Is There an Evolutionary Mismatch Between the Normal Physiology Of

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Molecular Psychiatry (2000) 5, 467–475  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 defined a field 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 define 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 specific 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 finalized 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 affluent societies. Molecular Psy- chiatry (2000) 5, 467–475. Keywords: evolution; limbic system; dopamine; stress; depression; emotions; Darwinian medicine

Introduction Table 1 Steps in brain evolution with increasing environmental interaction The essential steps in the evolution of the brain from early mammals1 to humans2 show an increasing motor3 4 1. Bipedalism and cognitive-emotional interaction with the external 2. Development of a cooling system world (Table 1). This ‘environmental pressure’ 3. Trichromatic vision required the development of a neuronal system which 4. Hemispheric dominance/use of tools was able to decipher and cope with the signals and 5. Nursing and maternal care stimuli coming from the brain’s surroundings. 6 Voluntary control of speech In this sense, the utilization of ‘the principle of 7. Separation call reward’5 by linking outcomes of behaviors to either 8. Self/other feelings awareness reinforcing or aversing sensations (and memorizing 9. Development of synthatic ability them), which is part of the normal physiology of the 10. Pressure to speak dopaminergic system, was absolutely instrumental in the course of evolution. Several authors, however, consider such a view an also motivate and coordinate the functions of higher over-simplification of the role of the mesolimbic and brain areas that mediate planning, foresight and pro- mesocortical dopamine circuits, which not only direct mote states of eagerness.6,7 By these functions animals finalized movement in both animals and humans, but become intensely interested in exploring the world around them, but by the same means they are exposed Correspondence: Dr L Pani, CNR Center for Neuropharmacology, and susceptible to the environmental stimuli that have Via Porcell, 4, 09124-I, Cagliari, Italy. E-mail: panilȰunica.it been sought and consumed. In mammals, and Received 3 January 2000; revised and accepted 10 April 2000 especially in primates, the mesocortical dopaminergic Evolutionary mismatch of the dopaminergic system L Pani 468 system generates and sustains curiosity, and it is quite representatives of the earliest craniates, lamprey and efficient at facilitating learning. It is particularly effec- hagfish, paralleling a high dopamine and noradrena- tive in memorizing information about where material line content throughout their brain.16 resources are located and the best way to obtain the things needed for survival, including food, water, Receptor family warmth and sex.8 The evolving vertebrate nervous system was always While telencephalic dopaminergic nuclei, such as accompanied by major gene duplication events which the nucleus accumbens and the caudate-putamen, have generated novel organs along with a definite sympath- been conserved in their gross and microscopic struc- etic system which was needed to monitor and control ture throughout evolution from rodents9 to humans,10 them. Vertebrate neural pathways synthesizing the structural organization of the cortical dopaminergic monoamine neurotransmitters (mostly dopamine and circuits, most strictly involved in human pathologies noradrenaline) were subsequently recruited in order to such as depression and psychosis, shows significant process increased information demands by mediating differences between rodents and primates.11,12 psychomotor functions, such as selective Recent data show that the major development of the attention/predictive reward and emotional drive, via cerebral cortex in primates was accompanied (or the activation of multiple G-protein linked catechola- produced?) by a similar expansion of the dopaminergic mine receptor subtypes. input to all cortical layers, with a specific and laminar At least 1000 million years ago (MYA), all the classi- redistribution of the dopaminergic terminals.11 It has cal transmitter ligand molecules evolved the ability to been speculated that the cortical dopamine targets that activate a wide range of ion channels, resulting in exci- developed most recently in phylogeny are to be con- tation, inhibition and biphasic or multiphasic sidered of particular functional value, and that the responses. In this respect, the invertebrate receptors mesocorticolimbic dopaminergic system is involved in which have so far been cloned show striking hom- more complex integrative functions than previously ologies with mammalian receptors, indicating that assumed. many of the basic receptor subtypes evolved at an early In the present paper I will argue that the evolved period, probably around 800 MYA.17 physiology of the mesocorticolimbic dopaminergic sys- The evolution of these receptor-mediated events was tem may be mismatched with respect to current similarly driven by forces of gene duplication, at the environmental conditions and may contribute to the cephalochordate/vertebrate transition. In amphioxus, a precipitation of human psychiatric disorders. single catecholamine receptor gene was found