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Schizophrenia: A Subcortical Neurotransmitter Imbalance Syndrome?
by Maria Cartsson and Arvld Carlsson
Abstract
Our starting point for a discussion of possible site(s) of the lesion(s) in schizophrenia has been pharmacological: Where in the brain is the antipsychotic action of neuroleptic drugs located? It is generally recognized that the neuroleptics act mainly by virtue of being dopamine receptor antagonists. In fact, it is clear that an antipsychotic action can be achieved by treatment with a selective dopamine D2 receptor antagonist, such as raclopride. Positron emission tomography (PET) studies by Farde et al. (1988a) have shown that a dopamine D2 receptor occupancy of between 65 and 80 percent is obtained in the striatum during treatment of chronic schizo-
Feedback Loops Controlling Sensory Input and Arousal We propose that the cerebral cortex is capable of controlling its sensory Reprint requests should be sent to Dr. M. Carlsson, Dept. of Pharmacology, University of Goteborg, P.O. Box 33031, S-40033 Goteborg, Sweden.
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Recent animal experiments suggest that glutamate plays a fundamental role in the control of psychomotor activity. This is illustrated by the finding that even in the virtually complete absence of dopamine, a marked behavioral activation is produced in mice following suppression of glutamatergic neurotransmission. This article discusses the possibility that a deficient activity "within the cortico-striatal glutamatergic pathway is an important pathophysiological component in some cases of schizophrenia and that glutamatergic agonists may prove beneficial in this disorder. In a broader perspective, schizophrenia may be looked upon as a syndrome induced by a neurotransmitter imbalance in a feedbackregulated system, where dopamine and glutamate play a crucial role in controlling arousal and the processing of signals from the outer world to the cerebral cortex via the thalamus.
phrenia using a variety of neuroleptic agents in doses sufficient to cause an antipsychotic response. The studies of Farde et al. (1988b) also show that the density of dopamine D2 receptors in the human cerebral cortex is extremely low, and this is in agreement with post-mortem data on the levels of dopamine in the human cerebral cortex (see Carlsson 1988). It thus seems less likely that the antipsychotic action is primarily located in this part of the brain. It should be noted that the dopamine level in the human cortex appears to be appreciably lower than in the cortex of lower primates, suggesting that the cortical dopaminergic system has lagged behind in the enormous growth of the cerebral cortex that has taken place in the evolution of man. Against this background we have asked ourselves if an action on the subcortical dopaminergic system can bring about the profound effect on cortical functions that is observed when an antipsychotic response to neuroleptic treatment takes place. To us, such an indirect effect appears to be the most likely alternative. In trying to answer this question, we have made use of the remarkable progress in the neuroanatomy of the basal ganglia and its connections that has been made during the past decade. We have thus arrived at the following hypothetical explanation.
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It seems appropriate to bring in the concept of the dorsal versus ventral striatum at this point. The former structure (the caudate nucleus-putamen) is often referred to as a motor and the latter as a "mental" structure. However, the anatomical connections of these structures suggest a more complex picture. For example, the dorsal striatum can be divided into an anterior part, mainly connected to the association areas of the cortex, and a posterior part (of the putamen), which has connections predominantly with the motor cortex. The ventral striatum consists of a number of dopamine-rich structures located
Figure 1. Schematic drawing illustrating the hypothesis that the cerebral cortex can control its sensory Input/arousal via dopaminemodulated feedback loops Involving the striatal complexes and the thalamus/mesencephalic reticular formation
Cerebral cortex
Subst. nigra/ VTA
Sense organs NBM=Nucleus basalis Meynert ventrally of the caudate nucleusputamen. The nucleus accumbens is one important component of the ventral striatum. It should be emphasized that in the human brain the counterpart of this nucleus in lower mammals extends into the caudate nucleus and actually forms a major, ventromedial part of this nucleus (for reviews and references concerning the neuroanatomy, see Heimer et al. [1985]; Selemon and Goldman-Rakic [1985]; Alexander et al. [1986]; Bjorklund and Lindvall [1986]; Goldman-Rakic and Selemon [1986]; Nauta [1989]). The afferent and efferent connections of the dorsal and the ventral striatum are organized in a similar
manner. The dorsal striatum receives its afferent supply largely from the neocortex, whereas the ventral striatum is mainly innervated by the limbic cortex. In either case, we are apparently dealing with glutamatergic fibers. This glutamatergic system will be especially focused upon here. There also seems to be an important glutamatergic supply to the striatum from the thalamus. The efferents from the dorsal and ventral striatum project to the dorsal and ventral pallidum, respectively, and they in turn innervate different thalamic nuclei. The dorsal projections go to the ventrolateral nucleus, which appears to project to the
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input and arousal by means of a negative feedback loop involving the striatal complexes, the thalamus, and the mesencephalic reticular formation (see figure 1). This feedback loop is assumed to be composed of several more or less parallel components representing motor, cognitive, and emotional functions. Each of these can probably be further divided into functional subsystems. Thus, Narabayashi (1988) has observed that by means of very small electrolytical lesions 2-3 mm in diameter, applied in the thalamus of Parkinson patients, tremors can be selectively alleviated by placing the lesions in the ventrointermedial nucleus, whereas rigidity can be eliminated by placing the lesions in the ventrolateral nucleus. Larger lesions in this area frequently lead to mental complications. In the future, it should prove possible to obtain a more complete map of pathways and nuclei involved in the various components of motor as well as mental functions within this complex feedback system. This will have to take into account the functional asymmetry of the cerebral hemispheres.
