- Email: [email protected]
Schizophrenia and dopamine regulation in the mesolimbic system
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m a k e s the distinction between cause and effect extremely difficult. For the m o m e n t , the theory of cerebellar involvement in the type of motor learning described seems viable and attractive as a working hypothesis. It could open m a n y perspectives on more explicit accounts of cerebellar function in m o t o r behaviour in general. The aspect of the storage of specific motor patterns would seem to deserve special attention in future investigations.
Schizophrenia and dopamine regulation in the mesolimbic system Janice R. Stevens
Acknowledgement I thank Barbara Winterson for her discussions concerning this manuscript.
Reading list 1. Collewijn, H. and Kleinschmidt, H. J. (1975) In: G. Lennerstrand and P. Bach-y-Rita (eds), Basic Mechanisms of Ocular Motility and their Clinical Implications, Pergamon, Oxford, pp. 477-483. 2. Collewiin, H. and Grootendorst, A. F. (1978) Arch. ltal. Biol. 116, 273-280. 3. Dufoss~, M., Ito, M., Jastreboff, J. and Miyashita, Y. (1978) Brain Res. 150,611~616. 4. Gauthier, G. M. and Robinson, D. A. (1975) Brain Res. 92, 331-335. 5. Gonshor, A. and Melvill Jones, G. (1976) J. Physiol. (London) 256, 361-379 and 381-414. 6. Haddad, G. M., Friendlich, A. R. and Robinson, D. A. (1977) Brain Res. 135, 192-196. 7. Ito, M. (1972) Brain Res. 40, 81-84. 8. lto, M., Nisimaru, N. and Yamamoto, M. (1973) Brain Res. 60, 238--243. 9. lto, M., Shiida, T., Yagi, N. and Yamamoto, M. (1974) Proc. Jpn. Acad. 50, 85-89. 10. Ito, M. and Miyashita, Y. (1975) Proc. Jpn. Acad. 51, 716-720. 11. Lisberger, S.G. and Fuchs, A.F. (1978) J. Neurophysiol. 41,733-763 and 764-777. 12. Melvill Jones, G. and Davies, P. (1976) Brain Res. 103, 551-554. 13. Miles, F. A. and Fuller, J. H. (1974) Brain Res. 80, 512-516. 14. Robinson, D. A. (1975) In: G. Lennerstrand and P. Bach-y-Rita (eds), Basic MechanisrrL~of Ocular Motility and their Clinical Implications, Pergamon, Oxford, pp. 337-374. 15. Robinson, D. A. (1976) J. Neurophysiol. 39, 954-969. 16. R6nne. H. (1923) Acta Oto-Laryngol. 5. 108-110. H. Collewqn is a member of the Department of Physiology, Erasmus University of Rotterdam, Faculty of Science, Postbox 1738, Rotterdam, The Netherlands.
Further articles related to this topic to be published shortly in Trends in NeuroSciences include "is the cerebellum really a computer?" by Masao Ito, and "Functional units of t h e cerebellum - sagittal zones and microzones" by OIov Oscarsson. Elsevier/North-Holland
Biomedical Press 1979
In the centre o f the phylogenetically older part o f the brain there are series o f complicated pathways interconnecting the brain stem and more rostral regions, including the limbic forebrain and the hypothalamus. In this article Janice Stevens describes the anatomy o f these connections and ties in the doparninergic pathways in these systems, while suggesting a role o f the ventral tegmental area in the brainstem as a dopaminergic "crossroad' with other transmitter pathways. Such a crucial crossroad has major implications for many brainstem-influenced neural functions, ranging from neuroendocrine control to the aetiology o f schizophrenia. Several lines of evidence have suggested that schizophrenia, the c o m m o n and disabling psychosis of youth and y o u n g adult life, is closely related to a disturbance in the function of the limbic system. T r e a t m e n t of schizophrenic psychoses with a group of drugs which have in c o m m o n a potent blocking action on the dopamine ( D A ) receptors of the brain ameliorates m a n y of the severe disturbances of attention, perception, and emotion which characterize the illness. Evidence that the potency of these drugs against the s y m p t o m s of schizophrenia is closely related to their affinity for cerebral D A receptors has focused interest on D A regulation in the limbic system as a potential key to the pathophysiology of schizophrenia.
Anatomy of the cerebral dopamine systems There are three principal cerebral D A systems of the brain: (1) the nigrostriatal system with D A cell bodies in substantia nigra (A-8,9) and axons projecting principally to caudate nucleus and putamen; (2) the tubero-infundibular D A system with cell bodies in the arcuate nucleus of the median eminence, and axons projecting into the pituitary stalk; (3) the mesolimbic system with cell bodies in the ventral tegmental area (A-10) and axons which ascend in the medial forebrain bundle to terminate in several nuclei of the limbic forebrain ~. These limbic forebrain nuclei, intimately associated with the expression of emotional and instinctual behaviour, have long been of
interest to investigators of normal and pathological behaviour in m a n and other mammals. A number of striking similarities between the subjective disturbances of patients with schizophrenia and the characteristic auras of epileptic seizures c o m m e n c i n g in the amygdala or hippocampus suggest that schizophrenia, like temporal lobe epilepsy, is a manifestation of pathological change in excitability in the limbic system. Many years ago Robert Heath, who explored the electrical activity of wide areas of the brain, using chronically implanted electrodes in patients with schizophrenia, reported that during the active phase of the psychosis schizophrenic patients demonstrated r a n d o m spike activity uniquely from the region of the N. accumbens, septal nuclei, head of the caudate nucleus, and the amygdala, regions now identified as the major terminals of the mesolimbic D A system4. An increase in the n u m b e r of D A receptors in the N. a c c u m b e n s of patients with schizophrenia has been reported by several investigators and now includes studies from patients who had not received prior neuroleptic treatmenP. These reports and studies, indicating that the therapeutic potency of neuroleptic agents against schizophrenia is more closely related to their capacity to increase D A turnover in N. accumbens than in neostriatum, lend support to electrophysiological and clinical data which suggest that faulty D A regtilation in the mesolimbic system m a y play a role in schizophrenia.