which, based on molecular phylogeny and functional analysis, forms a monophyletic group with both vertebrate dopa- Evolution of the dopaminergic system mine D1 and beta adrenergic receptor classes.18 These Enzymes data suggest that a dopamine D1/beta receptor gene The acquisition of the behaviors modulated by dopami- duplication was required for the elaboration of novel nergic innervation has been so indispensable in sur- catecholamine psychomotor adaptive responses, and vival that the enzymatic machinery needed to synthe- that a noradrenergic system specifically emerged at the size dopamine appeared very early in phylogenesis. origin of vertebrate evolution. Recent investigations One of the most rudimentary nervous systems, that of have confirmed that the dopamine D1A, D1B, and D1C the sea pansy Renilla koellikeri (Cnidaria), is able to receptors share molecular, pharmacological, and func- synthesize dopamine; such synthesis is inhibited by tional attributes that unambiguously allow for their alpha-methyl-p-tyrosine.13 In this invertebrate, the role evolutionary classification as distinct D1 receptor sub- of dopamine is that of giving bioluminescence and pro- types of the G-protein linked super-family, in the ver- ducing muscular contractions, which are most likely to tebrate phylum.18 be used to capture food or avoid danger; insufficient All these receptors conserve a fairly stable secondary to result in such superior animal characteristics as the structure, a moderate and reasonably steady rate of ability to feel pleasure and pain. The neurochemical sequence change, and usually lack introns within their basis of the effects of dopamino-mimetic drugs in other coding sequence. Several results indicate that the first distant organisms has not been fully elucidated, but the event to occur within this gene family was the diver- hyperkinesia induced by cocaine, a drug which blocks gence of the catecholamine receptors from the muscar- the dopamine transporter, in Planaria specimens sug- inic acetylcholine receptors, which occurred prior to gests that the selective site for pre-synaptic dopamine the divergence of the arthropod and vertebrate lin- re-uptake is already present in this flatworm.14 Gold- eages. Subsequently, the ability to activate specific fish show place preference for the water bowls where second-messenger pathways diverged independently they have received amphetamine, a drug of abuse that in both the muscarinic and the catecholamine recep- increases dopaminergic transmission.15 In the cephalo- tors. This appears to have occurred after the divergence chordate amphioxus, a sister group to vertebrates, the of the arthropod and vertebrate lineages, but before the presence of dopamine (but not of noradrenaline) has divergence of the avian and mammalian lineages. How- been assayed. In contrast, two distinct genes homolo- ever, the second-messenger pathways activated by gous to the jawed vertebrate dopamine D1 and beta adrenergic and dopamine receptors did not diverge adrenergic receptor genes were shown to be extant in independently. Rather, the ability of the catecholamine

Molecular Psychiatry Evolutionary mismatch of the dopaminergic system L Pani 469 receptors to bind to specific ligands, such as epine- Table 2 Years of significant inventions and technological phrine, norepinephrine, dopamine, or octopamine, was advancement repeatedly modified in evolutionary history, and in some cases was modified after the divergence of the 1550 Screwdriver second-messenger pathways.19 1690 Steam engine When the distribution of the dopamine D1 and D2 1770 Electrical battery receptors in the brain of a mouse, rat, or cat is com- 1853 Hypodermic needle pared with that of a monkey, similarities are found 1876 Telephone only in the basal ganglia; the highest density being 1885 Gas-engine auto 1886 Coca-Cola present in the caudate-putamen, in the nucleus accum- 1903 Airplane bens, in the olfactory tubercle, and in the substantia 1920 Radio broadcast nigra. Apart from these nuclei, and particularly in more 1926 Television recent structures such as the cerebellum and the frontal 1948 Transistors cortex, the absolute and relative values of the dopa- 1962 Minicomputer mine receptor subtypes is completely different in pri- 1969 Moon landing mates, suggesting that the transcriptional control of the 1972 Videogames gene encoding for the dopaminergic receptors has also 1978 Test tube baby undergone profound changes throughout evolution.20 1988 Patented animal life 1992 Global internet 2000 Human genome sequenced The dopaminergic system and the mismatch theory Large sets of data (for a review see Nesse and those mechanisms which determine satiety to food,23 Williams)21 have recently allowed the definition of a sex,24 and drugs of abuse.25 In all these conditions, the field theory called ‘evolutionary mismatch’, which most important dopamine systems involved are that of derives its attributes largely from the fact that current the terminal fields of the prefrontal cortex,26 and that environmental conditions in industrialized countries of the nucleus accumbens,27 both originating from neu- are completely different from those in which the rons located in the ventral tegmental area of the mid- human central nervous system evolved. The mismatch brain. Whether the stimulation of these neurons between evolved traits and contemporary lifestyle, the