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Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia
J. David Jentsch, John D. Elsworth, Jane R. Taylor, D. Eugene Redmond, Jr., and Robert H. Roth Departments of Neurobiology, Psychiatry, and Pharmacology Yale University School of Medicine New Haven, Connecticut 065 10
Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia It has been more than 35 years since it was first noted that phencyclidine (PCP, or Sernyl) induces psychotomimetic reactions in normal humans (1). Since that time, increasing usage of PCP as a psychedelic drug by humans has provided more insights regarding PCP as a behavioral and neurological model of schizophrenia, but as of yet, the critical neurobiological effects of PCP underlying the induction of schizophrenic-like behavior remain unknown. PCP induces several distinct behavioral effects in humans and animals that appear to represent schizophrenia-like symptomatology. In humans, acute PCP exposure can induce both positive and negative symptoms of schizophrenia (2). These acute effects, however, are usually transient. In contrast, repeated exposure to PCP in humans can lead to enduring presentation of both negative and positive symptoms of schizophrenia (2).Thus, repeated PCP administration may induce neurobiological defects that mimic those present in the brain of patients with schizophrenia. Despite the vast amount of data suggesting that PCP models the primary behavioral symptoms of schizophrenia, it is still unclear what pathophysiology underlies the PCP-induced behavior. Several plausible possibilities exist. First, PCP’s primary pharmacological action is noncompetitive antagonism of the Nmethyl-D-aspartate (NMDA)-sensitive glutamate receptor; thus, a hypoglutamatergic mechanism has been posited to underlid these effects (3). A second possible mechanism responsible for PCP-induced psychosis involves the anatomically distinct neuropathological effects of this drug. Neurons within the corticolimbic axis appear to be sensitive to PCP, undergoing pathological changes or even necrosis following acute or repeated administration. This pattern of neural damage has been suggested to roughly parallel that observed in 810
Advances in Pharmacology, Volume 42 Copyright Q 1998 by Academic Press. All rights of reproduction in any form reserved. 1054-3589/98 $25.00
Dysregulation of Mesoprefrontal DA Neurons by PCP Administration
8I I
schizophrenia (4). A final substrate by which PCP can induce psychotic-like symptoms in humans is dysregulation of mesotelencephalic dopamine (DA) systems. Acute PCP administration has been shown to activate the rnesoprefrontal DA system in the rat ( 5 ) . In this chapter, we will discuss some of our recent studies on the effects of acute and repeated PCP administration on the rodent and nonhuman primate DA systems and how these neurobiological effects may underlie the psychotomimetic properties of PCP. Finally, we will evaluate the relevance of DAergic dysfunction for the hypoglutamatergic and neuropathological hypotheses of PCP's effects. We have replicated the finding that PCP markedly increases prefrontal cortex (PFC) and nucleus accumbens DA metabolism in the rodent (Fig. 1) and have extended those findings by demonstrating that the isomers of 3amino-1-hydroxypyrrolid-2-one(HA966) and the az-noradrenergic receptor agonist clonidine, which can block stress-induced increases in PFC DA metabolism, can also prevent the activation of mesoPFC DA neurons after acute PCP without altering DA turnover in that area on their own. These data suggest
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Acute
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Saline
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PCP
Saline
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-
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**
*
T
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E aE P
n
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4
4
4
Rat
PFC
4
Monkey Dorsolateral PFC
FIGURE I Acute PCP administration increases while subchronic PCP exposure decreases DA turnover in the rat PFC cortex (left) and monkey dorsolateral PFC (right).In addition, the effects of an acute PCP challenge dose on PFC DA turnover is reduced in the rat and eliminated in the monkey after subchronic PCP administration. Significantly increased versus salinelsaline: " p < .05; " * p < .01. tSignificantly reduced versus saline/saline: p < .05.
