22
Fifteen Years of Continued Research in Psychopharmacology A. Carlsson Department of Pharmacology, University of Göteborg, Göteborg, Sweden
I received the Anna-Monika Prize in 1975 for research on the mode of action of antidepressants and neuroleptics. In the present review I shall focus on those aspects of my subsequent research which deal with these issues, this includes work on drugs acting on dopamine autoreceptors and on serotonergic transmission. I shall also discuss the interaction between monoaminergic and non-monoarninergic systems and their role in the crosstalk between the cerebral cortex and subcortical structures. Dopaminergic autoreceptors
Our work on autoreceptors goes back to 1972, when we discovered that the synthesis of dopamine could be inhibited by a doparnine receptor agonist and stimulated by an antagonist even after exclusion of a feedback 100p by means ofaxotomy (Kehr et al., 1972). We therefore postulated that the receptors involved were presynaptic. In order to avoid confusion about the nature of these receptors, wbich appeared to be 10cated on various parts of the neuron and to possess a special functional significance among the presynaptic receptors, I proposed calling them "autoreceptors" (CarIsson, 1975a), and this term has since become generally accepted. I also suggested that agents with se1ective action on autoreceptors might prove useful not only as research tools but also as therapeutic agents (Carlsson, 1975b). We already knew that low doses of a dopaminergic receptor agonist could have a preferential action on autoreceptors and thus cause a paradoxical behavioral inhibition.
mon the property of being partial receptor agonists. Several such agents, with varying intrinsic activities, are now being clinically tested, mainly as antipsychotic agents. A perhaps even more fascinating line of autoreceptor research deals with the preferential dopamine autoreceptor antagonists, wbich were also developed by our research group (Svensson et al., 1986). A prototype for these agents is (+ )-UH-232 (= N,N-dipropyl-cis-( +)-( 1S,2R)-5methoxy-l-methyl-2-aminotetralin). This agent presents an intriguing mixture of behaviorally stimulating and depressant properties. At lower dosages it tends to be predominantly stimulating, apparently due to a preferential antagonistic action on dopaminergic autoreceptors, whereas higher doses tend to be predominantly depressant, especially if the baseline behaviorallevel of the animal is high. This latter effect is apparently due to an antagonistic action on dopaminergic postsynaptic receptors. These agents have not yet reached the stage of clinical trial, but will hopefully do so in the near future. Their potential clinical usefulness appears to cover a broad area in psychopharmacology. They may prove therapeutically active both in depression and schizophrenia, and in the latter case they appear especially promising in the treatment of negative symptoms. As to the antidepressant action of neuroleptics, the possibility seems attractive that tbis efTects is due to an albeit weak preference for dopaminergic autoreceptors. The much stronger preference of (+ )-UH-232 and related agents for these receptors would then be expected to lend a more powerful antidepressant efficacy to these drugs (CarIsson, 1988).
Four years later our collaboration with expert organic chemists led to the discovery of 3-PPP (= 3-(3-hydroxyphenyl)-N-n-propylpiperidine). The (+ )-form turned out to be an agonist rather similar to apomorphine, whereas the (-)-form was found to have moderately agonistic efTects on the doparninergic autoreceptors. On postsynaptic dopamine (D-2) receptors the (-)-form behaved as an antagonist with low intrinsic activity; it seemed devoid of cataleptogenic properties and thus presumably of extrapyramidal sideefTects (Hjorth et al., 1981, 1983; Carlsson, 1987). Subsequent work revealed that the profIle of (-)-3-PPP, now also called preclamol, is shared by manY other dopaminergic agents, wbich all appear to have in com-
Pharmacopsychiat. 25 (1992) 22-24 © Georg Thieme Verlag Stuttgart· New York