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In figure 1 the intrinsic circuitries of the striatal complexes have been omitted; they are not yet fully elucidated. Moreover, this aspect is not essential for the main argument of our hypothesis. It will, however, be discussed in a forthcoming article (Carlsson and Carlsson 1990). Pathophyslological Aspects Huntington's chorea provides a good argument for a role of the striatum in mental, including cognitive functions. Schizophrenia-like symptomatology may precede the motor disturbances by several years in this neurodegenerative disorder, which is essentially confined to lesions in the striatum (Mattsson 1971). Lesions of the prefrontal cortex or of the pathways from the cortex to the striatum may induce a "disinhibition syndrome" and an increased sensitivity to amphetamine (see Iversen 1977). (There are also indications that lesions in this area may cause inability to switch between different activity programs; see the following section.) A disturbance in arousal and filter mechanisms in schizophrenia has been proposed before. Vfenables (1964, 1987) suggested from McGhie and Chapman's (1961) description of the experiences of early schizophrenic patients that these patients are "flooded by sensory impressions from all quarters." Lehmann (1966) proposed that if a person can cope with a supernormal influx of stimuli, because he has an adequate "central processing apparatus," he will have exceptional creativity. If his integrative capacity is insufficient, however, he may become psychotic. In support of disintegration, Arieti (1966) describes severely psychotic patients, who can grasp but a small part of the sensory input at a time.
An anatomical substrate for such functions was discussed by Stevens (1973, 1989), who proposed that the dorsal and ventral striata "filter, compress, modulate or 'gate' information from sensory to motor systems in neostriatum and from amygdala-hippocampal affect and memory processing regions projecting to limbic striatum en route to thalamus, hypothalamus and frontal lobe" (Stevens 1989, p. 74). Early work on the mode of action of chlorpromazine focused on the mesencephalic reticular formation (see Bradley 1968). It was proposed that the inhibitory effect of chlorpromazine was due to the blockade of excitatory noradrenergic synapses in the mesencephalic reticular formation, thus interfering with arousal. Unfortunately, these studies do not seem to have been extended to more dopamine-specific neuroleptics (cf. Bradley 1986). Thus, the influence of dopaminergic mechanisms was not definitely established. The Glutamatergic System: Pathophyslological and Pharmacological Aspects Our model predicts that a deficient corticostriatal glutamatergic function would lead to functional disturbances similar to those caused by dopaminergic agonists, such as the amphetamines. This seems actually to be the case. Phencyclidine (PCP, "angel dust") is a psychotogenic agent, capable of mimicking schizophrenic symptomatology even more faithfully than the amphetamines (Domino and Luby 1973; Angrist 1987). The main target of this agent appears to be an ion channel linked to the N-methyl-D-aspartate (NMDA) receptor, that is, one of the major glutamate receptors (Lodge et al.
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neocortex, whereas the ventral striatum projects to nuclei in the thalamus, which in turn project to the frontal and limbic cortex and the amygdala (see Nauta 1989). Some of the fibers leaving the pallidum appear to innervate the mesencephalic reticular formation rather than the thalamus. The overall impression of this organization is that part of the feedback system deals with precisely targeted functions, whereas others, involving parts of the thalamus and the mesencephalic Teticuiar formation, may rather be engaged in the control of cortical arousal. Taken together, these systems may provide a means for the cerebral cortex to control its sensory input by adjusting a thalamic filter, as well as to control the activity of the subcortical arousal systems. In this feedback mechanism, the mesostriatal dopamine pathways appear to play an important modulatory role. They seem to be inhibitory on the striatum, which in turn is a powerful inhibitory structure, acting, for example, on the thalamus/mesencephalk reticular formation. Stimulation of dopaminergic mechanisms will thus counteract this inhibition, leading to an increased sensory input and arousal. The corticostriatal glutamate system acts in the opposite direction by stimulating the inhibitory function of the striatum. Insofar as the mesencephalic reticular formation is concerned, it is tempting to suggest that the noradrenergic system of the locus ceruleus and perhaps also the serotonergic system of the raphe nuclei participate in the control of arousal, mediated via the dorsal and ventral striata. The close relationship between the striatum and the basal nucleus of Meynert, whose cholinergic system appears to promote arousal, is also worth mentioning (Richardson and DeLong 1988).