8 12
J. David Jentsch et of.
that PCP-stimulated PFC DA metabolism is dependent on increased impulse flow in mesoPFC DA neurons, a conclusion supported by in vivo microdialysis studies demonstrating that PCP-induced PFC DA release is tetrodotoxinsensitive (6),and that the enantiomers of HA966 and clonidine can selectively modulate stimulated states of these neurons. In the primate, acute PCP administration causes a selective activation of DA metabolism in the frontal cortex (see Fig. l),while sparing subcortical DA systems. In addition, as in the rodent, S-(-)HA966 blocks PCP-induced increases in DA turnover in the monkey frontal cortex (7). This finding demonstrates that the DAergic activation noted in rodent brain after PCP is conserved in the primate and that this effect can be pharmacologically modulated in a fashion similar to that observed in the rodent. These neurochemical effects of acute PCP exposure do have relevance to observed behavioral effects of PCP in humans. Research from our laboratory has already demonstrated that increased DA turnover in rodent and monkey PFC impairs spatial working-memory function (8). Thus, it is likely that the impairments in cognitive functioning observed in normal human subjects after acute PCP exposure are due to a hyperdopaminergic state of the PFC and that compounds that attenuate this increased DA-receptor activation in the PFC will ameliorate the cognitive deficits. The marked activation of mesoPFC DA systems after an acute PCP challenge is consistent with hypotheses involving hypoglutamatergic and neuropathological mechanisms in the PCP model of schizophrenia. First, there is developing evidence that NMDA receptors have a predominant role in regulating recurrent inhibition (RI)in the cortex (9)and that by blocking NMDA receptors, a preferential reduction in RI is lost, leading to increases in the firing of excitatory corticomesencephalic fibers. Thus, acute PCP may lead to a stimulation of DA neurons indirectly by activating cerebral cortical output circuits. This loss of R l in the cortex and stimulation of monoamine neuron firing may explain the almost paradoxical psychostimulant effects of this potent glutamatergic antagonist. Increases in DA transmission by acute PCP challenge may also explain the neuropathological effects of this compound. Interestingly, the antipsychotic drugs haloperidol and clozapine, both of which are DA-receptor antagonists, and the a2-noradrenergicagonist clonidine, which blocks the activation of PFC DA turnover after PCP exposure, all prevent the PCP-induced neural injury in rat brain ( 3 ) .This suggests that activation of DA systems by PCP may be involved in the development of neuropathology after acute PCP administration. Data from schizophrenics, however, support the idea that there is a hypoactivity, rather than hyperactivity, of the PFC DA innervation in schizophrenia. Interestingly, we have recently observed that subchronic PCP administration, a paradigm that induces enduring schizophreniform symptoms in humans, reduces basal DA turnover in the rat and monkey PFC (see Fig. 1).In addition, the response to an acute PCP challenge dose in the rat and monkey PFC is blunted after repeated PCP exposure (see Fig. 1).These data suggest that there is an inhibition of basal and stimulated DA metabolism in rat and monkey brain after repeated PCP administration (10).
Dysregulation of Mesoprefrontal D A Neurons by PCP Administration
8 13
To determine whether there are functional consequences to this DAergic depression, we tested monkeys on an object retrieval-detour task, the performance of which is sensitive to reductions in mesotelencephalic DA function. Successful performance of this task is dependent on the capacity for response inhibition and the absence of perseverative behavior. Normal, saline-treated monkeys perform almost perfectly on this task, while monkeys previously treated subchronically with PCP were significantly impaired, as measured by a significantly higher incidence of perseverative response than controls and increased context-specific inappropriate responses (10). Perseverative behavior and incapacity for response inhibition are behavioral deficits displayed by schizophrenics. Finally, we most recently observed that the cognitive deficits displayed by monkeys subchronically treated with PCP are partially ameliorated with the atypical antipsychotic drug clozapine (lo), as are the negative symptoms of