At present (+ )-UH-232 and related agents are attracting increasing interest in view of their preferential affinity for the recently cloned dopamine D-3 receptor subtype (Sokoloffet al., 1990). Research on serotonin
The tricyclic antidepressants were first shown to block the reuptake of noradrenalin, and thus this neurotransmitter was claimed to play a major role in the control of mood and drive. Later however, we discovered, that the tricyclic antidepressants also had a powerful action on the reuptake of serotonin, and that tbis applied especially to some ofthe most wide1y used antidepressants (for references, see Carlsson, 1976). Also, zimelidine (see below) and subsequently a number of other selective serotonin uptake inhibitors were developed and found to be efficacious antidepressants.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Introduction
Fifteen Years 0/ Continued Research in Psychopharmacology
This area is now in a dynamic phase, with the development of reversible monoamine oxidase A inhibitors lacking the "cheese effect" (Youdim et al., 1988) and selective 5·HT·IA receptor agonists possessing both antidepressant and anxiolytic properties. The advent of these novel research tools and therapeutic agents may be expected to further expand our knowledge ofthe role ofserotonin in brain function and brain disorders (Dourish et al., 1987). The driving force of new pharmacologicaJ research tools My research group is fortunate in having had the opportunity, since the early 1960s, to work together with skilled organic chernists in the development of new, more specific, and powerful phannacological research tools. This work began with the collaboration with the late Hans Corrodi, a highly talented Swiss chemist, and culrninated in the development of the first se1ective 5-HT uptake inhibitor, zimelidine (Berndtsson et al., 1972; Carlsson, 1982, 1986), which turned out to be an active antidepressant agent but was withdrawn because of certain rare but serious side-effects. We were encouraged by this experience, and managed to obtain funds to establish a team of organic chemists within our department of pharmacology. Subsequently we developed (-)-3-PPP, the first dopamine receptor agonist with strong preference for the autoreceptors (Hjorth et al., 1981), (+ )-UH-232 and (+ )-AJ-76, the first preferential dopamine autoreceptor antagonists (Svensson et al., 1986), and finally 8-0H-DPAT, the first selective 5-HT-IA receptor agonist (Hjorth et al., 1982). All these agents were developed in collaboration with chemists working in our own department and in the school of pharmacy at the University of Uppsala, Sweden, and are now being widely used as research tools. In addition, agents of these types have a potential as therapeutic agents in various neuropsychiatric disorders. This collaborative experience is very encouraging. I hope that, in the future, units of organic chemistry will also be set up in other departments of pharmacology. It should be noted that this kind of work in an academic setting will differ from similar work in the pharmaceutical industry in being more directed towards the development of research tools, which may or may not prove useful as therapeutic agents. Neurotransmitter interactions The dopaminergic system of the brain has its cell bodies in the mesencephalon and the majority of its nerve terminals in the striatum, a large mass of grey substance located in the cerebral hemispheres below the cortex. A dorsal portion of this structure, consisting of the caudate nucleus and putamen, is mainly associated with the neocortex, whereas a ventral portion is associated with the (limbic) allocortex. In both cases the association consists in a powerfu! input of glutamatergicjaspartergic corticostriatal fibers. According to our hypothesis, the corticostriatal glutamatergic
23