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Anatomy of the mesoUmbic dolmmine system Arising from cell bodies in the ventral tegmental area of Tsai (VTA), located just medial and superior to the substantia nigra (SN), the axons of the mesolimbic system are topographically distributed to the N. accumbens, the olfactory tubercle, the bed nuclei of the stria terminalis and the diagonal band, and the central amygdala, collectively defined as the limbic striatum, and to the lateral septal nuclei and the inferior frontal cortex. The N. accumbens forms the largest component of the limbic striatum in man. Surrounding the inferior margin of the anterior horn of the lateral ventricle, the N. accumbens is contiguous with the ventromedial portion of the caudate nucleus with which it shares an intense dopamine-fluorescence and similar histological structure. Inferiorally, the N. accumbens is continuous with the olfactory tubercle, and the dopamine-fluorescence of these structures extends caudally to merge with the histologically similar bed nucleus of the stria terminalis. The limbic and neostriatal systems converge again where the tail of the caudate nucleus arches forward to terminate in the dopamine-fluorescent central nucleus of the amygdala (archistriatum).
There are a number of parallels between the projections of the neocortex onto the DA-rich crescent of caudateputamen, and the convergence of hippocampal, amygdala, and pyriform cortical axons on the D A fluorescent nuclei of the limbic striatum. Just as the neocortex projects topographically from anterior to posterior on the head, body, and tail of the caudate nucleus and putamen, the several nuclei of the limbic striatum receive topographically ordered projections from hippocampus, from the corticomedial and basolateral amygdala, and the allocortex, regions which are of central importance for affective life and expression of social, exploratory, defensive, feeding, reproductive, and maternal behaviours (Fig. 1).
Efferent projections of the limbic striatum In addition to parallel, topographically ordered input systems from neo- and limbic cortical structures, the neo- and limbic striata have discrete and separate output pathways. The neostriatum projects to the globus pallidus and thence to the substantia nigra and to the ventrolateral thalamus, cerebellum, and motor cortex. The N. accumbens, in keeping with its more medial and ventral position in phylogenetically older parts of the forebrain, projects topographically in analogous fashion to more axial structures. As
Fig. 1. Diagrammatic representation o f the fan-like confluence of neocortical structures on the caudate-putamen (CP), which receives dopamine axons from the substantia nigra (SN). A similar confluence toward the limbic striatum includes projections o f the amygdala (Am) to the bed nucleus o f the stria terminalis (NST), the hippocampus (Hippo)to the nucleus accumbens (Acc),and the piriform cortex (PC) to the olfactory tubercle (OT). A separate dopamine projection ascends from the ventral tegmental area (VTA). Output from the neostriatum via the globus pallidus to the thalamus (not shown) parallels limbic striatal efferents which exit via the ventral pallidum to the frontal lobe (FL) and the hypothalamus (HT). (Adapted from Stevens'.)
demonstrated in recent, certain to be classic, studies of WaUe Nanta and his colleagues, fibres originating in the N. accumbeus terminate massively in a ventral extension of the globus pallidus, then spread medially and dorsally into the adjacent lateral preoptic areas of the hypothalamus, the bed nucleus of the stria terminalis, and the lateral septal nucleuss. From these structures, fibres join the medial forebrain bundle with which they travel through the lateral hypothalamus to the most caudal levels of the midbrain, issuing fascicles to adjacent structures in the course of this long trajectory. In parallel to fibres emerging from the caudate nucleus, axons from some units of the N. accumbens reach the ventral midbrain, but, in contrast with the striatonigral pathway, fibres of which terminate on pars reticulata interneurones and in the entopeduncular nucleus, the accumbens axons appear to project both to more axially disposed nigral units of the pars compacta and to the D A units of A-8 and A-10 (Fig. 2). Other fibres terminate in the region of the central grey, the paramedial reticular formation, and the dorsal raphe nuclei. Nauta and his colleagues have called attention to the striking similarity of the N. accumbens projection to the mesencephalon, with the mesencephalic projections from the preoptic and other hypothalamic nuclei. Although their studies do not permit conclusions regarding actual terminal synapses, it appears that the 'feedback' pathway from the accumbens may differ from that of the caudate-putamen, in that it projects directly to DA units of A-10, the medial portion of A-9, and to A-8, rather than to the non-DA cells of the pars reticulata, as is the case for the nigral directed fibres of caudate origin. Whether this anatomical difference indicates a more direct control of DA units by the accumbens than is the case for the caudate-putamen is still unknown. It has been shown, however, that electrical stimulation of the N. accumbens suppresses firing in the ventral tegmental area and that this suppression is y-aminobutyric acid (GABA)mediated 13. In addition to receiving direct pathways from the N. accumbens and the hypothalamus via the medial forebrain bundle, the VTA receives,*or is traversed by, fibres from the habenula, the mammillary bodies and the accessory optic tract. Dopamine-biased gating As is evident from Fig. 1, a high ratio of input to output is implicit in the fan-like