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Our hypothesis would suggest a more profound effect of the corticostriatal pathway on the striatum. In our model, the catalepsy and strong psychomotor inhibition induced by eliminating the dopaminergic function is due to an active inhibitory impact of the striatum, now released from the inhibitory influence of the dopaminergic system. An important corollary would be that even in the absence of dopamine, a psychomotorstimulating influence of MK-801 should persist. This actually proved to be the case (Carlsson and Carlsson 1989a 1989b; Carlsson and Svensson, in press). MK-801 was found to cause a dose-dependent stimulation of locomotor activity of mice, whose stores of catecholamines had been virtually completely depleted by
combined treatment with reserpine and o-methyltyrosine. This was shown in experiments where the locomotor activity was measured by means of photocells in rectangular cages. It was observed, however, that when an animal came to a corner of the cage it was stuck, apparently because it could not switch from forward locomotion to another movement program. This is reminiscent of the "compulsory approaching syndrome" observed in cats following bilateral caudectomy (Wlablanca et al. 1976). Therefore, we started to use rotundas, where an animal treated with MK-801 as a rule only moved in one and the
same direction throughout the experiment. This stimulation of locomotor activity (see figure 2) could not be blocked by the dopamine-receptor antagonists haloperidol and raclopride, confirming that the movements were independent of dopaminergic function. Our experiments have so far been limited to systemic injections of glutamatergic antagonists. However, following striatal injection NMDA has been found to inhibit and an NMDA antagonist has been found to stimulate psychomotor activity (Schmidt and Bury 1988; Raffa et al. 1989), supporting a striatal site of action in our experiments.
Figure 2. Effects of various doses of MK-801 on motor activity in monoamlne-depleted mice
50
I 40
1 :#
30 20 10 0 0.5
3 4 MK-801. mg/kg
Raserpine (10 mg/kg i.p.) was administered 18 hours and e-methyttyrosine (250 mg/kg l.p.) 30 minutes before the i.p. MK-801 treatment. Forward locomotion was registered for 30 minutes, beginning 60 minutes after MK-601 administration. Shown are the means and SEM, n - 4. There was a significant correlation between dose and number of meters covered in 30 minutes (/ - 0.6, p < 0.01). (Data from M. Cartsson and A. Carlsson 19896.)
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1987). In essence, PCP is thus a noncompetitive glutamate antagonist. The substance, (+)-5-methyl-10,lldihydro-5H-dibenzo(a,d) cyclohepten-5,10-imine (MK-801) is a more specific NMDA antagonist, acting on the same ion-channel site as PCP (Wong et al. 1986), and it should thus prove useful for testing our hypothesis that the corticostriatal glutamatergic pathway enhances the inhibitory influence of the striatum on thalamic nuclei as well as on the mesencephalic reticular formation. The sensory input to the cortex, as well as the arousal, is thus under cortical control. From previous work with PCP it has been suggested that this agent can induce release of catecholamines (Clineschmidt et al. 1982a, 1982b, 1982c), and this has later been interpreted to mean that the corricostriatal glutamate pathway can inhibit catecholamine release. The signs of behavioral stimulation of PCP and MK-801 have thus been suggested to be mediated via release of catecholamines.
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Is Schizophrenia Caused by a Dopamlne-Glutamate Imbalance? It seems as though we have to revise our views on the role of dopamine in the regulation of mental and motor activities as well as in the pathogenesis of neuropsychiatric disorders. Until now, there has been a trend to consider dopamine as an absolutely essential stimulant for a variety of brain functions: without dopamine, mental and motor activi-
Figure 3a. Effects of MK-801 (1 mg/kg I.p.) and clonidine (2 mg/kg i.p.) given separately or In combination on forward locomotion in monoamine-depleted mice1
ties go down to an extremely low level. While this is essentially true, it now emerges that the virtual lack of activity in the absence of dopamine receptor stimulation may be due to an active inhibition exerted by the corticostriatal glutamatergic pathway via striatum on the thalamus and the mesencephalic reticular formation (presumably other subcortical structures are also involved in this regulatory mechanism). If this inhibition is removed or reduced by Hocking glutamate receptors, the
Figure 3b. An analogous experiment with apomorphlne (0.1 mg/kg I.p.) instead of clonidine1
*
a 100
20
80
15
60 10
I* 20 0
0 NaCI
Clon
'Data from M. Carlsson and A. Carlsson (19896).
MK MK*Clon * " p < 0001, vs. MK-801 (Mann-Whitney U test).
NaCI
Apo
MK MK+Apo
*p < 002, vs. MK-801 (Mann-Whitney U test).
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We later found that MK-801 is capable of potentiating a variety of arousal-inducing agents, such as clonidine (figure 3a-3b), apomorphine, and atropine. The effect of MK-801 + clonidine could be antagonized by a2-blocking agents, but not by an aj-blocker. Interestingly, the stimulating action of clonidine could be antagonized by clozapine, which reinforces the notion that this agent may in part exert its antipsychotic action by blocking areceptore (see Carlsson 1978).
