Molecular Psychiatry (2000) 5, 467475 2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.

com/mp

MILLENNIUM ARTICLE

Is there an evolutionary mismatch between the normal physiology of the human dopaminergic system and current environmental conditions in industrialized countries?
L Pani
CNR Center for Neuropharmacology, BB Brodie Department of Neuroscience, University of Cagliari and Neuroscienze Scarl, Cagliari, Italy
A large body of evidence has recently dened a eld theory known as evolutionary mismatch, which derives its attributes largely from the fact that current environmental conditions are completely different from those in which the human central nervous system evolved. Current views on the evolutionary mismatch theory lack, however, any attempts to dene which brain areas or neuronal circuits should be mostly involved in coding such misevolved traits and to what extent our neurobiological knowledge can be applied to the topographical localization of a specic psychopathology. In this respect the mesocorticolimbic dopaminergic circuits have long been misconceptualized as simple reward or reinforcement systems. Instead, they motivate and coordinate the functions of the higher brain areas that mediate planning and foresight and direct nalized movement in both animals and humans. These systems make animals intensely interested in exploring the world around them, but by the same means they also make them susceptible to the environmental stimuli that have been sought and consumed. It is has been speculated that the cortical dopamine targets that developed most recently in phylogeny are of particular functional value, and that the mesocorticolimbic dopaminergic system is involved in more complex integrative functions than previously assumed. In the present paper I will argue that some mental disorders may have their deep roots in the evolutionary mismatch between the normal physiology of the mesocorticolimbic dopaminergic system and the current environmental conditions in afuent societies. Molecular Psychiatry (2000) 5, 467475. Keywords: evolution; limbic system; dopamine; stress; depression; emotions; Darwinian medicine

Introduction The essential steps in the evolution of the brain from early mammals1 to humans2 show an increasing motor3 and cognitive-emotional interaction4 with the external world (Table 1). This environmental pressure required the development of a neuronal system which was able to decipher and cope with the signals and stimuli coming from the brains surroundings. In this sense, the utilization of the principle of reward5 by linking outcomes of behaviors to either reinforcing or aversing sensations (and memorizing them), which is part of the normal physiology of the dopaminergic system, was absolutely instrumental in the course of evolution. Several authors, however, consider such a view an over-simplication of the role of the mesolimbic and mesocortical dopamine circuits, which not only direct nalized movement in both animals and humans, but
Correspondence: Dr L Pani, CNR Center for Neuropharmacology, Via Porcell, 4, 09124-I, Cagliari, Italy. E-mail: panilunica.it Received 3 January 2000; revised and accepted 10 April 2000

Table 1 Steps in brain evolution with increasing environmental interaction 1. 2. 3. 4. 5. 6 7. 8. 9. 10. Bipedalism Development of a cooling system Trichromatic vision Hemispheric dominance/use of tools Nursing and maternal care Voluntary control of speech Separation call Self/other feelings awareness Development of synthatic ability Pressure to speak

also motivate and coordinate the functions of higher brain areas that mediate planning, foresight and promote states of eagerness.6,7 By these functions animals become intensely interested in exploring the world around them, but by the same means they are exposed and susceptible to the environmental stimuli that have been sought and consumed. In mammals, and especially in primates, the mesocortical dopaminergic

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system generates and sustains curiosity, and it is quite efcient at facilitating learning. It is particularly effective in memorizing information about where material resources are located and the best way to obtain the things needed for survival, including food, water, warmth and sex.8 While telencephalic dopaminergic nuclei, such as the nucleus accumbens and the caudate-putamen, have been conserved in their gross and microscopic structure throughout evolution from rodents9 to humans,10 the structural organization of the cortical dopaminergic circuits, most strictly involved in human pathologies such as depression and psychosis, shows signicant differences between rodents and primates.11,12 Recent data show that the major development of the cerebral cortex in primates was accompanied (or produced?) by a similar expansion of the dopaminergic input to all cortical layers, with a specic and laminar redistribution of the dopaminergic terminals.11 It has been speculated that the cortical dopamine targets that developed most recently in phylogeny are to be considered of particular functional value, and that the mesocorticolimbic dopaminergic system is involved in more complex integrative functions than previously assumed. In the present paper I will argue that the evolved physiology of the mesocorticolimbic dopaminergic system may be mismatched with respect to current environmental conditions and may contribute to the precipitation of human psychiatric disorders.