104 convergence of fibres from wide areas of the neocortex onto the neostriatal crescent prior to exit via the vastly diminished globus pallidus. Similarly, the convergence of fibres from the hippocampus, amygdala, and ailocortex on limbic striatal nuclei, which in turn project via the narrowing funnel of the ventral pallidum to the medial forebrain bundle, requires marked information compression. The high ratio of input to output for these two analogous dopamine-rich striatal systems suggests that the neo- and limbic striata might function as parallel DA-biasedgates or filters between their respective large afferent and much reduced efferent systems. Disturbances of D A transmission in neostriatum are accompanied by loss of smooth voluntary motion, muscular rigidity, and hypokinesia, as in Parkinson's disease or in the hyperkinesia of chorea. Similar disturbances of DA modulation in specific limbic striatai nuclei could cause a pathological increase, decrease, or distortion of the social bonding, affective, instinctual, and mnemonic responses, 'gated' from the hippocampus, amygdala and archipallium through limbic striatal nuclei en route to the hypothalamus, brainstem, and frontal lobeL Originally based on anatomical and clinical observations, the striatal gate hypothesis receives support from experimental studies which demonstrate characteristic behavioural changes following excitation of the mesolimbic D A system. Excitation of the nigrostriatal D A system in animals, whether by stimulation of substantia nigra or instillation of DA directly into the caudate nucleus, induces contralateral turning behaviour. In contrast, excitation of the mesolimbic system by application of DA in the N. accumbens or by chemical blockade of the putative G A B A inhibitory system in the ventral tegmentum elicits hyperactivity, fearfulness, or exploratory activity. Similar behaviour results from administration of low-dose (1-1.5 mg/kg) amphetamine in the rat. In contrast with the stereotyped gnawing, biting, grooming, and licking, elicited by higher doses of amphetamine and by D A instillation in the caudate nuclei, the DA-elicited exploratory behaviours are abolished by destruction of DA terminals in the N. accumbens, but not by lesions in the caudate nucleusL In the cat, excitation of the mesolimbic DA system by instillation of micro amounts of the potent G A B A inhibitor bicuculline in the VTA elicited a remarkable series of behaviours, in which previously tame and affectionate animals abruptly became
TINS -April 1979 fearful, backed into corners, slunk along prolactin activity in the mesolimbic system walls of the laboratory, or searched the than in the nigro-neostriatal network. In room vigorously. The same agent in the contrast, substance P, acetylcholine, and substantia nigra caused slight behaviour nigral autoreeeptor activity appear to be change, circling, or unilateral hyper- of greater importance in neostriatal DA algesia 1°. Instillation of DA into the N. regulation. Stress, which evokes the accumbens of waking monkeys following release of a number of peptides in the pretreatment with an MAO inhibitor pituitary gland, also increases DA turninduced increased locomotor behaviour, over in the N. accumbens and in the pacing, searching, grooming, and stereo- cortical terminals of the mesolimbic DA typed submissive posturing ~. system ix. An immunofluorescent luteinizOther effects of activation or lesions in ing hormone-releasing hormone (LHRH) nigrostriatal and mesolimbic systems pathway from the hypothalamus termiillustrate their quite separate 'wiring nates in the vicinity of the VTA, and diagrams'. Lesions in the substantia nigra cholinergic fibres from the lateral induce rigidity and movement disorders habenula nucleus traverse this region en which simulate the Parkinson syndrome; route to the interpeduncular nucleus. lesions in the VTA abolish ovulation in Recently, several laboratories have the rat and change exploratory, hoarding, demonstrated a suppressive effect of and maternal behaviourL Instillation of prolactin on DA release and turnover in cholinergic agents in the head of the the N. accumbens, and there is evidence caudate nucleus of the cat causes contra- that oestrogen, luteinizing hormone, and lateral circling, while the same agent LHRH depress central DA activityL placed in the limbic striatum induced These observations are of particular intense arousal, sniffing, and exploratory interest in view of the temporal relationactivity. Hypervigilance, hyperactivity, ship often found between adolescence and and searching, displayed by cats and rats schizophrenic psychoses, and suggest that following stimulation of the mesolimbic the surge of hypothalamic peptides and DA system, led Susan Iversen to suggest gonadal steroids at puberty must be that excitation of this pathway elicits a accompanied by appropriate 'feedback' heightened 'search for meaning' in the adjustments of DA release or sensitivity in environmente. It is precisely this height- the mesolimbic as well as the tuberoened significance of internal and external infundibular system. Failure of DA units stimuli which is so characteristic of the of the VTA to undergo normal suppresearly stages of clinical schizophrenia and sion or development of postsynaptic of schizophrenia-like paranoid psychoses supersensitivity following physiological inproduced by chronic amphetamine intoxi- volution of DA-mediated gonadotrophic inhibition at puberty could set the stage cation in man. for pathologically augmented DA transRegulation of dopamine release in the mission in elements of the limbic system. mesolimbic system There is growing evidence that the Several laboratories have reported that cyclic daily and seasonal fluctuations of a dopamine regulation in the caudate- number of hormones, as well as sleep, putamen and the N. accumbens may foraging, and breeding behaviours are depend upon a 'feedback' loop from modulated or mediated by central monopostsynaptic receptors in the caudate- amine systems. Since rhythmic fluctuaphtamen or the N. accumbens to cell tions of these cerebral monoamines, bodies or interneurones in the substantia including mesolimbic D A excitability, are nigra or VTA, and that this feedback loop entrained by the terrestrial light cycle, 'speaks in GABAnese', i.e. utilizes the information regarding length of daylight inhibitory neurotransmitter