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alleviated by manipulation of the dopaminergic system, manipulation of the corticostriatal glutamate pathway may have similar consequences. The psychotogenic actions of PCP, ketamine, and MK-801 support this view. Schizophrenia may be induced by a deficiency of the corticostriatal glutamate pathway. Certain observations on postmortem brains of schizophrenic patients do indeed suggest that abnormalities of glutamatergic pathways exist in schizophrenia, even though an effect of chronic neuroleptic treatment remains to be excluded (KornhubeT et al. 1989). By the same token, glutamatergic agonists may prove to possess antipsychotic properties and to be clinically useful, provided that one can circumvent the side effects that can be anticipated in view of the ubiquitous occurrence of glutamatergic systems in the brain. A role of glutamatergic mechanisms in schizophrenia has been proposed on somewhat different grounds (Kornhuber et al. 1984; Kim et al. 1985). However, schizophrenia is probably a heterogeneous disorder, where neurotransmitter imbalances of various kinds may be considered. Excessive dopamine or deficient glutamate function appear to be plausible alternatives, but otheT neurotransmitter disturbances may also be important. For example, noradrenalin, serotonin, and yaminobutyric acid may play a role. By the same token, the site of the lesion may be, for example, in the cortex, the striatum, the thalamus, or the lower brainstem. Hardly any part of the brain can be excluded at present. Regardless of the primary site, however, a striatal imbalance may exist, at least in cases responding to neuroleptic treatment.
References Alexander, G.E.; DeLong M.R.; and Strick, P.L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9:357-381, 1986. Angrist, B. Pharmacological models of schizophrenia. In: Henn, F.A., and Delisi, L.E., eds. Handbook of Schizophrenia. \fol. 2. Neurochemistry and Neuropharmacology of Schizophrenia. Amsterdam: Elsevier, 1987. pp. 391-424 Arieti, S.A. Schizophrenic cognition. In: Hoch, P.H., and Zubin, J., eds. Psychopathology of Schizophrenia. New York: Grune and Stratton, 1966. pp. 37-48. Bjorklund, A., and Lindvall, O. Catecholaminergic brain stem regulatory systems. In: Field, J., ed. Handbook of Physiology—The Nervous System IV. Washington, DC: American Psychological Society, 1986. pp. 155-235. Bradley, P.B. The pharmacology of synapses in the central nervous system. In: Robson, J.M., and Stacey, R.S., eds. Recent Advances in Pharmacology. 4th ed. London: Churchill, 1968. pp. 311-348. Bradley, P.B. Pharmacology of antipsychotic drugs. In: Bradley, P.B., and Hirsch, S.R., eds. The Psychopharmacology and Treatment of Schizophrenia. Oxford-New York-Tokyo: Oxford University Press, 1986. pp. 27-70. Carlsson, A. Antipsychotic drugs, neurotransmitters and schizophrenia. American Journal of Psychiatry, 135:164-173, 1978. Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology, 1:179-186, 1988.
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ability of the brain to induce "psychomotor activity" in the absence of dopaminergic stimulation is disclosed. In fact, it appears that the corticostriatal glutamatergic pathway is a very strong suppressant on a numbeT of arousal mechanisms, as indicated, for example, by the activation induced by the a-adrenergic agonist clonidine and the antimuscarinic agent atropine in the presence of a subthreshold dose of the NMDA receptor antagonist MK-801. In addition to these postsynaptic mechanisms, the glutamatergic system appears to inhibit the release of catecholamines (see above). The inhibitory action of the corticostriatal glutamate pathway on brain activity may be assumed to be selective in the sense that it allows for adequate and purposeful responses to external stimuli. When the pathway is blocked by MK-801, only forward locomotion appears to be activated at the expense of otheT programs. This suggests that the selection of purposeful programs, as well as the switch from one program to another, is an important function of the corticostriatal glutamate pathway. Recently, we obtained indirect support for this contention. We discovered that considerable psychomotor activity can be induced in monoamine-depleted mice (treated with reserpine + tunethyltyrosine) by combined treatment with clonidine + atropine (Carlsson and Carlsson 1989c). In this case, with the glutamatergic system apparently intact, the movements induced appeared as normal, purposeful behavior. In many respects, the corticostriatal glutamate pathway can be looked upon as an antagonist to the mesostriatal dopaminergic system. Thus, just as a psychotic condition can be induced, aggravated, or
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Goldman-Rakic, P.S., and Selemon, L.D. Topography of corticostriatal projections in nonhuman primates and implications for functional parcellation of the neostriatum. In: Jones, E.G., and Peters, A., eds. Cerebral Cortex. \fol. 5. New York: Plenum Publishing Corporation, 1986. pp. 447-466.
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Carlsson, M., and Carlsson, A. The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice, journal of Neural Transmission, 75:221-226, 1989a. Carlsson, M., and Carlsson, A. Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice, journal of
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Raffa, R.B.; Ortegon, M.E.; Robisch, D.M.; and Martin, G.E. In vivo demonstration of the enhancement of MK-801 by L-glutamate. Life Sciences, 44:1593-1599, 1989. Richardson, R.T., and DeLong, M.R. A reappraisal of the functions of the nucleus basalis of Meynert. Trends in Neuroscience, 11:264-267, 1988.