mediates the incentive salience (reviewed in Berridge presence of evolutionary trade-offs (eg selection of and Robinson),28 or the associative learning29 some traits over others), and historical constraints (eg capacities of an event, is still a matter of intense debate. how a trait has evolved), has resulted in the poor spe- According to the first hypothesis, rewarding (and thus cialization of selected traits, as well as a particular sus- also averse) stimuli that have acquired motivational ceptibility to mental disorders. significance (salience) are part of a phenomenon which To explain the somatic correlates of such an evo- is neither unitary nor subjective; dopamine-related lutionary view of diseases, it is assumed that pathogens neural circuits mediating only a specific component of that attack humans evolve faster than we do. If the reward, ie the attribution of incentive salience to an ever-mutating environmental conditions, where otherwise neutral event. In contrast, others have argued change is mostly due to fast technological advance- that mesolimbic dopaminergic pathways do not code ment (Table 2), could now be assimilated to organic for such an ability, but serve only to respond to specific pathogens, their rapid rate of evolution and change stimuli which possess high motivational impact, as a would impose a pressure that is not paralleled by an result of their novelty, unpredictability, specific sen- evolution of the brain structures which are able to ana- sory modalities, or occurrence under a deprivation lyze, process, and elaborate on such rapid variations. state;29 in these conditions, dopamine neurons define For example, a poor fit between strongly evolved traits the substrate for precise associative learning abilities. (eg dependency) and the current urban social environ- From an evolutionary perspective, the two mech- ment may account for the increase in frequency of anx- anisms must play an equally important role in the iety and depressive disorders in modern societies.22 attribution of an incentive value to ethologically Current views on the evolutionary mismatch theory relevant stimuli, and must facilitate, by means of both lack, however, a definition of which brain areas or neu- incentive-salience and associative-learning, the selec- ronal circuits should be involved in coding such mis- tion and the memory of appropriate behavioral evolved traits, and to what extent our neurobiological responses. The conservation of such principles knowledge can be applied to the topographical localiz- throughout evolution explains why pharmacological ation of a specific psychopathology. manipulations of the dopaminergic transmission are The appetitive and consummatory phases of similarly able to modify basic behaviors in distant behaviors triggered by environmental cues which are species such as lizards and rats (Table 3). Stimulation associated with survival properties (whether rewarding of the dopaminergic transmission will increase these or aversive for the individual) are known to be behaviors, while the blocking of dopaminergic recep- mediated by sensory-specific dopaminergic neuronal tors or lesions of the dopaminergic pathways will circuits. These dopaminergic systems are involved in decrease them. This confirms that dopamine is an

Molecular Psychiatry Evolutionary mismatch of the dopaminergic system L Pani 470 Table 3 Special forms of basic behaviorsa putamen; nucleus accumbens and internal capsule), at variance with that of the olfactory bulb. Thus, two 1. Establishing a ‘territory’ heavily innervated dopaminergic structures—one 2. Showing place preference coupled to taste related reward and satiety, and the 3. Hunting other to olfactory satiety—seemed to be mutually 4. Greeting exclusive in their development. These complementary 5. Social grouping characteristics have been conserved in modern 6. Feeding and drinking humans.34 The neural mechanisms of sensory-specific 7. Grooming satiety in primates are implemented in the orbitofron- 8. Courtship 9. Mating tal cortex, which has an important integrative function. 10. Breeding Neurons in this region of the cortex were indeed found 11. Maternal behavior to respond to stimulation of the taste, olfactory, or vis- 12. Play (mammals only) ual systems. In addition, some neurons were found to possess a bimodal response; responding, for example, aAdapted from Reference 6. 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 important neurotransmitter coding for sensory-specific unimodal sensory neurons were intermingled, it is responses, in the sense that a perceived environmental possible that the orbitofrontal cortex represents the first clue is acted on cognitively, either with an increase in cortical area of convergence for these three modalities exploration (by means of curiosity and reward) or a in primates.35 decrease (through fear and aversion),30 but also show that the physiological responses of the dopaminergic Conditions that have changed through evolution system are strictly ‘environment sensitive’. Electrophy- and which interfere with the function of the siological recordings have indicated that key cortical dopaminergic system and subcortical dopaminergic regions are involved in these motivated behaviors. Among these, a particular Empirical data suggest a causal relationship between role in primates is given to the connections between