GABA. Pre- and darkness must be transmitted to liminary reports suggest that new and monoamine units of the brainstem by the potent GABA-potentiating agents are eye. In the search for regulatory mechauseful in the treatment of several nisms of DA release in the mesolimbic disorders in which dopamine hyper- system, our attention has been drawn to activity or hypersensitivity is postulated, two pathways from the retina which but are less useful in schizophrenia terminate in, or traverse, the VTA. The (G. Bartholini, communication to the accessory optic tract, which orginates in World Congress of Biological Psychiatry, peripheral ganglion cells of the retina, projects to a medial terminal nucleus Barcelona, September, 1978). Several studies have suggested a more which lies between the DA nuclei of the significant regulatory role for nor- SN and the VTA, in a strategic position for adrenaline, endogenous opiate, and local photic modulation of the mesencephalic
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It is evident that its morphology confers important and complex constraints and possibilities for altering D A release in the mesolimbic system. The multiple transmitters which impinge upon the VTA and other major brain crossroads appear to be 'languages' by which the brain suppresses or engages specific cell constellations for specific activities. Although this is an elegant design to assure specificity of stimulus and response, the very complexity of the system also risks dysfunction if a crucial signal or inhibitory system fails to respond optimally. Schizophrenia, a common and severe disorder of adolescence and young adult life, is, like epilepsy, probably a syndrome which has several causes. As in epilepsy, investigation of mechanisms by which neurotransmitters and receptors are regulated by maturation, experience, and the physical environment, promises to bridge the chasm between nature and nurture, and thus to increase our feeble understanding of this devastating illness. Acknowledgements The author acknowledges with gratitude the valuable contributions of Arthur Livermore, Jr., Karl Wetzel, Stuart Rosenblum, Suzanne Moody, and Rexine Hayes. This research was supported by National Institute of Mental Fig. 2. Diagrammatic representation of the analogous, overlapping, but separate, pro]ections o f the nigrostriatal Health grant 18055. and mesolimbic dopamine systems on the neostriatum (Candate) and the l/mb/c striatum (Ace: IV. accumbens; OT: olfactory tubercle; NST: bed nucleus of the stria terminalis). Possible and demonstrated regulatory Reading list pathways to the substantia nigra (SN) and the ventral tegmental area (VT A ) include the accessory optic tract to the medial terminal nucleus o f the accessory optic tract (AON), the habenido-interpeduncular tract (Haben), and the medial forebrain bundle (MF'B). DA: dopamine; GABA: ?~linobutyric acid; SP: substance P; ACh: acetylcholine. To avoid even more complexity, the retinohypothalamic pathway, the globus pallidus and the ventral pallidum have been omitted from the diagram.
dopamine nuclei (Fig. 2). In addition, from the suprachiasmatic nucleus, a hypothalamic 'biological clock' which receives a direct retinal projection from the retina, a multisynaptic pathway descends via the medial forebrain bundle, traversing the VTA en route to the spinal cord and the pineal gland. Experiments now in progress in our laboratory indicate that pulsed photic information is transmitted to the suprachiasmatic nucleus and the VTA by the rapid eye movements of paradoxical sleep '1, and that elimination of these eye movements alters the rhythm and amplitude of the daily excitability cycle of the mesolimbic DA system. In summary Investigation of dopamine regulation in the mesolimbic pathway may offer important clues to the pathophysiology of schizophrenia. The ventral tegmental area, the origin of the mesolimbic DA
1. Crow, T. J., Johnstone, E. C., Longden, A. J. and Owen, F. (1978) Life Sei. 23, 563-568. 2. Dahlstrom, A. and Fuxe, K. (1964) Aeta Physiol. Scand. 62, Suppl. 232, 1-55. 3. Dill, R.E., Jones, D.L., Gillin, J.C. and Murphy, G. (1978) Neurosci. Abs. 219, 678. 4. Heath, R. G. (1954) Studies in Schizophrenia. Harvard University Press, Cambridge. 5. Fuxe, K., Eneroth, P., Gustaffson, J.A., Lofstrom, A. and Skett, P. (1977) Brain Res. 122, 177-182. 6. Iversen, S. D. (1977) In: A. R. Cools, A. H. M. Lohman and J. H. L. van der Bercken (eds), Psychobiology o f the Striatum. North-Holland, Amsterdam, pp. 99-118. 7. Le Moal, M., Stinus, L. and Galey, D. (1976) Exp. Neurol. 50, 521. 8. Nanta, W. J. H., Smith, G. P., Faull, R. L. M. and Domesick, V. B. (1978) Neuroscience 3, 385-401. 9. Stevens, J. R. (1973) Arch. Gen. Psychiatry 29, 177-189. 10. Stevens, J. R., Wi/son, K. and Foote, W. (1974) Psychopharmucologia (Bed.) 39, 105--119. 11. Stevens, J. R. and Livermore, A. Jr. (1978) Exp. NeuroL 60, 541-556. 12. Thierry, A. M. and Glowinski, J. (1973) Frons. Catecholamine Res., pp. 649--651. 13. Wolf, P., Olpe, H.-R., Avrith, D. and Haas, H. L. (1978) Experientia 34, 73-74.
pathway, is located at the crossroad of a number of phylogenetically ancient neural pathways, including routes from the neuroendocrine centres of the septum and the hypothalamus, and from the retina. Much of our knowledge of the function of the dopamine system derives from the study of animals in which only gross behavioural changes can be measured. A growing body of experimental evidence indicates that there are important relationships between DA release and hormonal activity, not only in the tuberoinfundibnlar system, but also in the mesolimbic system. The parallel convergence of projections from the limbic forebrain and the hypothalamus on the ventral tegmental dopamine nuclei suggests that the profound disturbances in sexual, social, and maternal behaviour of patients with schizophrenia derive from a disturbance in limbic neuroendocrine J. R. Stevens is Professor o f Neurology and Psychiatry, University o f Oregon Health Sciences regulation. Center, Portland, OR 97201, U.S.A.