and the mesostriatal dopaminergic pathways are mutually antagonistic: while the former stimulate, the latter inhibit stri· atal output neurons. A major target of the striatum is the thalamus, with an intermediate re1ay station in the (dorsal and ventral) pallidum. The striatum would seem to have an inhibitory influence on the thalamus, and this influence is enhanced by the glutamatergic and antagonized by the dopaminergic pathway. Cortico-striato-pallido-thalamo-eorticalloops are weil described in the literature. In our hypothesis they are negative feedback loops. These loops may serve to protect the cerebral cortex from an overload of incoming signals, and this negative feedback may also serve as a selective fIlter, allowing the cortex to focus on re1evance and novelty (Carisson, 1988). In support of our model we have found that the extreme immobility and low responsiveness induced by removing doparnine from the brain (by means of reserpine and alpha-methyl-tyrosine treatment) can be alleviated by agents blocking different sites of the glutamatergic NMDA receptor (NMDA = N-methyl-D-aspartic acid). This indicates that the strong inhibition of movement and mental activity induced by antidopaminergic agents or following degeneration of dopaminergic neurons is actually due to an enhanced negative feedback through the loops described above (Carlsson and Carlsson, 1989 a, b, c, 1990; Carlsson and Svensson, 1990). We believe that this feedback is an important mechanism, allowing the cerebral cortex to concentrate on relevant issues while fIltering off trivial information and freeing the cortex of activities that can be handled automatically by subcortical structures. The glutamatergic system appears to interact with the dopaminergic and noradrenergic systems large1y at the postsynaptic level by reducing the responsiveness of dopaminergic and alpha-adrenergic receptors. Disturbances in this important regulatory mechanism may play a role in various disorders, such as schizophrenia, affective disorders and Parkinson's disease. This working hypothesis opens up strategies for the development of new therapeutic principles, e. g. glutamatergic agonists in schizophrenia and mania. References Berndtsson. P. B.• P. A. E. Car/sson. H. R. Co"odi: Belg. Pat. 781105 (1972) (72-4-14) Car/sson, A.: Receptor-mediated contral of dopamine metabolism. In: Usdin, E., W. E. Bunney (eds.): Pre- and Postsynaptic Receptors. Marcel Dekker, New York (1975 a) 49-65 Car/sson, A.: Dopaminergic autoreceptors. In: A1mgren, 0., A. Carlsson, J. Engel (eds.): Chemical Tools in Catecholamine Research, Vol. II. North-Holland Publishing Company, Amsterdam (l975b) 219-224 Car/sson, A.: The contribution of drug research to investigating the nature of endogenous depression. Pharmakopsychiat. 9 (1976) 2-10 Car/sson. A.: Recent observations on new potential and established antidepressant drugs. Pharmakopsychiat. 15 (1982) 116---120 Car/sson, A.: Current views on the mode of action of antidepressant drugs. Adv. Pharmacother. 2 (1986) 167-174 Car/sson. A.: Pharmacology of selective dopamine receptor agonists. In: Mutschler, E., E. Winterfeldt (eds.): Trends in Medicinal Chemistry. VCH Verlagsgesellschaft, Weinheim, FRG (1987)
313-321
Downloaded by: University of Iowa Libraries. Copyrighted material.
Recently, serotonin has started to attract a great deal of attention in the control of anxiety. Panic disorders appear to respond especially weil to serotonin uptake inhibitors. Most remarkably, obsessive-eompulsive conditions appear to respond specifically to serotonergic drugs (Eriks· son and Humble, 1990).
Pharmacopsychiat. 25 (1992)
A. Carlsson
Pharmacopsychiat. 25 (1992) Car/sson. A.: The current status of the dopamine hypothesis of schizophrenia. With cornmentaries and author's reply. Neuropsychopharmacology I (1988) 179-203 Car/sson. M.. A. Car/sson: The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J. Neural. Transm. 75 (l989a) 221-226 Car/sson. M .• A. Car/sson: Dramatic synergism between MK-801 and c10nidine with respect to locomotor stimulatory etTect in monoamine-depleted mice. J. Neural. Transm. 77 (1989 b) 65-71 Car/sson. M.• A. Car/sson: Marked locomotor stimulation in monoarnine-depleted mice following treatment with atropine in combination with c1onidine. J. Neural. Transm. (P-D Section) 1 (1989c) 317-322 Car/sson. M.