mg/kg). There was a dissociation between the elicited grooming amount, the pattern frequency, and the pattern completion or sequential stereotypy after these drugs. Quinpirole and ACTH both reduced the likelihood that the sequential pattern would be completed in the normal pattern (and reduced the overall amount of grooming). Administration of either SKF 38393 or SKF 82958 increased the tendency to engage in complex stereotyped sequential patterns of grooming (even though only the partial D1 agonist increased the total amount of grooming). In addition, SKF 38393 increased the sequential stereotypy of the already-stereotyped pattern itself (as measured by the probability of completing the stereotyped sequence once it began). Thus, dopamine D1 receptor activation appears to contribute to a kind of sequential super-stereotypy in which a complex, stereotyped behavioral sequence is initiated more frequently and more often goes to completion.

Super-stereotypy II: enhancement of a complex movement sequence by intraventricular dopamine D1 agonists.

This study compared the effect of intraventricular administration of dopamine D1 or D2 agonists or of ACTH on the sequential stereotypy of a serial pattern of grooming movements ("syntactic chain"). In a previous study, we showed that peripheral administration of D1 agonists increased the probability of occurrence and enhanced the stereotypy of the already-stereotyped movement pattern. Here we made microinjections of either SKF 38393 (a partial D1 agonist; 5, 10, 15, 20, 40 microg), SKF 82958 (a full D1 agonist; 5, 10, 20 microg), quinpirole (a D2 agonist; 5, 10, 20 microg), or ACTH-(1-24) (2, 5, 10 microg) into the lateral ventricles of rats. We measured the amount of grooming, the relative probability that the complex sequence pattern would occur, and the degree to which the syntactic pattern was completed faithfully. The total amount of grooming behavior was increased by intraventricular SKF 82958 and by ACTH, but was not changed by SKF 38393 and was decreased by quinpirole. Super-stereotypy of the sequential pattern was produced only by dopamine D1 agonists. The relative probability of initiating the syntactical sequence was increased by both SKF 38393 and SKF 82958, but was reduced by quinpirole and ACTH. The full D1 agonist, SKF 82958, also increased the likelihood that the pattern would be completed, thus causing sequential super-stereotypy in the strongest sense. Our results highlight a role for dopamine D1 receptors, probably within the basal ganglia, in the production of sequential super-stereotypy of complex behavioral patterns.

Food intake after diazepam, morphine or muscimol: microinjections In the nucleus accumbens shell.

This study examined the effect on food intake of bilateral microinfusions of the benzodiazepine agents, diazepam and midazolam, the opioid agonist, morphine, and the GABA(A) agonist, muscimol into the shell of the nucleus accumbens in rats. Both muscimol (at 0.075 microg, combined bilateral dose) and morphine (1.0 microg) in the nucleus accumbens shell increased feeding as expected. However, it was clear that diazepam (2.5, 5.0, 25, 50 microg) and midazolam (7.5 microg) both failed to enhance feeding even at doses that are effective when microinjected in the brain stem. We conclude that opioid and GABA(A) agents promote feeding behavior by acting on receptors in the nucleus accumbens shell, but that benzodiazepines probably act elsewhere in the brain to increase food intake.

Opioid site in nucleus accumbens shell mediates eating and hedonic 'liking' for food: map based on microinjection Fos plumes.