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m a k e s the distinction between cause and effect extremely difficult. For the m o m e n t , the theory of cerebellar involvement in the type of motor learning described seems viable and attractive as a working hypothesis. It could open m a n y perspectives on more explicit accounts of cerebellar function in m o t o r behaviour in general. The aspect of the storage of specific motor patterns would seem to deserve special attention in future investigations.
Schizophrenia and dopamine regulation in the mesolimbic system Janice R. Stevens
Acknowledgement I thank Barbara Winterson for her discussions concerning this manuscript.
Reading list 1. Collewijn, H. and Kleinschmidt, H. J. (1975) In: G. Lennerstrand and P. Bach-y-Rita (eds), Basic Mechanisms of Ocular Motility and their Clinical Implications, Pergamon, Oxford, pp. 477-483. 2. Collewiin, H. and Grootendorst, A. F. (1978) Arch. ltal. Biol. 116, 273-280. 3. Dufoss~, M., Ito, M., Jastreboff, J. and Miyashita, Y. (1978) Brain Res. 150,611~616. 4. Gauthier, G. M. and Robinson, D. A. (1975) Brain Res. 92, 331-335. 5. Gonshor, A. and Melvill Jones, G. (1976) J. Physiol. (London) 256, 361-379 and 381-414. 6. Haddad, G. M., Friendlich, A. R. and Robinson, D. A. (1977) Brain Res. 135, 192-196. 7. Ito, M. (1972) Brain Res. 40, 81-84. 8. lto, M., Nisimaru, N. and Yamamoto, M. (1973) Brain Res. 60, 238--243. 9. lto, M., Shiida, T., Yagi, N. and Yamamoto, M. (1974) Proc. Jpn. Acad. 50, 85-89. 10. Ito, M. and Miyashita, Y. (1975) Proc. Jpn. Acad. 51, 716-720. 11. Lisberger, S.G. and Fuchs, A.F. (1978) J. Neurophysiol. 41,733-763 and 764-777. 12. Melvill Jones, G. and Davies, P. (1976) Brain Res. 103, 551-554. 13. Miles, F. A. and Fuller, J. H. (1974) Brain Res. 80, 512-516. 14. Robinson, D. A. (1975) In: G. Lennerstrand and P. Bach-y-Rita (eds), Basic MechanisrrL~of Ocular Motility and their Clinical Implications, Pergamon, Oxford, pp. 337-374. 15. Robinson, D. A. (1976) J. Neurophysiol. 39, 954-969. 16. R6nne. H. (1923) Acta Oto-Laryngol. 5. 108-110. H. Collewqn is a member of the Department of Physiology, Erasmus University of Rotterdam, Faculty of Science, Postbox 1738, Rotterdam, The Netherlands.
Further articles related to this topic to be published shortly in Trends in NeuroSciences include "is the cerebellum really a computer?" by Masao Ito, and "Functional units of t h e cerebellum - sagittal zones and microzones" by OIov Oscarsson. Elsevier/North-Holland
Biomedical Press 1979
In the centre o f the phylogenetically older part o f the brain there are series o f complicated pathways interconnecting the brain stem and more rostral regions, including the limbic forebrain and the hypothalamus. In this article Janice Stevens describes the anatomy o f these connections and ties in the doparninergic pathways in these systems, while suggesting a role o f the ventral tegmental area in the brainstem as a dopaminergic "crossroad' with other transmitter pathways. Such a crucial crossroad has major implications for many brainstem-influenced neural functions, ranging from neuroendocrine control to the aetiology o f schizophrenia. Several lines of evidence have suggested that schizophrenia, the c o m m o n and disabling psychosis of youth and y o u n g adult life, is closely related to a disturbance in the function of the limbic system. T r e a t m e n t of schizophrenic psychoses with a group of drugs which have in c o m m o n a potent blocking action on the dopamine ( D A ) receptors of the brain ameliorates m a n y of the severe disturbances of attention, perception, and emotion which characterize the illness. Evidence that the potency of these drugs against the s y m p t o m s of schizophrenia is closely related to their affinity for cerebral D A receptors has focused interest on D A regulation in the limbic system as a potential key to the pathophysiology of schizophrenia.
Anatomy of the cerebral dopamine systems There are three principal cerebral D A systems of the brain: (1) the nigrostriatal system with D A cell bodies in substantia nigra (A-8,9) and axons projecting principally to caudate nucleus and putamen; (2) the tubero-infundibular D A system with cell bodies in the arcuate nucleus of the median eminence, and axons projecting into the pituitary stalk; (3) the mesolimbic system with cell bodies in the ventral tegmental area (A-10) and axons which ascend in the medial forebrain bundle to terminate in several nuclei of the limbic forebrain ~. These limbic forebrain nuclei, intimately associated with the expression of emotional and instinctual behaviour, have long been of
interest to investigators of normal and pathological behaviour in m a n and other mammals. A number of striking similarities between the subjective disturbances of patients with schizophrenia and the characteristic auras of epileptic seizures c o m m e n c i n g in the amygdala or hippocampus suggest that schizophrenia, like temporal lobe epilepsy, is a manifestation of pathological change in excitability in the limbic system. Many years ago Robert Heath, who explored the electrical activity of wide areas of the brain, using chronically implanted electrodes in patients with schizophrenia, reported that during the active phase of the psychosis schizophrenic patients demonstrated r a n d o m spike activity uniquely from the region of the N. accumbens, septal nuclei, head of the caudate nucleus, and the amygdala, regions now identified as the major terminals of the mesolimbic D A system4. An increase in the n u m b e r of D A receptors in the N. a c c u m b e n s of patients with schizophrenia has been reported by several investigators and now includes studies from patients who had not received prior neuroleptic treatmenP. These reports and studies, indicating that the therapeutic potency of neuroleptic agents against schizophrenia is more closely related to their capacity to increase D A turnover in N. accumbens than in neostriatum, lend support to electrophysiological and clinical data which suggest that faulty D A regtilation in the mesolimbic system m a y play a role in schizophrenia.