Schmidt, W.J., and Bury, D. Behavioural effects of N-methyl-Daspartate in the anterodorsal striatum of the rat. Life Sciences, 43:545-549, 1988. Selemon, L.D., and Goldman-Rakic, P.S. Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. Journal of Neuroscience, 5:776-794, 1985. Stevens, J.R. An anatomy of schizophrenia? Archives of General Psychiatry, 29:177-189, 1973. Stevens, J.R. The search for an anatomic basis of schizophrenia: Review and update. In: Mueller, J., ed. Neurology and Psychiatry: A Meeting of Minds. Basel-MunchenParis: Karger, 1989. pp. 64-87. \fenables, P.H. Input dysfunction in schizophrenia. In: Maher, B., ed. Progress in Experimental Personality Research. New York: Academic Press, 1964. pp. 1-41. Venables, P.H. Cognitive and attentional disorders in the development
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The Authors Maria Carlsson, M.D., is Research Assistant, and Arvid Carlsson, M.D., is Professor of Pharmacology, Department of Pharmacology, University of Goteborg, Goteborg, Sweden.
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Schizophrenia: A Subcortical Neurotransmitter Imbalance Syndrome?
by Maria Cartsson and Arvld Carlsson
Abstract
Our starting point for a discussion of possible site(s) of the lesion(s) in schizophrenia has been pharmacological: Where in the brain is the antipsychotic action of neuroleptic drugs located? It is generally recognized that the neuroleptics act mainly by virtue of being dopamine receptor antagonists. In fact, it is clear that an antipsychotic action can be achieved by treatment with a selective dopamine D2 receptor antagonist, such as raclopride. Positron emission tomography (PET) studies by Farde et al. (1988a) have shown that a dopamine D2 receptor occupancy of between 65 and 80 percent is obtained in the striatum during treatment of chronic schizo-
Feedback Loops Controlling Sensory Input and Arousal We propose that the cerebral cortex is capable of controlling its sensory Reprint requests should be sent to Dr. M. Carlsson, Dept. of Pharmacology, University of Goteborg, P.O. Box 33031, S-40033 Goteborg, Sweden.
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Recent animal experiments suggest that glutamate plays a fundamental role in the control of psychomotor activity. This is illustrated by the finding that even in the virtually complete absence of dopamine, a marked behavioral activation is produced in mice following suppression of glutamatergic neurotransmission. This article discusses the possibility that a deficient activity "within the cortico-striatal glutamatergic pathway is an important pathophysiological component in some cases of schizophrenia and that glutamatergic agonists may prove beneficial in this disorder. In a broader perspective, schizophrenia may be looked upon as a syndrome induced by a neurotransmitter imbalance in a feedbackregulated system, where dopamine and glutamate play a crucial role in controlling arousal and the processing of signals from the outer world to the cerebral cortex via the thalamus.
phrenia using a variety of neuroleptic agents in doses sufficient to cause an antipsychotic response. The studies of Farde et al. (1988b) also show that the density of dopamine D2 receptors in the human cerebral cortex is extremely low, and this is in agreement with post-mortem data on the levels of dopamine in the human cerebral cortex (see Carlsson 1988). It thus seems less likely that the antipsychotic action is primarily located in this part of the brain. It should be noted that the dopamine level in the human cortex appears to be appreciably lower than in the cortex of lower primates, suggesting that the cortical dopaminergic system has lagged behind in the enormous growth of the cerebral cortex that has taken place in the evolution of man. Against this background we have asked ourselves if an action on the subcortical dopaminergic system can bring about the profound effect on cortical functions that is observed when an antipsychotic response to neuroleptic treatment takes place. To us, such an indirect effect appears to be the most likely alternative. In trying to answer this question, we have made use of the remarkable progress in the neuroanatomy of the basal ganglia and its connections that has been made during the past decade. We have thus arrived at the following hypothetical explanation.
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It seems appropriate to bring in the concept of the dorsal versus ventral striatum at this point. The former structure (the caudate nucleus-putamen) is often referred to as a motor and the latter as a "mental" structure. However, the anatomical connections of these structures suggest a more complex picture. For example, the dorsal striatum can be divided into an anterior part, mainly connected to the association areas of the cortex, and a posterior part (of the putamen), which has connections predominantly with the motor cortex. The ventral striatum consists of a number of dopamine-rich structures located
Figure 1. Schematic drawing illustrating the hypothesis that the cerebral cortex can control its sensory Input/arousal via dopaminemodulated feedback loops Involving the striatal complexes and the thalamus/mesencephalic reticular formation
Cerebral cortex
Subst. nigra/ VTA
Sense organs NBM=Nucleus basalis Meynert ventrally of the caudate nucleusputamen. The nucleus accumbens is one important component of the ventral striatum. It should be emphasized that in the human brain the counterpart of this nucleus in lower mammals extends into the caudate nucleus and actually forms a major, ventromedial part of this nucleus (for reviews and references concerning the neuroanatomy, see Heimer et al. [1985]; Selemon and Goldman-Rakic [1985]; Alexander et al. [1986]; Bjorklund and Lindvall [1986]; Goldman-Rakic and Selemon [1986]; Nauta [1989]). The afferent and efferent connections of the dorsal and the ventral striatum are organized in a similar
manner. The dorsal striatum receives its afferent supply largely from the neocortex, whereas the ventral striatum is mainly innervated by the limbic cortex. In either case, we are apparently dealing with glutamatergic fibers. This glutamatergic system will be especially focused upon here. There also seems to be an important glutamatergic supply to the striatum from the thalamus. The efferents from the dorsal and ventral striatum project to the dorsal and ventral pallidum, respectively, and they in turn innervate different thalamic nuclei. The dorsal projections go to the ventrolateral nucleus, which appears to project to the
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input and arousal by means of a negative feedback loop involving the striatal complexes, the thalamus, and the mesencephalic reticular formation (see figure 1). This feedback loop is assumed to be composed of several more or less parallel components representing motor, cognitive, and emotional functions. Each of these can probably be further divided into functional subsystems. Thus, Narabayashi (1988) has observed that by means of very small electrolytical lesions 2-3 mm in diameter, applied in the thalamus of Parkinson patients, tremors can be selectively alleviated by placing the lesions in the ventrointermedial nucleus, whereas rigidity can be eliminated by placing the lesions in the ventrolateral nucleus. Larger lesions in this area frequently lead to mental complications. In the future, it should prove possible to obtain a more complete map of pathways and nuclei involved in the various components of motor as well as mental functions within this complex feedback system. This will have to take into account the functional asymmetry of the cerebral hemispheres.