Microinjection of opioid agonists, such as morphine, into the nucleus accumbens shell produces increases in eating behavior (i.e. 'wanting' for food). This study (1) reports direct evidence that activation of accumbens opioid receptors in rats also augments food 'liking', or the hedonic impact of taste, and (2) identified a neural site that definitely contains receptors capable of increasing food intake. Morphine microinjections (0.5 microgram) into accumbens shell, which caused rats to increase eating, were found also to cause selective increases in positive hedonic patterns of behavioral affective reaction elicited by oral sucrose, using the 'taste reactivity' test of hedonic palatability. This positive shift indicated that morphine microinjections enhanced the hedonic impact of food palatability. The accumbens site mediating morphine-induced increases in food 'wanting' and 'liking' was identified using a novel method based on local expression of Fos induced directly by drug microinjections. The plume-shaped region of drug-induced increase in Fos immunoreactivity immediately surrounding a morphine microinjection site (Fos plume) was objectively mapped. A point-sampling procedure was used to measure the shape and size of 'positive' plumes of Fos expression triggered by microinjections of morphine at locations that caused increases in eating behavior. This revealed a functionally 'positive' neural region, containing receptors directly activated by behaviorally-effective drug microinjections. A subtraction mapping procedure was then used to eliminate all surrounding regions containing any 'negative' Fos plumes that failed to increase food intake. The subtraction produced a conservative map of the positive site, by eliminating regions that gave mixed effects, and leaving only a positive region that must contain receptors capable of mediating increases in food intake. The resulting mapped 'opioid eating site' was contained primarily within the medial caudal subregion of the nucleus accumbens shell, and did not substantially penetrate either into the accumbens core or into other subregions of the shell. Several other structures outside the nucleus accumbens (such as rostral ventral pallidum), immediately medial and adjacent to the shell, also appeared to be included in the functional site. Opioid receptors within this site thus are capable of mediating morphine-induced increases in eating, in part by enhancing the hedonic reward properties of food.

Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns.

The hedonic impact of taste is reflected in affective facial reactions made by human infants, other primates, and even rats. Originally studied in human infants, affective reactions to taste have also been used by affective neuroscience to identify hedonic brain systems in studies of animals (via application of neural stimulation, pharmacological activation, and neural lesion manipulations). The chief limitation of measuring affective reactions is that it is difficult for experimenters to know how to interpret them, and therefore how to interpret changes produced by brain manipulations. This paper notes guidelines to interpretation. It examines the phylogenetic continuity between humans, other primates, and rats in terms of the microstructure of taste-elicited affective reactions. It reviews evidence that affective taste reactivity patterns truly reflect a 'core hedonic process' of palatability or affect, rather than being an ingestion measure, consummatory behavior measure, or a sensory reflex measure. It reviews affective neuroscience studies of taste reactivity that have identified true hedonic brain substrates, and discriminated them from false hedonic brain substrates. It considers the neural bases of incentive 'wanting' versus 'liking'. Finally, it notes the difference between human subjective affective ratings of pleasure and 'core hedonic processes' reflected by behavioral affective reactions.

Conditioned taste aversion in rats for a threonine-deficient diet: demonstration by the taste reactivity test.

Rats avoid a diet that is deficient in one or more essential amino acids (EAAs). This phenomenon is thought to involve the development of a "learned aversion" for the sensory properties or spatial placement associated with the deficient diet. The dietary self-selection technique has been widely used to show this avoidance of the deficient diet. Because avoidance does not necessarily imply taste aversion, we used the Taste Reactivity Test initially created by Grill and Norgren (1978) to analyze the affective reactivity pattern of rats that ingested a threonine-deficient diet. The results showed that there was an increase in the aversive responses when ingesting the threonine-deficient (Thr-Dev) diet, compared to a control diet, without changes in the hedonic responses. The aversive reactions were mainly gaping, and to a lesser extent chin rubbing and head shaking. This asymmetrical shift in the Thr-Dev diet palatability is consistent with a two-dimensional hypothesis of palatability, indicating that the aversive palatability of the deficient diet was increased while the positive palatability did not change. Further evidence indicates that rats do not develop a normal behavioral satiety sequence after ingesting the threonine-deficient diet. These results indicate that a true aversion is formed to the taste of a diet that is deficient in an essential amino acid.

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is 'no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the 'taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for 'wanting' incentives, but not for 'liking' them or for learning new 'likes' and 'dislikes'.

Action sequencing is impaired in D1A-deficient mutant mice.