103
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Anatomy of the mesoUmbic dolmmine system Arising from cell bodies in the ventral tegmental area of Tsai (VTA), located just medial and superior to the substantia nigra (SN), the axons of the mesolimbic system are topographically distributed to the N. accumbens, the olfactory tubercle, the bed nuclei of the stria terminalis and the diagonal band, and the central amygdala, collectively defined as the limbic striatum, and to the lateral septal nuclei and the inferior frontal cortex. The N. accumbens forms the largest component of the limbic striatum in man. Surrounding the inferior margin of the anterior horn of the lateral ventricle, the N. accumbens is contiguous with the ventromedial portion of the caudate nucleus with which it shares an intense dopamine-fluorescence and similar histological structure. Inferiorally, the N. accumbens is continuous with the olfactory tubercle, and the dopamine-fluorescence of these structures extends caudally to merge with the histologically similar bed nucleus of the stria terminalis. The limbic and neostriatal systems converge again where the tail of the caudate nucleus arches forward to terminate in the dopamine-fluorescent central nucleus of the amygdala (archistriatum).
There are a number of parallels between the projections of the neocortex onto the DA-rich crescent of caudateputamen, and the convergence of hippocampal, amygdala, and pyriform cortical axons on the D A fluorescent nuclei of the limbic striatum. Just as the neocortex projects topographically from anterior to posterior on the head, body, and tail of the caudate nucleus and putamen, the several nuclei of the limbic striatum receive topographically ordered projections from hippocampus, from the corticomedial and basolateral amygdala, and the allocortex, regions which are of central importance for affective life and expression of social, exploratory, defensive, feeding, reproductive, and maternal behaviours (Fig. 1).
Efferent projections of the limbic striatum In addition to parallel, topographically ordered input systems from neo- and limbic cortical structures, the neo- and limbic striata have discrete and separate output pathways. The neostriatum projects to the globus pallidus and thence to the substantia nigra and to the ventrolateral thalamus, cerebellum, and motor cortex. The N. accumbens, in keeping with its more medial and ventral position in phylogenetically older parts of the forebrain, projects topographically in analogous fashion to more axial structures. As
Fig. 1. Diagrammatic representation o f the fan-like confluence of neocortical structures on the caudate-putamen (CP), which receives dopamine axons from the substantia nigra (SN). A similar confluence toward the limbic striatum includes projections o f the amygdala (Am) to the bed nucleus o f the stria terminalis (NST), the hippocampus (Hippo)to the nucleus accumbens (Acc),and the piriform cortex (PC) to the olfactory tubercle (OT). A separate dopamine projection ascends from the ventral tegmental area (VTA). Output from the neostriatum via the globus pallidus to the thalamus (not shown) parallels limbic striatal efferents which exit via the ventral pallidum to the frontal lobe (FL) and the hypothalamus (HT). (Adapted from Stevens'.)
demonstrated in recent, certain to be classic, studies of WaUe Nanta and his colleagues, fibres originating in the N. accumbeus terminate massively in a ventral extension of the globus pallidus, then spread medially and dorsally into the adjacent lateral preoptic areas of the hypothalamus, the bed nucleus of the stria terminalis, and the lateral septal nucleuss. From these structures, fibres join the medial forebrain bundle with which they travel through the lateral hypothalamus to the most caudal levels of the midbrain, issuing fascicles to adjacent structures in the course of this long trajectory. In parallel to fibres emerging from the caudate nucleus, axons from some units of the N. accumbens reach the ventral midbrain, but, in contrast with the striatonigral pathway, fibres of which terminate on pars reticulata interneurones and in the entopeduncular nucleus, the accumbens axons appear to project both to more axially disposed nigral units of the pars compacta and to the D A units of A-8 and A-10 (Fig. 2). Other fibres terminate in the region of the central grey, the paramedial reticular formation, and the dorsal raphe nuclei. Nauta and his colleagues have called attention to the striking similarity of the N. accumbens projection to the mesencephalon, with the mesencephalic projections from the preoptic and other hypothalamic nuclei. Although their studies do not permit conclusions regarding actual terminal synapses, it appears that the 'feedback' pathway from the accumbens may differ from that of the caudate-putamen, in that it projects directly to DA units of A-10, the medial portion of A-9, and to A-8, rather than to the non-DA cells of the pars reticulata, as is the case for the nigral directed fibres of caudate origin. Whether this anatomical difference indicates a more direct control of DA units by the accumbens than is the case for the caudate-putamen is still unknown. It has been shown, however, that electrical stimulation of the N. accumbens suppresses firing in the ventral tegmental area and that this suppression is y-aminobutyric acid (GABA)mediated 13. In addition to receiving direct pathways from the N. accumbens and the hypothalamus via the medial forebrain bundle, the VTA receives,*or is traversed by, fibres from the habenula, the mammillary bodies and the accessory optic tract. Dopamine-biased gating As is evident from Fig. 1, a high ratio of input to output is implicit in the fan-like