• A. Car/sson: Interactions between g1utamatergic and monoarninergic systems with the basal ganglia - implications for schizophrenia and Parkinson's disease. Trends in Neurosei. 13 (1990) 272-276 Car/sson. M., A. Svensson: Interfering with g1utamatergic neurotransmission by means of MK-801 administration discloses the locomotor stimulatory potential of other transmitter systems in rats and mice. Pharmacol. Biochem. Behav. 36 (1990) 45-50 Dourish. C. T., S. Ah/enius. P. H. Hutson (eds):Brain 5-HT-IA Receptors. Ellis Horwood, Chichester (1987) 1-306 Eriksson. E.• M. Humb/e: Serotonin in psychiatrie pathophysiology. In: Pohl, R., S. Gershon (eds.): The Biological Basis of Psychiatrie Treatment. Progr. Basic Clin. Pharmacol., Karger, Basel, Vol.3 (1990) 66-119 Hjorth. S. A.• H. Car/sson, H. Wikström. P. Lindberg. D. Sanchez, U. Hackse//. L.-E. Arvidsson. U. Svensson. J. L. G. Ni/sson: 3-PPP, a new centrally acting DA-receptor argonist with selectivity for autoreceptors. Life Sei 28 (1981) 1225-1238 Hjorth. S.• A. Car/sson. P. Lindberg. D. Sanchez, H. Wikström. L.-E. Arvidsson. U. Hackse//. J. L. G. Ni/sson:8-Hydroxy-2-(di-n-propylarnino)tetralin, 8-0H-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. J. Neural. Transm. 55 (1982) 169-188 Hjorth. s.. A. Car/sson. D. C/ark. K. Svensson. H. Wikström. D. Sanchez. P. Lindberg. U. Hackse//. L.-E. Arvidsson. A. Johansson. J. L. G. Ni/sson: Central doparnine receptor agonist and antagonist actions of the enantiomers of 3-PPP. Psychopharmacology 81 (1983) 89-99 Kehr. W.• A. Car/sson. M. Lindqist. T. Magnusson. C. Atack: Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase. J. Pharm. Pharmacol. 24 (1972) 744-747 Sok%ff. P.• B. Giros. M.-P. Martres, M.-L. Bouthenet. J.-c. Schwartz: Molecular cloning and characterization of a novel dopamine receptor (D-3) as a target for neuroleptics. Nature 347 (1990) 146151 Svensson. K.. S. Hjorth. D. C/ark, A. Car/sson. H. Wikström. B. Andersson. D. Sanchez. A. M. Johansson. L.-E. Arvidsson. U. Hackse//. J. L. G. Ni/sson: (+)-UH-232 and (+)-UH-242: Novel stereoselective DA receptor antagonists with preferential action on autoreceptors. J. Neural. Transm. 65 (1986) 1-27 Youdim. M. B. H.. M. Da Prada. R. Amrein (eds.): The Cheese EtTect and new reversible MAO-A inhibitors. J. Neural. Transm. Suppt. 26 (1988) 1-136
Prof Arvid Car/sson
Dept. of Pharmacology University of Göteborg PO Box 33031 8-40033 Göteborg Sweden
Downloaded by: University of Iowa Libraries. Copyrighted material.
24
Fifteen Years of Continued Research in Psychopharmacology A. Carlsson Department of Pharmacology, University of Göteborg, Göteborg, Sweden
I received the Anna-Monika Prize in 1975 for research on the mode of action of antidepressants and neuroleptics. In the present review I shall focus on those aspects of my subsequent research which deal with these issues, this includes work on drugs acting on dopamine autoreceptors and on serotonergic transmission. I shall also discuss the interaction between monoaminergic and non-monoarninergic systems and their role in the crosstalk between the cerebral cortex and subcortical structures. Dopaminergic autoreceptors
Our work on autoreceptors goes back to 1972, when we discovered that the synthesis of dopamine could be inhibited by a doparnine receptor agonist and stimulated by an antagonist even after exclusion of a feedback 100p by means ofaxotomy (Kehr et al., 1972). We therefore postulated that the receptors involved were presynaptic. In order to avoid confusion about the nature of these receptors, wbich appeared to be 10cated on various parts of the neuron and to possess a special functional significance among the presynaptic receptors, I proposed calling them "autoreceptors" (CarIsson, 1975a), and this term has since become generally accepted. I also suggested that agents with se1ective action on autoreceptors might prove useful not only as research tools but also as therapeutic agents (Carlsson, 1975b). We already knew that low doses of a dopaminergic receptor agonist could have a preferential action on autoreceptors and thus cause a paradoxical behavioral inhibition.