representatives of the earliest craniates, lamprey and hagsh, paralleling a high dopamine and noradrenaline content throughout their brain.16 Receptor family The evolving vertebrate nervous system was always accompanied by major gene duplication events which generated novel organs along with a denite sympathetic system which was needed to monitor and control them. Vertebrate neural pathways synthesizing monoamine neurotransmitters (mostly dopamine and noradrenaline) were subsequently recruited in order to process increased information demands by mediating psychomotor functions, such as selective attention/predictive reward and emotional drive, via the activation of multiple G-protein linked catecholamine receptor subtypes. At least 1000 million years ago (MYA), all the classical transmitter ligand molecules evolved the ability to activate a wide range of ion channels, resulting in excitation, inhibition and biphasic or multiphasic responses. In this respect, the invertebrate receptors which have so far been cloned show striking homologies with mammalian receptors, indicating that many of the basic receptor subtypes evolved at an early period, probably around 800 MYA.17 The evolution of these receptor-mediated events was similarly driven by forces of gene duplication, at the cephalochordate/vertebrate transition. In amphioxus, a single catecholamine receptor gene was found which, based on molecular phylogeny and functional analysis, forms a monophyletic group with both vertebrate dopamine D1 and beta adrenergic receptor classes.18 These data suggest that a dopamine D1/beta receptor gene duplication was required for the elaboration of novel catecholamine psychomotor adaptive responses, and that a noradrenergic system specically emerged at the origin of vertebrate evolution. Recent investigations have conrmed that the dopamine D1A, D1B, and D1C receptors share molecular, pharmacological, and functional attributes that unambiguously allow for their evolutionary classication as distinct D1 receptor subtypes of the G-protein linked super-family, in the vertebrate phylum.18 All these receptors conserve a fairly stable secondary structure, a moderate and reasonably steady rate of sequence change, and usually lack introns within their coding sequence. Several results indicate that the rst event to occur within this gene family was the divergence of the catecholamine receptors from the muscarinic acetylcholine receptors, which occurred prior to the divergence of the arthropod and vertebrate lineages. Subsequently, the ability to activate specic second-messenger pathways diverged independently in both the muscarinic and the catecholamine receptors. This appears to have occurred after the divergence of the arthropod and vertebrate lineages, but before the divergence of the avian and mammalian lineages. However, the second-messenger pathways activated by adrenergic and dopamine receptors did not diverge independently. Rather, the ability of the catecholamine

Evolution of the dopaminergic system

Enzymes The acquisition of the behaviors modulated by dopaminergic innervation has been so indispensable in survival that the enzymatic machinery needed to synthesize dopamine appeared very early in phylogenesis. One of the most rudimentary nervous systems, that of the sea pansy Renilla koellikeri (Cnidaria), is able to synthesize dopamine; such synthesis is inhibited by alpha-methyl-p-tyrosine.13 In this invertebrate, the role of dopamine is that of giving bioluminescence and producing muscular contractions, which are most likely to be used to capture food or avoid danger; insufcient to result in such superior animal characteristics as the ability to feel pleasure and pain. The neurochemical basis of the effects of dopamino-mimetic drugs in other distant organisms has not been fully elucidated, but the hyperkinesia induced by cocaine, a drug which blocks the dopamine transporter, in Planaria specimens suggests that the selective site for pre-synaptic dopamine re-uptake is already present in this atworm.14 Goldsh show place preference for the water bowls where they have received amphetamine, a drug of abuse that increases dopaminergic transmission.15 In the cephalochordate amphioxus, a sister group to vertebrates, the presence of dopamine (but not of noradrenaline) has been assayed. In contrast, two distinct genes homologous to the jawed vertebrate dopamine D1 and beta adrenergic receptor genes were shown to be extant in
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receptors to bind to specic ligands, such as epinephrine, norepinephrine, dopamine, or octopamine, was repeatedly modied in evolutionary history, and in some cases was modied after the divergence of the second-messenger pathways.19 When the distribution of the dopamine D1 and D2 receptors in the brain of a mouse, rat, or cat is compared with that of a monkey, similarities are found only in the basal ganglia; the highest density being present in the caudate-putamen, in the nucleus accumbens, in the olfactory tubercle, and in the substantia nigra. Apart from these nuclei, and particularly in more recent structures such as the cerebellum and the frontal cortex, the absolute and relative values of the dopamine receptor subtypes is completely different in primates, suggesting that the transcriptional control of the gene encoding for the dopaminergic receptors has also undergone profound changes throughout evolution.20