104 convergence of fibres from wide areas of the neocortex onto the neostriatal crescent prior to exit via the vastly diminished globus pallidus. Similarly, the convergence of fibres from the hippocampus, amygdala, and ailocortex on limbic striatal nuclei, which in turn project via the narrowing funnel of the ventral pallidum to the medial forebrain bundle, requires marked information compression. The high ratio of input to output for these two analogous dopamine-rich striatal systems suggests that the neo- and limbic striata might function as parallel DA-biasedgates or filters between their respective large afferent and much reduced efferent systems. Disturbances of D A transmission in neostriatum are accompanied by loss of smooth voluntary motion, muscular rigidity, and hypokinesia, as in Parkinson's disease or in the hyperkinesia of chorea. Similar disturbances of DA modulation in specific limbic striatai nuclei could cause a pathological increase, decrease, or distortion of the social bonding, affective, instinctual, and mnemonic responses, 'gated' from the hippocampus, amygdala and archipallium through limbic striatal nuclei en route to the hypothalamus, brainstem, and frontal lobeL Originally based on anatomical and clinical observations, the striatal gate hypothesis receives support from experimental studies which demonstrate characteristic behavioural changes following excitation of the mesolimbic D A system. Excitation of the nigrostriatal D A system in animals, whether by stimulation of substantia nigra or instillation of DA directly into the caudate nucleus, induces contralateral turning behaviour. In contrast, excitation of the mesolimbic system by application of DA in the N. accumbens or by chemical blockade of the putative G A B A inhibitory system in the ventral tegmentum elicits hyperactivity, fearfulness, or exploratory activity. Similar behaviour results from administration of low-dose (1-1.5 mg/kg) amphetamine in the rat. In contrast with the stereotyped gnawing, biting, grooming, and licking, elicited by higher doses of amphetamine and by D A instillation in the caudate nuclei, the DA-elicited exploratory behaviours are abolished by destruction of DA terminals in the N. accumbens, but not by lesions in the caudate nucleusL In the cat, excitation of the mesolimbic DA system by instillation of micro amounts of the potent G A B A inhibitor bicuculline in the VTA elicited a remarkable series of behaviours, in which previously tame and affectionate animals abruptly became
TINS -April 1979 fearful, backed into corners, slunk along prolactin activity in the mesolimbic system walls of the laboratory, or searched the than in the nigro-neostriatal network. In room vigorously. The same agent in the contrast, substance P, acetylcholine, and substantia nigra caused slight behaviour nigral autoreeeptor activity appear to be change, circling, or unilateral hyper- of greater importance in neostriatal DA algesia 1°. Instillation of DA into the N. regulation. Stress, which evokes the accumbens of waking monkeys following release of a number of peptides in the pretreatment with an MAO inhibitor pituitary gland, also increases DA turninduced increased locomotor behaviour, over in the N. accumbens and in the pacing, searching, grooming, and stereo- cortical terminals of the mesolimbic DA typed submissive posturing ~. system ix. An immunofluorescent luteinizOther effects of activation or lesions in ing hormone-releasing hormone (LHRH) nigrostriatal and mesolimbic systems pathway from the hypothalamus termiillustrate their quite separate 'wiring nates in the vicinity of the VTA, and diagrams'. Lesions in the substantia nigra cholinergic fibres from the lateral induce rigidity and movement disorders habenula nucleus traverse this region en which simulate the Parkinson syndrome; route to the interpeduncular nucleus. lesions in the VTA abolish ovulation in Recently, several laboratories have the rat and change exploratory, hoarding, demonstrated a suppressive effect of and maternal behaviourL Instillation of prolactin on DA release and turnover in cholinergic agents in the head of the the N. accumbens, and there is evidence caudate nucleus of the cat causes contra- that oestrogen, luteinizing hormone, and lateral circling, while the same agent LHRH depress central DA activityL placed in the limbic striatum induced These observations are of particular intense arousal, sniffing, and exploratory interest in view of the temporal relationactivity. Hypervigilance, hyperactivity, ship often found between adolescence and and searching, displayed by cats and rats schizophrenic psychoses, and suggest that following stimulation of the mesolimbic the surge of hypothalamic peptides and DA system, led Susan Iversen to suggest gonadal steroids at puberty must be that excitation of this pathway elicits a accompanied by appropriate 'feedback' heightened 'search for meaning' in the adjustments of DA release or sensitivity in environmente. It is precisely this height- the mesolimbic as well as the tuberoened significance of internal and external infundibular system. Failure of DA units stimuli which is so characteristic of the of the VTA to undergo normal suppresearly stages of clinical schizophrenia and sion or development of postsynaptic of schizophrenia-like paranoid psychoses supersensitivity following physiological inproduced by chronic amphetamine intoxi- volution of DA-mediated gonadotrophic inhibition at puberty could set the stage cation in man. for pathologically augmented DA transRegulation of dopamine release in the mission in elements of the limbic system. mesolimbic system There is growing evidence that the Several laboratories have reported that cyclic daily and seasonal fluctuations of a dopamine regulation in the caudate- number of hormones, as well as sleep, putamen and the N. accumbens may foraging, and breeding behaviours are depend upon a 'feedback' loop from modulated or mediated by central monopostsynaptic receptors in the caudate- amine systems. Since rhythmic fluctuaphtamen or the N. accumbens to cell tions of these cerebral monoamines, bodies or interneurones in the substantia including mesolimbic D A excitability, are nigra or VTA, and that this feedback loop entrained by the terrestrial light cycle, 'speaks in GABAnese', i.e. utilizes the information regarding length of daylight inhibitory neurotransmitter