evolutionary-new environmental factors, specific dys- the nucleus accumbens and the frontal cortex,31 which regulation of the physiological ability of the dopami- I will consider as primary sites for the evolutionary nergic system to process environmental stimuli and mismatch between the dopaminergic system and the specific psychiatric disorders. Accordingly, the use of ability to process significant environmental-driven psychotropic medication in outpatient medical prac- change-related information that guides coherent tice rose dramatically during the last 10 years, behavioral responses. especially in industrialized countries. Around 10 years ago, Gershon et al showed that the rates of bipolar, schizoaffective, and unipolar disorders Expansion and regression of dopaminergic were higher in the cohorts born after 1940 than in the innervation cohorts born earlier.36 It was suggested that an ominous Animals with big brains are scarce, because bigger neu- trend could be present, leading to an increase in preva- ronal structures are more costly in terms of energy lence of a broad spectrum of familial affective disorders expenditure, development time, and anatomical com- in the coming decades. This prediction proved to be plexity. It was always supposed that a much better diet correct and confirmed by more recent reports where (in terms of caloric value) must have been the starting changes in the prescribing patterns of psychotropic point for the development of a much larger cerebral medications by office-based United-States physicians mass. Recently it was described how, about 40 MYA, were examined.37 In the 9 years period between 1985 a duplication of the gene coding for a retinal cone pig- and 1994, the number of visits during which a psycho- ment in an ancestor of prosimians resulted in the tropic medication was prescribed increased from 32.73 development of trichromatic vision.32 This ability to million to 45.64 million. Antianxiety or hypnotic drug see in color was instrumental in detecting ripe fruit, visits, previously the largest category, decreased and and gave an immediate evolutionary advantage over were surpassed by antidepressant visits, which green-leaf eaters. At about the same time, the system doubled from 10 to 20 million in the last 5 years per- for emotional communication via facial expression iod; and stimulant drug visits increased more than five- expanded and the olfactory bulb completed its fold in the same period. These dramatic trends are in regression in primates. agreement with our findings (Table 4), where we con- Recently, this hypothesis was confirmed, showing sider the Italian sales of psychotropic medications that a highly predictable relationship exists between classified into three major categories: anxiolytics, anti- the relative size of the neocortex and that of the total depressants, and antipsychotics and confirmed a sig- brain.33 When the sizes of 10 measured brain divisions nificant tendency toward increase for antidepressants from 131 species are plotted as a function of total brain (+34%) and antipsychotics (+15%) but not for anxio- size, the two most expanded structures in all species lytics (+4%) in the last 5 years. are, in fact, the neocortex and the striatum (caudate- Thus, it appears that in current affluent societies the

Molecular Psychiatry Evolutionary mismatch of the dopaminergic system L Pani 471 Table 4 The Italian market for psychotropic compounds psychological). Drugs of abuse that convey a signal that falsely indicates the arrival of a huge fitness benefit Millions of prescriptions per year (much higher than food, water, sex, etc), actively change behavioral hierarchies. As a consequence, drug- 1995 1996 1997 1998 1999 seeking increases in frequency to the point where it becomes the only dominant behavior, displacing all the Antipsychotics 11675 12432 12468 12940 13428 other adaptive traits.39 Antidepressants 16750 18275 19413 20524 22493 Anxiolytics 33143 34589 34093 34917 34487 Stress The definition of the term stress has gone from ‘a non- specific response of the body to any demands made upon it’,40 to ‘both a survival mechanism and an indi- frequency of psychiatric disorders requiring medi- cator of internal and external cues’.41 Both acute and cations which modulate the function of (and not only chronic stress have a detrimental impact on the normal of) the dopaminergic system is increasing. In addition, function of the dopaminergic system (for a recent the outcomes of acute affective disorders are consider- review see Pani et al).42 The response of the dopami- ably more favorable in developing countries than in nergic system to stress is neither homogenous nor gen- comparable studies in developed settings38 where at eralized, and numerous results suggest that mesopre- least four areas of evolutionary novelty can contribute frontal cortex dopaminergic projections are selectively and will be briefly discussed below. activated by sudden changes in environmental conditions, whether expected or not.43 Drugs of abuse The fine tuning of dopamine extracellular concen- The ability to extract, purify and lately synthesize psy- tration in the medial prefrontal cortex seems to be choactive compounds has increased their availability essential for the decision-taking protocols of the medial to the general population in quantities and qualities prefrontal cortex in the rat and the