Table 2 Years of signicant inventions and technological advancement 1550 1690 1770 1853 1876 1885 1886 1903 1920 1926 1948 1962 1969 1972 1978 1988 1992 2000 Screwdriver Steam engine Electrical battery Hypodermic needle Telephone Gas-engine auto Coca-Cola Airplane Radio broadcast Television Transistors Minicomputer Moon landing Videogames Test tube baby Patented animal life Global internet Human genome sequenced

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The dopaminergic system and the mismatch theory

Large sets of data (for a review see Nesse and Williams)21 have recently allowed the denition of a eld theory called evolutionary mismatch, which derives its attributes largely from the fact that current environmental conditions in industrialized countries are completely different from those in which the human central nervous system evolved. The mismatch between evolved traits and contemporary lifestyle, the presence of evolutionary trade-offs (eg selection of some traits over others), and historical constraints (eg how a trait has evolved), has resulted in the poor specialization of selected traits, as well as a particular susceptibility to mental disorders. To explain the somatic correlates of such an evolutionary view of diseases, it is assumed that pathogens that attack humans evolve faster than we do. If the ever-mutating environmental conditions, where change is mostly due to fast technological advancement (Table 2), could now be assimilated to organic pathogens, their rapid rate of evolution and change would impose a pressure that is not paralleled by an evolution of the brain structures which are able to analyze, process, and elaborate on such rapid variations. For example, a poor t between strongly evolved traits (eg dependency) and the current urban social environment may account for the increase in frequency of anxiety and depressive disorders in modern societies.22 Current views on the evolutionary mismatch theory lack, however, a denition of which brain areas or neuronal circuits should be involved in coding such misevolved traits, and to what extent our neurobiological knowledge can be applied to the topographical localization of a specic psychopathology. The appetitive and consummatory phases of behaviors triggered by environmental cues which are associated with survival properties (whether rewarding or aversive for the individual) are known to be mediated by sensory-specic dopaminergic neuronal circuits. These dopaminergic systems are involved in those mechanisms which determine satiety to food,23 sex,24 and drugs of abuse.25 In all these conditions, the most important dopamine systems involved are that of the terminal elds of the prefrontal cortex,26 and that of the nucleus accumbens,27 both originating from neurons located in the ventral tegmental area of the midbrain. Whether the stimulation of these neurons mediates the incentive salience (reviewed in Berridge and Robinson),28 or the associative learning29 capacities of an event, is still a matter of intense debate. According to the rst hypothesis, rewarding (and thus also averse) stimuli that have acquired motivational signicance (salience) are part of a phenomenon which is neither unitary nor subjective; dopamine-related neural circuits mediating only a specic component of reward, ie the attribution of incentive salience to an otherwise neutral event. In contrast, others have argued that mesolimbic dopaminergic pathways do not code for such an ability, but serve only to respond to specic stimuli which possess high motivational impact, as a result of their novelty, unpredictability, specic sensory modalities, or occurrence under a deprivation state;29 in these conditions, dopamine neurons dene the substrate for precise associative learning abilities. From an evolutionary perspective, the two mechanisms must play an equally important role in the attribution of an incentive value to ethologically relevant stimuli, and must facilitate, by means of both incentive-salience and associative-learning, the selection and the memory of appropriate behavioral responses. The conservation of such principles throughout evolution explains why pharmacological manipulations of the dopaminergic transmission are similarly able to modify basic behaviors in distant species such as lizards and rats (Table 3). Stimulation of the dopaminergic transmission will increase these behaviors, while the blocking of dopaminergic receptors or lesions of the dopaminergic pathways will decrease them. This conrms that dopamine is an
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Table 3 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

a

Special forms of basic behaviorsa Establishing a territory Showing place preference Hunting Greeting Social grouping Feeding and drinking Grooming Courtship Mating Breeding Maternal behavior Play (mammals only)