GABA. Pre- and darkness must be transmitted to liminary reports suggest that new and monoamine units of the brainstem by the potent GABA-potentiating agents are eye. In the search for regulatory mechauseful in the treatment of several nisms of DA release in the mesolimbic disorders in which dopamine hyper- system, our attention has been drawn to activity or hypersensitivity is postulated, two pathways from the retina which but are less useful in schizophrenia terminate in, or traverse, the VTA. The (G. Bartholini, communication to the accessory optic tract, which orginates in World Congress of Biological Psychiatry, peripheral ganglion cells of the retina, projects to a medial terminal nucleus Barcelona, September, 1978). Several studies have suggested a more which lies between the DA nuclei of the significant regulatory role for nor- SN and the VTA, in a strategic position for adrenaline, endogenous opiate, and local photic modulation of the mesencephalic
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It is evident that its morphology confers important and complex constraints and possibilities for altering D A release in the mesolimbic system. The multiple transmitters which impinge upon the VTA and other major brain crossroads appear to be 'languages' by which the brain suppresses or engages specific cell constellations for specific activities. Although this is an elegant design to assure specificity of stimulus and response, the very complexity of the system also risks dysfunction if a crucial signal or inhibitory system fails to respond optimally. Schizophrenia, a common and severe disorder of adolescence and young adult life, is, like epilepsy, probably a syndrome which has several causes. As in epilepsy, investigation of mechanisms by which neurotransmitters and receptors are regulated by maturation, experience, and the physical environment, promises to bridge the chasm between nature and nurture, and thus to increase our feeble understanding of this devastating illness. Acknowledgements The author acknowledges with gratitude the valuable contributions of Arthur Livermore, Jr., Karl Wetzel, Stuart Rosenblum, Suzanne Moody, and Rexine Hayes. This research was supported by National Institute of Mental Fig. 2. Diagrammatic representation of the analogous, overlapping, but separate, pro]ections o f the nigrostriatal Health grant 18055. and mesolimbic dopamine systems on the neostriatum (Candate) and the l/mb/c striatum (Ace: IV. accumbens; OT: olfactory tubercle; NST: bed nucleus of the stria terminalis). Possible and demonstrated regulatory Reading list pathways to the substantia nigra (SN) and the ventral tegmental area (VT A ) include the accessory optic tract to the medial terminal nucleus o f the accessory optic tract (AON), the habenido-interpeduncular tract (Haben), and the medial forebrain bundle (MF'B). DA: dopamine; GABA: ?~linobutyric acid; SP: substance P; ACh: acetylcholine. To avoid even more complexity, the retinohypothalamic pathway, the globus pallidus and the ventral pallidum have been omitted from the diagram.
dopamine nuclei (Fig. 2). In addition, from the suprachiasmatic nucleus, a hypothalamic 'biological clock' which receives a direct retinal projection from the retina, a multisynaptic pathway descends via the medial forebrain bundle, traversing the VTA en route to the spinal cord and the pineal gland. Experiments now in progress in our laboratory indicate that pulsed photic information is transmitted to the suprachiasmatic nucleus and the VTA by the rapid eye movements of paradoxical sleep '1, and that elimination of these eye movements alters the rhythm and amplitude of the daily excitability cycle of the mesolimbic DA system. In summary Investigation of dopamine regulation in the mesolimbic pathway may offer important clues to the pathophysiology of schizophrenia. The ventral tegmental area, the origin of the mesolimbic DA
1. Crow, T. J., Johnstone, E. C., Longden, A. J. and Owen, F. (1978) Life Sei. 23, 563-568. 2. Dahlstrom, A. and Fuxe, K. (1964) Aeta Physiol. Scand. 62, Suppl. 232, 1-55. 3. Dill, R.E., Jones, D.L., Gillin, J.C. and Murphy, G. (1978) Neurosci. Abs. 219, 678. 4. Heath, R. G. (1954) Studies in Schizophrenia. Harvard University Press, Cambridge. 5. Fuxe, K., Eneroth, P., Gustaffson, J.A., Lofstrom, A. and Skett, P. (1977) Brain Res. 122, 177-182. 6. Iversen, S. D. (1977) In: A. R. Cools, A. H. M. Lohman and J. H. L. van der Bercken (eds), Psychobiology o f the Striatum. North-Holland, Amsterdam, pp. 99-118. 7. Le Moal, M., Stinus, L. and Galey, D. (1976) Exp. Neurol. 50, 521. 8. Nanta, W. J. H., Smith, G. P., Faull, R. L. M. and Domesick, V. B. (1978) Neuroscience 3, 385-401. 9. Stevens, J. R. (1973) Arch. Gen. Psychiatry 29, 177-189. 10. Stevens, J. R., Wi/son, K. and Foote, W. (1974) Psychopharmucologia (Bed.) 39, 105--119. 11. Stevens, J. R. and Livermore, A. Jr. (1978) Exp. NeuroL 60, 541-556. 12. Thierry, A. M. and Glowinski, J. (1973) Frons. Catecholamine Res., pp. 649--651. 13. Wolf, P., Olpe, H.-R., Avrith, D. and Haas, H. L. (1978) Experientia 34, 73-74.
pathway, is located at the crossroad of a number of phylogenetically ancient neural pathways, including routes from the neuroendocrine centres of the septum and the hypothalamus, and from the retina. Much of our knowledge of the function of the dopamine system derives from the study of animals in which only gross behavioural changes can be measured. A growing body of experimental evidence indicates that there are important relationships between DA release and hormonal activity, not only in the tuberoinfundibnlar system, but also in the mesolimbic system. The parallel convergence of projections from the limbic forebrain and the hypothalamus on the ventral tegmental dopamine nuclei suggests that the profound disturbances in sexual, social, and maternal behaviour of patients with schizophrenia derive from a disturbance in limbic neuroendocrine J. R. Stevens is Professor o f Neurology and Psychiatry, University o f Oregon Health Sciences regulation. Center, Portland, OR 97201, U.S.A.