mon the property of being partial receptor agonists. Several such agents, with varying intrinsic activities, are now being clinically tested, mainly as antipsychotic agents. A perhaps even more fascinating line of autoreceptor research deals with the preferential dopamine autoreceptor antagonists, wbich were also developed by our research group (Svensson et al., 1986). A prototype for these agents is (+ )-UH-232 (= N,N-dipropyl-cis-( +)-( 1S,2R)-5methoxy-l-methyl-2-aminotetralin). This agent presents an intriguing mixture of behaviorally stimulating and depressant properties. At lower dosages it tends to be predominantly stimulating, apparently due to a preferential antagonistic action on dopaminergic autoreceptors, whereas higher doses tend to be predominantly depressant, especially if the baseline behaviorallevel of the animal is high. This latter effect is apparently due to an antagonistic action on dopaminergic postsynaptic receptors. These agents have not yet reached the stage of clinical trial, but will hopefully do so in the near future. Their potential clinical usefulness appears to cover a broad area in psychopharmacology. They may prove therapeutically active both in depression and schizophrenia, and in the latter case they appear especially promising in the treatment of negative symptoms. As to the antidepressant action of neuroleptics, the possibility seems attractive that tbis efTects is due to an albeit weak preference for dopaminergic autoreceptors. The much stronger preference of (+ )-UH-232 and related agents for these receptors would then be expected to lend a more powerful antidepressant efficacy to these drugs (CarIsson, 1988).
Four years later our collaboration with expert organic chemists led to the discovery of 3-PPP (= 3-(3-hydroxyphenyl)-N-n-propylpiperidine). The (+ )-form turned out to be an agonist rather similar to apomorphine, whereas the (-)-form was found to have moderately agonistic efTects on the doparninergic autoreceptors. On postsynaptic dopamine (D-2) receptors the (-)-form behaved as an antagonist with low intrinsic activity; it seemed devoid of cataleptogenic properties and thus presumably of extrapyramidal sideefTects (Hjorth et al., 1981, 1983; Carlsson, 1987). Subsequent work revealed that the profIle of (-)-3-PPP, now also called preclamol, is shared by manY other dopaminergic agents, wbich all appear to have in com-
Pharmacopsychiat. 25 (1992) 22-24 © Georg Thieme Verlag Stuttgart· New York
At present (+ )-UH-232 and related agents are attracting increasing interest in view of their preferential affinity for the recently cloned dopamine D-3 receptor subtype (Sokoloffet al., 1990). Research on serotonin
The tricyclic antidepressants were first shown to block the reuptake of noradrenalin, and thus this neurotransmitter was claimed to play a major role in the control of mood and drive. Later however, we discovered, that the tricyclic antidepressants also had a powerful action on the reuptake of serotonin, and that tbis applied especially to some ofthe most wide1y used antidepressants (for references, see Carlsson, 1976). Also, zimelidine (see below) and subsequently a number of other selective serotonin uptake inhibitors were developed and found to be efficacious antidepressants.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Introduction
Fifteen Years 0/ Continued Research in Psychopharmacology
This area is now in a dynamic phase, with the development of reversible monoamine oxidase A inhibitors lacking the "cheese effect" (Youdim et al., 1988) and selective 5·HT·IA receptor agonists possessing both antidepressant and anxiolytic properties. The advent of these novel research tools and therapeutic agents may be expected to further expand our knowledge ofthe role ofserotonin in brain function and brain disorders (Dourish et al., 1987). The driving force of new pharmacologicaJ research tools My research group is fortunate in having had the opportunity, since the early 1960s, to work together with skilled organic chernists in the development of new, more specific, and powerful phannacological research tools. This work began with the collaboration with the late Hans Corrodi, a highly talented Swiss chemist, and culrninated in the development of the first se1ective 5-HT uptake inhibitor, zimelidine (Berndtsson et al., 1972; Carlsson, 1982, 1986), which turned out to be an active antidepressant agent but was withdrawn because of certain rare but serious side-effects. We were encouraged by this experience, and managed to obtain funds to establish a team of organic chemists within our department of pharmacology. Subsequently we developed (-)-3-PPP, the first dopamine receptor agonist with strong preference for the autoreceptors (Hjorth et al., 1981), (+ )-UH-232 and (+ )-AJ-76, the first preferential dopamine autoreceptor antagonists (Svensson et al., 1986), and finally 8-0H-DPAT, the first selective 5-HT-IA receptor agonist (Hjorth et al., 1982). All