monkey.44 This sup- never experienced before in the history of mankind. In ports the idea of a critical range of dopamine turnover addition, the development of new routes of adminis- for optimal prefrontal cortical cognitive functioning, tration (eg hypodermic needles, crack smoking, organic with reduced or excessive dopamine turnover leading solvents) has increased the penetration of drugs of to cognitive impairment. Several data point to ventral abuse into the brain, and has contributed to a change tegmental area projections,45 dopamine receptors,46 in the traditional relationship between the use of the and a loss of inhibitory tone on ventral tegmental area natural source of the drug (eg the chewing of coca- dopamine cells47 and lateral-basolateral amygdala (see leaves) to that of its active component (eg the endoven- below) as important regulatory sites for maintaining ous injection of cocaine hydrochloride). superior cognitive functions. The increased ability to Drugs of abuse offer a remarkable example of evo- remove dopamine in chronically stressed animals has lutionary mismatch at the level of the dopaminergic also indicated that altered dopamine clearance may system, and help to clarify its role in the general physi- serve as an adaptive mechanism in the medial pre- ology of the central nervous system. If drugs of abuse frontal cortex.48 It has been further suggested that that act on the dopaminergic system (that is all of them, increased dopamine D1 receptor stimulation during directly or indirectly) were used solely for their stress may serve to take the medial prefrontal cortex hedonic and ‘reward producing’ potential, then this ‘off-line’, in order to allow posterior cortical and sub- capacity, ie the pure ability to experience pleasure, cortical structures to regulate more ‘primitive’ forms of would be the only one to be mainly affected by their behavior.49 Since dopaminergic innervation of the chronic use. Instead, after a variable period of use, all medial prefrontal cortex is able to regulate the activity drugs which determine a state of dependence interfere of subcortical dopamine innervations, disruption of the with the global adaptation of an individual to its medial prefrontal cortex dopamine fibers may result in environment, producing not only an impairment of the altered biochemical responsiveness of the dopa- his/her hedonic capacities, but also a more disruptive mine subcortical innervations.50 effect on the cognitive and emotional abilities that are In humans, the balance between cortical and subcort- necessary for an effective interaction with the external ical dopaminergic activity may serve as a protection world (maladaptation). The limbic portion of the dopa- against psychotic decompensation from chronic minergic system is essential for the generation of the endogenous or exogenous insult,51 and the failure of basic emotions that mediate various pro-social this coping mechanism may well contribute to the vul- behaviors, such as maternal care, playfulness, and nerability of the medial prefrontal cortex in many friendship, and which have been learned and have neuropsychiatric disorders related to the stress evolved to influence motivational states and, ulti- response.52 mately, to increase fitness. All these behaviors, along with the emotions which are related to them and their Chronic emotional reactions cognitive implications, are profoundly altered in a drug Emotional responses can be difficult to differentiate addict, much more than just the capacity to experience from generic reactions to stress, in laboratory animals pleasure or avoid pain (whether physical or as well as in humans. In addition, emotions such as

Molecular Psychiatry Evolutionary mismatch of the dopaminergic system L Pani 472 empathy seem to be uniquely human, and therefore system in rodents have, however, produced inconsist- impossible to mimic in animal models. In spite of this, ent data. While some results suggest an important several animal behaviors such as freezing, self- relationship between social and motor reactivity, as grooming, exploration and defecation have been con- well as an important, albeit again strain-dependent, sidered as valid somatic correlates to human emotional role for dopamine D1 receptors in mediating specific responses in which the dopaminergic system is emotional behaviors,59 others demonstrate that long- involved. In all the models, the chronic nature of the term administration of low, pre-synaptic doses of the stimulus is essential to produce a stable change in the dopamine D2 antagonist l-sulpiride is highly effective normal physiology of the dopaminergic system. In in an animal model of anticipatory anxiety/panic modern times this can be obtained by generic stress behavior.60 In contrast, recent findings suggest that due to sleep disruption, time shifts, poor physical quinpirole (a dopamine D2 agonist) decreases fear by activity, increased physical constraints, and unnatural blocking the retrieval of a learned association between social rules. In diseases in which dopamine function a conditioned and an unconditioned stimulus.61 is compromised, humans exhibit a constellation of emotional symptoms, suggesting that the dopamine Chronic sleep deprivation system plays an important role in the integration of Humans have conserved mechanisms, like those that superior cortical functions. A