The role of dopamine in the production of behaviour is multifarious in that it can influence different aspects of movement (e.g. movement initiation, sensorimotor integration, and movement sequencing). A characteristic of the dopamine system which seems to be critical for the expression of this diverse influence is its varied receptor population. Previous studies have shown that specific receptor subtype activation leads to specific behavioural responses or alterations of selective aspects of movement. It is known that one of the important influences of dopamine includes sequential co-ordination of 'syntactic' patterns of grooming movements because moderate loss of the dopaminergic nigrostriatal projections specifically disrupts these patterns without affecting grooming actions in a general fashion (Berridge, K.C. Psychobiology, 15, 336, 1989). The specific receptors of the dopamine family which play a key part in this co-ordination of movement sequences is not known. In the present study, we examined the serial order of particular syntactic sequences or chains of grooming actions in mice lacking D1A receptors to explore the relationship between this receptor subtype and movement sequencing. Mutant mice had shorter grooming bouts and a disruption of the organization of sequential patterns compared with wild-type littermate controls. Sequential disruption was reflected in the failure of D1A mutants to follow the syntactic pattern of grooming to completion. This sequential disruption deficit appeared to be specific, as mutant mice initiated more syntactic chains than wild-type controls even though they were less likely to complete them. These results support the hypothesis that D1A receptor activation plays a part in the sequencing of natural action. This conclusion has important implications for the understanding of the functional heterogeneity of dopamine receptor subtypes and of the aetiology of symptoms observed in patients with basal ganglia disease.

Coding of serial order by neostriatal neurons: a "natural action" approach to movement sequence.

The neostriatum controls behavioral sequencing, or action syntax, as well as simpler aspects of movement. Yet the precise nature of the neostriatums role in sequencing remains unclear. Here we used a "natural action" approach that combined electrophysiological and neuroethological techniques. We identified neostriatal neurons that code the serial order of natural movement sequences of rats. During grooming behavior, rats emit complex but highly predictable species-specific sequences of movements, termed "syntactic chains." Neuronal activity of 41% of cells in the dorsolateral and ventromedial neostriatum coded the sequential pattern of syntactic chains. Only 14% coded simple motor properties of grooming movements. Neurons fired preferentially during syntactic chains compared with similar grooming movements made in different sequential order or to behavioral resting. Sequential coding differed between the dorsolateral and ventromedial neostriatum. Neurons in the dorsolateral site increased firing by 116% during syntactic chains, compared with only a 30% increase by neurons in the ventromedial site, and dorsolateral neurons showed strongest coding of grooming syntax by several additional criteria. These data demonstrate that neostriatal neurons code abstract properties of serial order for natural movement and support the hypothesis that the dorsolateral neostriatum plays a special role in implementing action syntax.

Pimozide does not shift palatability: separation of anhedonia from sensorimotor suppression by taste reactivity.

Several "taste reactivity" studies of dopamine and reward have concluded that pimozide suppresses the hedonic reaction patterns normally elicited by sucrose but enhances aversive reaction patterns elicited by quinine. However, other taste reactivity studies have failed to find hedonic/aversive shifts in reaction patterns after dopamine antagonists or dopamine lesions. The divergent conclusions have come from two different laboratories. To resolve the controversy regarding dopamine blockade and palatability, the present study joined the two laboratories to investigate the effect of pimozide on taste reactivity patterns elicited by sucrose and quinine. The results replicated many (but not all) of the earlier findings and identified procedural factors responsible for different outcomes. Overall, the results provide evidence for sensorimotor effects of pimozide on taste reactivity but not for a hedonic shift in palatability. Pimozide suppressed both hedonic and aversive reaction patterns in a gradual sensorimotor fashion when the eliciting taste stimulus was repeated or continued for several minutes. The general suppression typically did not alter the initial reaction to a taste but emerged only after an oral infusion of sucrose or quinine continued for several minutes or trials. Aversive reactions were never enhanced. The balance between hedonic and aversive reaction patterns was not shifted by pimozide. We conclude that pimozide produces a sensorimotor impairment of taste reactivity patterns but does not shift taste palatability toward anhedonia or aversion.

Psychoactive drug use in evolutionary perspective.

Pure psychoactive drugs and direct routes of administration are evolutionarily novel features of our environment. They are inherently pathogenic because they bypass adaptive information processing systems and act directly on ancient brain mechanisms that control emotion and behavior. Drugs that induce positive emotions give a false signal of a fitness benefit. This signal hijacks incentive mechanisms of "liking" and "wanting," and can result in continued use of drugs that no longer bring pleasure. Drugs that block negative emotions can impair useful defenses, although there are several reasons why their use is often safe nonetheless. A deeper understanding of the evolutionary origins and functions of the emotions and their neural mechanisms is needed as a basis for decisions about the use of psychoactive drugs.