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In figure 1 the intrinsic circuitries of the striatal complexes have been omitted; they are not yet fully elucidated. Moreover, this aspect is not essential for the main argument of our hypothesis. It will, however, be discussed in a forthcoming article (Carlsson and Carlsson 1990). Pathophyslological Aspects Huntington's chorea provides a good argument for a role of the striatum in mental, including cognitive functions. Schizophrenia-like symptomatology may precede the motor disturbances by several years in this neurodegenerative disorder, which is essentially confined to lesions in the striatum (Mattsson 1971). Lesions of the prefrontal cortex or of the pathways from the cortex to the striatum may induce a "disinhibition syndrome" and an increased sensitivity to amphetamine (see Iversen 1977). (There are also indications that lesions in this area may cause inability to switch between different activity programs; see the following section.) A disturbance in arousal and filter mechanisms in schizophrenia has been proposed before. Vfenables (1964, 1987) suggested from McGhie and Chapman's (1961) description of the experiences of early schizophrenic patients that these patients are "flooded by sensory impressions from all quarters." Lehmann (1966) proposed that if a person can cope with a supernormal influx of stimuli, because he has an adequate "central processing apparatus," he will have exceptional creativity. If his integrative capacity is insufficient, however, he may become psychotic. In support of disintegration, Arieti (1966) describes severely psychotic patients, who can grasp but a small part of the sensory input at a time.
An anatomical substrate for such functions was discussed by Stevens (1973, 1989), who proposed that the dorsal and ventral striata "filter, compress, modulate or 'gate' information from sensory to motor systems in neostriatum and from amygdala-hippocampal affect and memory processing regions projecting to limbic striatum en route to thalamus, hypothalamus and frontal lobe" (Stevens 1989, p. 74). Early work on the mode of action of chlorpromazine focused on the mesencephalic reticular formation (see Bradley 1968). It was proposed that the inhibitory effect of chlorpromazine was due to the blockade of excitatory noradrenergic synapses in the mesencephalic reticular formation, thus interfering with arousal. Unfortunately, these studies do not seem to have been extended to more dopamine-specific neuroleptics (cf. Bradley 1986). Thus, the influence of dopaminergic mechanisms was not definitely established. The Glutamatergic System: Pathophyslological and Pharmacological Aspects Our model predicts that a deficient corticostriatal glutamatergic function would lead to functional disturbances similar to those caused by dopaminergic agonists, such as the amphetamines. This seems actually to be the case. Phencyclidine (PCP, "angel dust") is a psychotogenic agent, capable of mimicking schizophrenic symptomatology even more faithfully than the amphetamines (Domino and Luby 1973; Angrist 1987). The main target of this agent appears to be an ion channel linked to the N-methyl-D-aspartate (NMDA) receptor, that is, one of the major glutamate receptors (Lodge et al.
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neocortex, whereas the ventral striatum projects to nuclei in the thalamus, which in turn project to the frontal and limbic cortex and the amygdala (see Nauta 1989). Some of the fibers leaving the pallidum appear to innervate the mesencephalic reticular formation rather than the thalamus. The overall impression of this organization is that part of the feedback system deals with precisely targeted functions, whereas others, involving parts of the thalamus and the mesencephalic Teticuiar formation, may rather be engaged in the control of cortical arousal. Taken together, these systems may provide a means for the cerebral cortex to control its sensory input by adjusting a thalamic filter, as well as to control the activity of the subcortical arousal systems. In this feedback mechanism, the mesostriatal dopamine pathways appear to play an important modulatory role. They seem to be inhibitory on the striatum, which in turn is a powerful inhibitory structure, acting, for example, on the thalamus/mesencephalk reticular formation. Stimulation of dopaminergic mechanisms will thus counteract this inhibition, leading to an increased sensory input and arousal. The corticostriatal glutamate system acts in the opposite direction by stimulating the inhibitory function of the striatum. Insofar as the mesencephalic reticular formation is concerned, it is tempting to suggest that the noradrenergic system of the locus ceruleus and perhaps also the serotonergic system of the raphe nuclei participate in the control of arousal, mediated via the dorsal and ventral striata. The close relationship between the striatum and the basal nucleus of Meynert, whose cholinergic system appears to promote arousal, is also worth mentioning (Richardson and DeLong 1988).