Adapted from Reference 6.

important neurotransmitter coding for sensory-specic responses, in the sense that a perceived environmental clue is acted on cognitively, either with an increase in exploration (by means of curiosity and reward) or a decrease (through fear and aversion),30 but also show that the physiological responses of the dopaminergic system are strictly environment sensitive. Electrophysiological recordings have indicated that key cortical and subcortical dopaminergic regions are involved in these motivated behaviors. Among these, a particular role in primates is given to the connections between the nucleus accumbens and the frontal cortex,31 which I will consider as primary sites for the evolutionary mismatch between the dopaminergic system and the ability to process signicant environmental-driven change-related information that guides coherent behavioral responses.

putamen; nucleus accumbens and internal capsule), at variance with that of the olfactory bulb. Thus, two heavily innervated dopaminergic structuresone coupled to taste related reward and satiety, and the other to olfactory satietyseemed to be mutually exclusive in their development. These complementary characteristics have been conserved in modern humans.34 The neural mechanisms of sensory-specic satiety in primates are implemented in the orbitofrontal cortex, which has an important integrative function. Neurons in this region of the cortex were indeed found to respond to stimulation of the taste, olfactory, or visual systems. In addition, some neurons were found to possess a bimodal response; responding, for example, to both taste and olfactory, or taste and visual stimuli. Since these multimodal neurons were found in very close proximity to unimodal neurons, and since the unimodal sensory neurons were intermingled, it is possible that the orbitofrontal cortex represents the rst cortical area of convergence for these three modalities in primates.35

Conditions that have changed through evolution and which interfere with the function of the dopaminergic system
Empirical data suggest a causal relationship between evolutionary-new environmental factors, specic dysregulation of the physiological ability of the dopaminergic system to process environmental stimuli and specic psychiatric disorders. Accordingly, the use of psychotropic medication in outpatient medical practice rose dramatically during the last 10 years, especially in industrialized countries. Around 10 years ago, Gershon et al showed that the rates of bipolar, schizoaffective, and unipolar disorders were higher in the cohorts born after 1940 than in the cohorts born earlier.36 It was suggested that an ominous trend could be present, leading to an increase in prevalence of a broad spectrum of familial affective disorders in the coming decades. This prediction proved to be correct and conrmed by more recent reports where changes in the prescribing patterns of psychotropic medications by ofce-based United-States physicians were examined.37 In the 9 years period between 1985 and 1994, the number of visits during which a psychotropic medication was prescribed increased from 32.73 million to 45.64 million. Antianxiety or hypnotic drug visits, previously the largest category, decreased and were surpassed by antidepressant visits, which doubled from 10 to 20 million in the last 5 years period; and stimulant drug visits increased more than vefold in the same period. These dramatic trends are in agreement with our ndings (Table 4), where we consider the Italian sales of psychotropic medications classied into three major categories: anxiolytics, antidepressants, and antipsychotics and conrmed a signicant tendency toward increase for antidepressants (+34%) and antipsychotics (+15%) but not for anxiolytics (+4%) in the last 5 years. Thus, it appears that in current afuent societies the

Expansion and regression of dopaminergic innervation

Animals with big brains are scarce, because bigger neuronal structures are more costly in terms of energy expenditure, development time, and anatomical complexity. It was always supposed that a much better diet (in terms of caloric value) must have been the starting point for the development of a much larger cerebral mass. Recently it was described how, about 40 MYA, a duplication of the gene coding for a retinal cone pigment in an ancestor of prosimians resulted in the development of trichromatic vision.32 This ability to see in color was instrumental in detecting ripe fruit, and gave an immediate evolutionary advantage over green-leaf eaters. At about the same time, the system for emotional communication via facial expression expanded and the olfactory bulb completed its regression in primates. Recently, this hypothesis was conrmed, showing that a highly predictable relationship exists between the relative size of the neocortex and that of the total brain.33 When the sizes of 10 measured brain divisions from 131 species are plotted as a function of total brain size, the two most expanded structures in all species are, in fact, the neocortex and the striatum (caudateMolecular Psychiatry

