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Is There an Evolutionary Mismatch Between the Normal Physiology Of 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 con- sumed. 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 dopa- minergic 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 dopami- nergic 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 environ- mental 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
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