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Our hypothesis would suggest a more profound effect of the corticostriatal pathway on the striatum. In our model, the catalepsy and strong psychomotor inhibition induced by eliminating the dopaminergic function is due to an active inhibitory impact of the striatum, now released from the inhibitory influence of the dopaminergic system. An important corollary would be that even in the absence of dopamine, a psychomotorstimulating influence of MK-801 should persist. This actually proved to be the case (Carlsson and Carlsson 1989a 1989b; Carlsson and Svensson, in press). MK-801 was found to cause a dose-dependent stimulation of locomotor activity of mice, whose stores of catecholamines had been virtually completely depleted by
combined treatment with reserpine and o-methyltyrosine. This was shown in experiments where the locomotor activity was measured by means of photocells in rectangular cages. It was observed, however, that when an animal came to a corner of the cage it was stuck, apparently because it could not switch from forward locomotion to another movement program. This is reminiscent of the "compulsory approaching syndrome" observed in cats following bilateral caudectomy (Wlablanca et al. 1976). Therefore, we started to use rotundas, where an animal treated with MK-801 as a rule only moved in one and the
same direction throughout the experiment. This stimulation of locomotor activity (see figure 2) could not be blocked by the dopamine-receptor antagonists haloperidol and raclopride, confirming that the movements were independent of dopaminergic function. Our experiments have so far been limited to systemic injections of glutamatergic antagonists. However, following striatal injection NMDA has been found to inhibit and an NMDA antagonist has been found to stimulate psychomotor activity (Schmidt and Bury 1988; Raffa et al. 1989), supporting a striatal site of action in our experiments.
Figure 2. Effects of various doses of MK-801 on motor activity in monoamlne-depleted mice
50
I 40
1 :#
30 20 10 0 0.5
3 4 MK-801. mg/kg
Raserpine (10 mg/kg i.p.) was administered 18 hours and e-methyttyrosine (250 mg/kg l.p.) 30 minutes before the i.p. MK-801 treatment. Forward locomotion was registered for 30 minutes, beginning 60 minutes after MK-601 administration. Shown are the means and SEM, n - 4. There was a significant correlation between dose and number of meters covered in 30 minutes (/ - 0.6, p < 0.01). (Data from M. Cartsson and A. Carlsson 19896.)
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1987). In essence, PCP is thus a noncompetitive glutamate antagonist. The substance, (+)-5-methyl-10,lldihydro-5H-dibenzo(a,d) cyclohepten-5,10-imine (MK-801) is a more specific NMDA antagonist, acting on the same ion-channel site as PCP (Wong et al. 1986), and it should thus prove useful for testing our hypothesis that the corticostriatal glutamatergic pathway enhances the inhibitory influence of the striatum on thalamic nuclei as well as on the mesencephalic reticular formation. The sensory input to the cortex, as well as the arousal, is thus under cortical control. From previous work with PCP it has been suggested that this agent can induce release of catecholamines (Clineschmidt et al. 1982a, 1982b, 1982c), and this has later been interpreted to mean that the corricostriatal glutamate pathway can inhibit catecholamine release. The signs of behavioral stimulation of PCP and MK-801 have thus been suggested to be mediated via release of catecholamines.
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Is Schizophrenia Caused by a Dopamlne-Glutamate Imbalance? It seems as though we have to revise our views on the role of dopamine in the regulation of mental and motor activities as well as in the pathogenesis of neuropsychiatric disorders. Until now, there has been a trend to consider dopamine as an absolutely essential stimulant for a variety of brain functions: without dopamine, mental and motor activi-
Figure 3a. Effects of MK-801 (1 mg/kg I.p.) and clonidine (2 mg/kg i.p.) given separately or In combination on forward locomotion in monoamine-depleted mice1
ties go down to an extremely low level. While this is essentially true, it now emerges that the virtual lack of activity in the absence of dopamine receptor stimulation may be due to an active inhibition exerted by the corticostriatal glutamatergic pathway via striatum on the thalamus and the mesencephalic reticular formation (presumably other subcortical structures are also involved in this regulatory mechanism). If this inhibition is removed or reduced by Hocking glutamate receptors, the
Figure 3b. An analogous experiment with apomorphlne (0.1 mg/kg I.p.) instead of clonidine1
*
a 100
20
80
15
60 10
I* 20 0
0 NaCI
Clon
'Data from M. Carlsson and A. Carlsson (19896).
MK MK*Clon * " p < 0001, vs. MK-801 (Mann-Whitney U test).