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Table 4

The Italian market for psychotropic compounds Millions of prescriptions per year 1995 1996 1997 1998 1999

Antipsychotics Antidepressants Anxiolytics

11 675 12 432 12468 12 940 13 428 16 750 18 275 19413 20 524 22 493 33 143 34 589 34093 34 917 34 487

psychological). Drugs of abuse that convey a signal that falsely indicates the arrival of a huge tness benet (much higher than food, water, sex, etc), actively change behavioral hierarchies. As a consequence, drugseeking increases in frequency to the point where it becomes the only dominant behavior, displacing all the other adaptive traits.39 Stress The denition of the term stress has gone from a nonspecic response of the body to any demands made upon it,40 to both a survival mechanism and an indicator of internal and external cues.41 Both acute and chronic stress have a detrimental impact on the normal function of the dopaminergic system (for a recent review see Pani et al).42 The response of the dopaminergic system to stress is neither homogenous nor generalized, and numerous results suggest that mesoprefrontal cortex dopaminergic projections are selectively activated by sudden changes in environmental conditions, whether expected or not.43 The ne tuning of dopamine extracellular concentration in the medial prefrontal cortex seems to be essential for the decision-taking protocols of the medial prefrontal cortex in the rat and the monkey.44 This supports the idea of a critical range of dopamine turnover for optimal prefrontal cortical cognitive functioning, with reduced or excessive dopamine turnover leading to cognitive impairment. Several data point to ventral tegmental area projections,45 dopamine receptors,46 and a loss of inhibitory tone on ventral tegmental area dopamine cells47 and lateral-basolateral amygdala (see below) as important regulatory sites for maintaining superior cognitive functions. The increased ability to remove dopamine in chronically stressed animals has also indicated that altered dopamine clearance may serve as an adaptive mechanism in the medial prefrontal cortex.48 It has been further suggested that increased dopamine D1 receptor stimulation during stress may serve to take the medial prefrontal cortex off-line, in order to allow posterior cortical and subcortical structures to regulate more primitive forms of behavior.49 Since dopaminergic innervation of the medial prefrontal cortex is able to regulate the activity of subcortical dopamine innervations, disruption of the medial prefrontal cortex dopamine bers may result in the altered biochemical responsiveness of the dopamine subcortical innervations.50 In humans, the balance between cortical and subcortical dopaminergic activity may serve as a protection against psychotic decompensation from chronic endogenous or exogenous insult,51 and the failure of this coping mechanism may well contribute to the vulnerability of the medial prefrontal cortex in many neuropsychiatric disorders related to the stress response.52 Chronic emotional reactions Emotional responses can be difcult to differentiate from generic reactions to stress, in laboratory animals as well as in humans. In addition, emotions such as

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frequency of psychiatric disorders requiring medications which modulate the function of (and not only of) the dopaminergic system is increasing. In addition, the outcomes of acute affective disorders are considerably more favorable in developing countries than in comparable studies in developed settings38 where at least four areas of evolutionary novelty can contribute and will be briey discussed below. Drugs of abuse The ability to extract, purify and lately synthesize psychoactive compounds has increased their availability to the general population in quantities and qualities never experienced before in the history of mankind. In addition, the development of new routes of administration (eg hypodermic needles, crack smoking, organic solvents) has increased the penetration of drugs of abuse into the brain, and has contributed to a change in the traditional relationship between the use of the natural source of the drug (eg the chewing of cocaleaves) to that of its active component (eg the endovenous injection of cocaine hydrochloride). Drugs of abuse offer a remarkable example of evolutionary mismatch at the level of the dopaminergic system, and help to clarify its role in the general physiology of the central nervous system. If drugs of abuse that act on the dopaminergic system (that is all of them, directly or indirectly) were used solely for their hedonic and reward producing potential, then this capacity, ie the pure ability to experience pleasure, would be the only one to be mainly affected by their chronic use. Instead, after a variable period of use, all drugs which determine a state of dependence interfere with the global adaptation of an individual to its environment, producing not only an impairment of his/her hedonic capacities, but also a more disruptive effect on the cognitive and emotional abilities that are necessary for an effective interaction with the external world (maladaptation). The limbic portion of the dopaminergic system is essential for the generation of the basic emotions that mediate various pro-social behaviors, such as maternal care, playfulness, and friendship, and which have been learned and have evolved to inuence motivational states and, ultimately, to increase tness. All these behaviors, along with the emotions which are related to them and their cognitive implications, are profoundly altered in a drug addict, much more than just the capacity to experience pleasure or avoid pain (whether physical or