these agents were developed in collaboration with chemists working in our own department and in the school of pharmacy at the University of Uppsala, Sweden, and are now being widely used as research tools. In addition, agents of these types have a potential as therapeutic agents in various neuropsychiatric disorders. This collaborative experience is very encouraging. I hope that, in the future, units of organic chemistry will also be set up in other departments of pharmacology. It should be noted that this kind of work in an academic setting will differ from similar work in the pharmaceutical industry in being more directed towards the development of research tools, which may or may not prove useful as therapeutic agents. Neurotransmitter interactions The dopaminergic system of the brain has its cell bodies in the mesencephalon and the majority of its nerve terminals in the striatum, a large mass of grey substance located in the cerebral hemispheres below the cortex. A dorsal portion of this structure, consisting of the caudate nucleus and putamen, is mainly associated with the neocortex, whereas a ventral portion is associated with the (limbic) allocortex. In both cases the association consists in a powerfu! input of glutamatergicjaspartergic corticostriatal fibers. According to our hypothesis, the corticostriatal glutamatergic
23
and the mesostriatal dopaminergic pathways are mutually antagonistic: while the former stimulate, the latter inhibit stri· atal output neurons. A major target of the striatum is the thalamus, with an intermediate re1ay station in the (dorsal and ventral) pallidum. The striatum would seem to have an inhibitory influence on the thalamus, and this influence is enhanced by the glutamatergic and antagonized by the dopaminergic pathway. Cortico-striato-pallido-thalamo-eorticalloops are weil described in the literature. In our hypothesis they are negative feedback loops. These loops may serve to protect the cerebral cortex from an overload of incoming signals, and this negative feedback may also serve as a selective fIlter, allowing the cortex to focus on re1evance and novelty (Carisson, 1988). In support of our model we have found that the extreme immobility and low responsiveness induced by removing doparnine from the brain (by means of reserpine and alpha-methyl-tyrosine treatment) can be alleviated by agents blocking different sites of the glutamatergic NMDA receptor (NMDA = N-methyl-D-aspartic acid). This indicates that the strong inhibition of movement and mental activity induced by antidopaminergic agents or following degeneration of dopaminergic neurons is actually due to an enhanced negative feedback through the loops described above (Carlsson and Carlsson, 1989 a, b, c, 1990; Carlsson and Svensson, 1990). We believe that this feedback is an important mechanism, allowing the cerebral cortex to concentrate on relevant issues while fIltering off trivial information and freeing the cortex of activities that can be handled automatically by subcortical structures. The glutamatergic system appears to interact with the dopaminergic and noradrenergic systems large1y at the postsynaptic level by reducing the responsiveness of dopaminergic and alpha-adrenergic receptors. Disturbances in this important regulatory mechanism may play a role in various disorders, such as schizophrenia, affective disorders and Parkinson's disease. This working hypothesis opens up strategies for the development of new therapeutic principles, e. g. glutamatergic agonists in schizophrenia and mania. References Berndtsson. P. B.• P. A. E. Car/sson. H. R. Co"odi: Belg. Pat. 781105 (1972) (72-4-14) Car/sson, A.: Receptor-mediated contral of dopamine metabolism. In: Usdin, E., W. E. Bunney (eds.): Pre- and Postsynaptic Receptors. Marcel Dekker, New York (1975 a) 49-65 Car/sson, A.: Dopaminergic autoreceptors. In: A1mgren, 0., A. Carlsson, J. Engel (eds.): Chemical Tools in Catecholamine Research, Vol. II. North-Holland Publishing Company, Amsterdam (l975b) 219-224 Car/sson, A.: The contribution of drug research to investigating the nature of endogenous depression. Pharmakopsychiat. 9 (1976) 2-10 Car/sson. A.: Recent observations on new potential and established antidepressant drugs. Pharmakopsychiat. 15 (1982) 116---120 Car/sson, A.: Current views on the mode of action of antidepressant drugs. Adv. Pharmacother. 2 (1986) 167-174 Car/sson. A.: Pharmacology of selective dopamine receptor agonists. In: Mutschler, E., E. Winterfeldt (eds.): Trends in Medicinal Chemistry. VCH Verlagsgesellschaft, Weinheim, FRG (1987)
313-321
Downloaded by: University of Iowa Libraries. Copyrighted material.
Recently, serotonin has started to attract a great deal of attention in the control of anxiety. Panic disorders appear to respond especially weil to serotonin uptake inhibitors. Most remarkably, obsessive-eompulsive conditions appear to respond specifically to serotonergic drugs (Eriks· son and Humble, 1990).