NaCI
Apo
MK MK+Apo
*p < 002, vs. MK-801 (Mann-Whitney U test).
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We later found that MK-801 is capable of potentiating a variety of arousal-inducing agents, such as clonidine (figure 3a-3b), apomorphine, and atropine. The effect of MK-801 + clonidine could be antagonized by a2-blocking agents, but not by an aj-blocker. Interestingly, the stimulating action of clonidine could be antagonized by clozapine, which reinforces the notion that this agent may in part exert its antipsychotic action by blocking areceptore (see Carlsson 1978).
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alleviated by manipulation of the dopaminergic system, manipulation of the corticostriatal glutamate pathway may have similar consequences. The psychotogenic actions of PCP, ketamine, and MK-801 support this view. Schizophrenia may be induced by a deficiency of the corticostriatal glutamate pathway. Certain observations on postmortem brains of schizophrenic patients do indeed suggest that abnormalities of glutamatergic pathways exist in schizophrenia, even though an effect of chronic neuroleptic treatment remains to be excluded (KornhubeT et al. 1989). By the same token, glutamatergic agonists may prove to possess antipsychotic properties and to be clinically useful, provided that one can circumvent the side effects that can be anticipated in view of the ubiquitous occurrence of glutamatergic systems in the brain. A role of glutamatergic mechanisms in schizophrenia has been proposed on somewhat different grounds (Kornhuber et al. 1984; Kim et al. 1985). However, schizophrenia is probably a heterogeneous disorder, where neurotransmitter imbalances of various kinds may be considered. Excessive dopamine or deficient glutamate function appear to be plausible alternatives, but otheT neurotransmitter disturbances may also be important. For example, noradrenalin, serotonin, and yaminobutyric acid may play a role. By the same token, the site of the lesion may be, for example, in the cortex, the striatum, the thalamus, or the lower brainstem. Hardly any part of the brain can be excluded at present. Regardless of the primary site, however, a striatal imbalance may exist, at least in cases responding to neuroleptic treatment.
References Alexander, G.E.; DeLong M.R.; and Strick, P.L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9:357-381, 1986. Angrist, B. Pharmacological models of schizophrenia. In: Henn, F.A., and Delisi, L.E., eds. Handbook of Schizophrenia. \fol. 2. Neurochemistry and Neuropharmacology of Schizophrenia. Amsterdam: Elsevier, 1987. pp. 391-424 Arieti, S.A. Schizophrenic cognition. In: Hoch, P.H., and Zubin, J., eds. Psychopathology of Schizophrenia. New York: Grune and Stratton, 1966. pp. 37-48. Bjorklund, A., and Lindvall, O. Catecholaminergic brain stem regulatory systems. In: Field, J., ed. Handbook of Physiology—The Nervous System IV. Washington, DC: American Psychological Society, 1986. pp. 155-235. Bradley, P.B. The pharmacology of synapses in the central nervous system. In: Robson, J.M., and Stacey, R.S., eds. Recent Advances in Pharmacology. 4th ed. London: Churchill, 1968. pp. 311-348. Bradley, P.B. Pharmacology of antipsychotic drugs. In: Bradley, P.B., and Hirsch, S.R., eds. The Psychopharmacology and Treatment of Schizophrenia. Oxford-New York-Tokyo: Oxford University Press, 1986. pp. 27-70. Carlsson, A. Antipsychotic drugs, neurotransmitters and schizophrenia. American Journal of Psychiatry, 135:164-173, 1978. Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology, 1:179-186, 1988.
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ability of the brain to induce "psychomotor activity" in the absence of dopaminergic stimulation is disclosed. In fact, it appears that the corticostriatal glutamatergic pathway is a very strong suppressant on a numbeT of arousal mechanisms, as indicated, for example, by the activation induced by the a-adrenergic agonist clonidine and the antimuscarinic agent atropine in the presence of a subthreshold dose of the NMDA receptor antagonist MK-801. In addition to these postsynaptic mechanisms, the glutamatergic system appears to inhibit the release of catecholamines (see above). The inhibitory action of the corticostriatal glutamate pathway on brain activity may be assumed to be selective in the sense that it allows for adequate and purposeful responses to external stimuli. When the pathway is blocked by MK-801, only forward locomotion appears to be activated at the expense of otheT programs. This suggests that the selection of purposeful programs, as well as the switch from one program to another, is an important function of the corticostriatal glutamate pathway. Recently, we obtained indirect support for this contention. We discovered that considerable psychomotor activity can be induced in monoamine-depleted mice (treated with reserpine + tunethyltyrosine) by combined treatment with clonidine + atropine (Carlsson and Carlsson 1989c). In this case, with the glutamatergic system apparently intact, the movements induced appeared as normal, purposeful behavior. In many respects, the corticostriatal glutamate pathway can be looked upon as an antagonist to the mesostriatal dopaminergic system. Thus, just as a psychotic condition can be induced, aggravated, or
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The Authors Maria Carlsson, M.D., is Research Assistant, and Arvid Carlsson, M.D., is Professor of Pharmacology, Department of Pharmacology, University of Goteborg, Goteborg, Sweden.
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