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empathy seem to be uniquely human, and therefore impossible to mimic in animal models. In spite of this, several animal behaviors such as freezing, selfgrooming, exploration and defecation have been considered as valid somatic correlates to human emotional responses in which the dopaminergic system is involved. In all the models, the chronic nature of the stimulus is essential to produce a stable change in the normal physiology of the dopaminergic system. In modern times this can be obtained by generic stress due to sleep disruption, time shifts, poor physical activity, increased physical constraints, and unnatural social rules. In diseases in which dopamine function is compromised, humans exhibit a constellation of emotional symptoms, suggesting that the dopamine system plays an important role in the integration of superior cortical functions. A dorsal tier of dopamine neurons receives input from the nucleus accumbens and from the amygdala, and projects widely throughout the cortex. Through these projections, the dopaminergic limbic system has an enormous inuence on cortical output and can therefore affect the emotional and motivational coloring of a wide range of behaviors.53 In this respect, the lateral-basolateral amygdala receives sensory input from environmental stimuli and, along with the central amygdala, mediates conditional fear. Through its projections to forebrain, midbrain and hindbrain areas, the central amygdala governs the behavioral, autonomic, and endocrine responses that characterize a central fear state.54 Accumulating revelations about the amygdala-based fear system has led to considerable progress in delineating the neural connections and cellular mechanisms that underlie aversive emotionality, and very recently electrophysiological evidence has shown that neural discharge in the central amygdala is a consequence of repeated low-current, high-frequency electrical stimulation of dopaminergic nuclei of the ventral tegmental area.55 The introduction of Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats, two selectively bred lines that differ in their level of emotionality, into an unfamiliar environment, the application of a highintensity loud noise, or immobilization, are all associated with an increase in extracellular cortical dopamine metabolite levels in the RHA but not in the RLA line, suggesting that the differently evoked emotional reactions may produce a common activation of cognitive processes.56 This difference in reaction to a stressful stimulus, according to the genetic makeup of an individual, is an essential function of the mesencephalic dopaminergic neurons, and of their role in the organization of behavioral responses which are the reection of a heightened attention of the animal attempting to cope with the stressor.57 The mesocortical dopaminergic innervations seem to facilitate the functions of integrative structures, and to have a coordinated role in regulating the information ow between cortical structures.58 The study of fear and the role of the dopaminergic