Pharmacopsychiat. 25 (1992)
A. Carlsson
Pharmacopsychiat. 25 (1992) Car/sson. A.: The current status of the dopamine hypothesis of schizophrenia. With cornmentaries and author's reply. Neuropsychopharmacology I (1988) 179-203 Car/sson. M.. A. Car/sson: The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J. Neural. Transm. 75 (l989a) 221-226 Car/sson. M .• A. Car/sson: Dramatic synergism between MK-801 and c10nidine with respect to locomotor stimulatory etTect in monoamine-depleted mice. J. Neural. Transm. 77 (1989 b) 65-71 Car/sson. M.• A. Car/sson: Marked locomotor stimulation in monoarnine-depleted mice following treatment with atropine in combination with c1onidine. J. Neural. Transm. (P-D Section) 1 (1989c) 317-322 Car/sson. M.• A. Car/sson: Interactions between g1utamatergic and monoarninergic systems with the basal ganglia - implications for schizophrenia and Parkinson's disease. Trends in Neurosei. 13 (1990) 272-276 Car/sson. M., A. Svensson: Interfering with g1utamatergic neurotransmission by means of MK-801 administration discloses the locomotor stimulatory potential of other transmitter systems in rats and mice. Pharmacol. Biochem. Behav. 36 (1990) 45-50 Dourish. C. T., S. Ah/enius. P. H. Hutson (eds):Brain 5-HT-IA Receptors. Ellis Horwood, Chichester (1987) 1-306 Eriksson. E.• M. Humb/e: Serotonin in psychiatrie pathophysiology. In: Pohl, R., S. Gershon (eds.): The Biological Basis of Psychiatrie Treatment. Progr. Basic Clin. Pharmacol., Karger, Basel, Vol.3 (1990) 66-119 Hjorth. S. A.• H. Car/sson, H. Wikström. P. Lindberg. D. Sanchez, U. Hackse//. L.-E. Arvidsson. U. Svensson. J. L. G. Ni/sson: 3-PPP, a new centrally acting DA-receptor argonist with selectivity for autoreceptors. Life Sei 28 (1981) 1225-1238 Hjorth. S.• A. Car/sson. P. Lindberg. D. Sanchez, H. Wikström. L.-E. Arvidsson. U. Hackse//. J. L. G. Ni/sson:8-Hydroxy-2-(di-n-propylarnino)tetralin, 8-0H-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. J. Neural. Transm. 55 (1982) 169-188 Hjorth. s.. A. Car/sson. D. C/ark. K. Svensson. H. Wikström. D. Sanchez. P. Lindberg. U. Hackse//. L.-E. Arvidsson. A. Johansson. J. L. G. Ni/sson: Central doparnine receptor agonist and antagonist actions of the enantiomers of 3-PPP. Psychopharmacology 81 (1983) 89-99 Kehr. W.• A. Car/sson. M. Lindqist. T. Magnusson. C. Atack: Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase. J. Pharm. Pharmacol. 24 (1972) 744-747 Sok%ff. P.• B. Giros. M.-P. Martres, M.-L. Bouthenet. J.-c. Schwartz: Molecular cloning and characterization of a novel dopamine receptor (D-3) as a target for neuroleptics. Nature 347 (1990) 146151 Svensson. K.. S. Hjorth. D. C/ark, A. Car/sson. H. Wikström. B. Andersson. D. Sanchez. A. M. Johansson. L.-E. Arvidsson. U. Hackse//. J. L. G. Ni/sson: (+)-UH-232 and (+)-UH-242: Novel stereoselective DA receptor antagonists with preferential action on autoreceptors. J. Neural. Transm. 65 (1986) 1-27 Youdim. M. B. H.. M. Da Prada. R. Amrein (eds.): The Cheese EtTect and new reversible MAO-A inhibitors. J. Neural. Transm. Suppt. 26 (1988) 1-136
Prof Arvid Car/sson
Dept. of Pharmacology University of Göteborg PO Box 33031 8-40033 Göteborg Sweden
Downloaded by: University of Iowa Libraries. Copyrighted material.
24