dorsal tier of dopamine exist in other animals, which detect changes in day neurons receives input from the nucleus accumbens length and make corresponding adjustments in the dur- and from the amygdala, and projects widely through- ation of nocturnal periods. Several studies from Wehr out the cortex. Through these projections, the dopami- and collaborators62 have suggested that modern men’s nergic limbic system has an enormous influence on use of artificial light after dark and artificial darkness cortical output and can therefore affect the emotional during the daytime suppresses responses63 to seasonal and motivational ‘coloring’ of a wide range of changes in the duration of the natural scoto- and photo- behaviors.53 period that might otherwise occur at a given latitude, In this respect, the lateral-basolateral amygdala producing a chronic disturbance in the sleep pattern receives sensory input from environmental stimuli and decreasing, overall, the total amount of sleep. It is and, along with the central amygdala, mediates con- difficult to conceive that chronic sleep deprivation in ditional fear. Through its projections to forebrain, mid- humans could be obtained and maintained without any brain and hindbrain areas, the central amygdala gov- activation in the stress axis. erns the behavioral, autonomic, and endocrine Sleep deprivation in rats has been extensively stud- responses that characterize a central fear state.54 ied as a possible animal model of mania.64 Interest- Accumulating revelations about the amygdala-based ingly, at the end of the period of sleep deprivation fear system has led to considerable progress in deline- (approximately 72 h), the rat does not fall asleep as ating the neural connections and cellular mechanisms soon as it is returned to its home cage, but shows a that underlie aversive emotionality, and very recently period of wakefulness of about 30 min, during which electrophysiological evidence has shown that neural the animal presents a cohort of symptoms that appear discharge in the central amygdala is a consequence of to mimic those present in idiopathic mania. In parti- repeated low-current, high-frequency electrical stimu- cular, during this period the animal displays a high lation of dopaminergic nuclei of the ventral tegmen- degree of hyperactivity, irritability, aggressiveness, tal area.55 hyper-sexuality, and stereotypy. The model allowed The introduction of Roman high-avoidance (RHA) the discovery of an active role of limbic dopamine in and Roman low-avoidance (RLA) rats, two selectively the generation of arousal and insomnia related to sleep bred lines that differ in their level of emotionality, into deprivation-induced stress.65 Accordingly, direct evi- an unfamiliar environment, the application of a high- dence demonstrates that acute and chronic sleep depri- intensity loud noise, or immobilization, are all associa- vation may trigger a manic episode in otherwise heal- ted with an increase in extracellular cortical dopamine thy individuals,66 and that recurrent brief hypomania metabolite levels in the RHA but not in the RLA line, which lasts 1–3 days and belongs to the bipolar spec- suggesting that the differently evoked emotional reac- trum, is increasing in young adults.67 These findings tions may produce a common activation of cognitive are indirectly confirmed by the increased use of neuro- processes.56 This difference in reaction to a stressful leptics (Table 4) which, although their use has been stimulus, according to the genetic makeup of an indi- widely discouraged for mood disorders, are still the vidual, is an essential function of the mesencephalic standard treatment for acute bipolar mania.68 dopaminergic neurons, and of their role in the organization of behavioral responses which are the reflection Conclusions of a heightened attention of the animal attempting to cope with the stressor.57 The mesocortical dopami- The brain of Homo sapiens sapiens developed on the nergic innervations seem to facilitate the functions of African plains, in populations of a few hundred thou- integrative structures, and to have a coordinated role sand individuals; today there are six billion of us in regulating the information flow between cortical worldwide. structures.58 It is time to ask ourselves whether the structural The study of fear and the role of the dopaminergic organization and the neuronal plasticity of the human

Molecular Psychiatry Evolutionary mismatch of the dopaminergic system L Pani 473 brain are still able to control the evolution of the enhance our ability to cope with stress-related mental environment he has created. Some influential neuro- disorders in the modern environment, and sharpen our biologists have expressed strong doubts.69 wisdom in making decisions about the therapeutic use The dopaminergic innervation to the prefrontal cor- of psychoactive drugs. tex is essential for processing and elaborating on the ‘expectancy’ of events, and in the working memory Acknowledgements related to them, in both rats and monkeys.44 Environ- mentally induced changes in the activity of the dopa- I am grateful to Anna Porcella for her critical comments minergic system, either by conventional (food, water, and to David Webb for his precise editorial work on the sex etc) or non-conventional (drugs of abuse, chronic manuscript. 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