system in rodents have, however, produced inconsistent data. While some results suggest an important relationship between social and motor reactivity, as well as an important, albeit again strain-dependent, role for dopamine D1 receptors in mediating specic emotional behaviors,59 others demonstrate that longterm administration of low, pre-synaptic doses of the dopamine D2 antagonist l-sulpiride is highly effective in an animal model of anticipatory anxiety/panic behavior.60 In contrast, recent ndings suggest that quinpirole (a dopamine D2 agonist) decreases fear by blocking the retrieval of a learned association between a conditioned and an unconditioned stimulus.61 Chronic sleep deprivation Humans have conserved mechanisms, like those that exist in other animals, which detect changes in day length and make corresponding adjustments in the duration of nocturnal periods. Several studies from Wehr and collaborators62 have suggested that modern mens use of articial light after dark and articial darkness during the daytime suppresses responses63 to seasonal changes in the duration of the natural scoto- and photoperiod that might otherwise occur at a given latitude, producing a chronic disturbance in the sleep pattern and decreasing, overall, the total amount of sleep. It is difcult to conceive that chronic sleep deprivation in humans could be obtained and maintained without any activation in the stress axis. Sleep deprivation in rats has been extensively studied as a possible animal model of mania.64 Interestingly, at the end of the period of sleep deprivation (approximately 72 h), the rat does not fall asleep as soon as it is returned to its home cage, but shows a period of wakefulness of about 30 min, during which the animal presents a cohort of symptoms that appear to mimic those present in idiopathic mania. In particular, during this period the animal displays a high degree of hyperactivity, irritability, aggressiveness, hyper-sexuality, and stereotypy. The model allowed the discovery of an active role of limbic dopamine in the generation of arousal and insomnia related to sleep deprivation-induced stress.65 Accordingly, direct evidence demonstrates that acute and chronic sleep deprivation may trigger a manic episode in otherwise healthy individuals,66 and that recurrent brief hypomania which lasts 13 days and belongs to the bipolar spectrum, is increasing in young adults.67 These ndings are indirectly conrmed by the increased use of neuroleptics (Table 4) which, although their use has been widely discouraged for mood disorders, are still the standard treatment for acute bipolar mania.68

Conclusions
The brain of Homo sapiens sapiens developed on the African plains, in populations of a few hundred thousand individuals; today there are six billion of us worldwide. It is time to ask ourselves whether the structural organization and the neuronal plasticity of the human

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brain are still able to control the evolution of the environment he has created. Some inuential neurobiologists have expressed strong doubts.69 The dopaminergic innervation to the prefrontal cortex is essential for processing and elaborating on the expectancy of events, and in the working memory related to them, in both rats and monkeys.44 Environmentally induced changes in the activity of the dopaminergic system, either by conventional (food, water, sex etc) or non-conventional (drugs of abuse, chronic stress, emotional reactions etc) stimuli could mismatch the natural codes for reward-aversion, sensory-motor, incentive-salience mechanisms which have been conserved in the last millions of years and which are needed to associate a learned outcome of a given stimuli with a denite emotional state of the organism. In this sense, the dorsolateral portion of the prefrontal cortex is important in monitoring the context of the situation in relation to how, and what, reward is given.70 Patients with prefrontal lesion are poor in assessing how actions relate to goals. The results suggest that pre-frontal cortical lesions provoke a selective impairment in managerial knowledge that may contribute to difculties in the formulation and execution of plans.71 Neurons which are critical for the computation of sensory-specic satiety in the monkey are located in the orbitofrontal cortex and, in humans, decisionmaking processes depend on signals arising in the prefrontal cortex in association with peripheral somato-visceral signals that can introduce biases in the reasoning processes.72 When normal subjects experience situations that they associate with the possibility of negative consequences, they sense a peripheral reaction (mainly an adrenergic response) and learn to make decisions accordingly. Damage to the orbitofrontal cortex in adulthood as well as in early life73 disrupts the capacity to make these physiological responses, and impairs this ability to make crucial social decisions. Considering the profound inuence of prefrontal cortex damage on several adaptive behaviors in rats and primates, another question arises: is it possible that in the absence of organic pathologies, a functional uncoupling of the cognitive capacities (eg working memory, decision-making, associative learning) of the prefrontal cortex could be the site of the dopaminergic evolutionary mismatch? In this respect, the temperament (as the genetic model of personality)74 of an individual may strongly relate to this evolutionary model. If this theory holds true it should be possible to study by imaging techniques whether or not patients with different temperaments, obviously selected by natural selection for conferring evolutionary trade-off, such as the bipolaranxious temperament types,75,76 would show any difference in the functions of their prefrontal cortex activity. A better understanding of the mechanisms, origins and functions of the dopaminergic system as well as other neurotransmitters and modulators, will also

enhance our ability to cope with stress-related mental disorders in the modern environment, and sharpen our wisdom in making decisions about the therapeutic use of psychoactive drugs. Acknowledgements I am grateful to Anna Porcella for her critical comments and to David Webb for his precise editorial work on the manuscript. This work was supported by a CNR grant.

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