schizophrenia. Further, preliminary data suggest that a D4 mechanism is critically involved in the action of clozapine in this paradigm. These data suggest that subchronic PCP administration in the monkey induces a profound and chronic cognitive dysfunction similar to that manifested in schizophrenia and that the PCP-induced impairments respond to pharmacological treatment, as do the negative symptoms of schizophrenia. Taken together, our data indicate that repeated PCP administration may model the cognitive dysfunction of schizophrenia and suggest that this dysfunction may be due to an inhibition of DAergic function in the PFC. Further, this paradigm may represent a step forward in biological psychiatric research by offering a tool for evaluating the pathophysiology of the deficits of schizophrenia and a mechanism for the evaluation of novel agents that may be able to ameliorate the typically treatment-refractory negative symptoms in this debilitating disorders. Refeyences 1. Luby, E. D., Cohen, B. D., Rosenbaum, G., Gottleib, J. S., and Kelly, R. (1959). Study of a new schizophreniomimetic drug-Sernyl. Arch. NeuroZ. Psychiatry 81, 363-369. 2. Pearlson, G. D. (1981).Psychiatric and medical syndromes associated with phencyclidine (PCP) abuse. John Hopkins Med. J . 148, 25-33. 3. Olney, J. W., and Farber, N. B. (1995).Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 99 8- 1007. 4. Ellison, G. (1995). The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res. Rev. 20, 250-267. 5. Deutch, A. Y., Tam, S. Y., Freeman, A. S., Bowers, M. B., and Roth, R. H. (1987). Mesolimbic and mesocortical activation induced by phencyclidine: Contrasting pattern to striatal response. Eur. J. Pharmaiol. 134, 257-264. 6 . Nishijima, K., Kashiwa, A,, Hashimoto, A., Iwarna, H., Umino, A,, and Nishikawa T. (1996).Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striarum as revealed by in vivo dialysis. Synapse 22,304-312. 7. Jentscb, J. D., Elsworth, J. D., Redmond, D. E., and Roth, R. H. (1997). Phencyclidine increases monoamine turnover in rodent and monkey forebrain: Modulation by the isomers of HA966.J. Neurosci. 17, 1769-1776.
814
T. H.Svensson et 01.
8. Murphy, B. L., Arnsten, A. F. T., Goldman-Rakic, P. S., and Roth, R. H. (1996).Increased dopamine turnover in prefrontial cortex impairs spatial working memory in rats and monkeys. Proc. Natl. Acad. Sci. U.S.A. 93, 1325-1329. 9. Grunze, H. C., Rainnie, D. G., Hasselmo, M. E., Barkai, E., Hearn, E. F., McCarley, R. W., and Greene, R. W. (1996). NMDA-dependent modulation of CAI local circuit inhibition. J . Neurosci. 16, 2034-2043. 10. Jentsch, J. D., Redmond, D. E., Jr., Elsworth, J. D., Taylor, J. R., Youngren, K. D., and Roth, R. H. (1997). Enduring cognitive dysfunction and cortical dopamine deficits in monkeys after long-term phencyclidine administration. Science (in press).
T. H. Svensson, J. M. Mathe, G. G. Nomikos, B. Schilstrom, M. Marcus, and M. Fagerquist
Department of Physiology and Pharmacology Division of Pharmacology Karolinska lnstitutet S- I 7 I 77 Stockholm, Sweden
Interactions between Catecholamines and Serotonin: Relevance to the Pharmacology of Schizophrenia The glutamate-dopamine (DA)hypothesis of schizophrenia is largely based on indirect, pharmacological evidence. This includes the schizophrenomimetic effects of various N-methyl-D-aspartate (NMDA)-receptor antagonists, such as phencyclidine (PCP), MK-801, or ketamine, which can appear even with acute drug administration to healthy volunteers, as well as the fact that all approved antipsychotic drugs have one effect in common-to impair brain DA neurotransmission, mostly via DA-Dz-receptor antagonism-and that paranoid schizophrenics tend to worsen on administration of indirectly or directly acting DA-receptor agonists, as well as on PCP-like agents. However, although most neuroleptics, including selective Dz antagonists, in positron emission tomography studies display a D2-receptor occupancy of about 75% in clinically effective doses, the atypical antipsychotic drug clozapine shows only about 50% Dzreceptor occupancy in the human brain, in spite of superior clinical efficacy. Therefore, it is of considerable interest to find out how other properties of clozapine and other potentially atypical neuroleptics, such as a potent antagonistic action at central S-HT~A and al-adrenoceptors, may contribute to the antipsyAduances in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved. ioj4-3j89/98 $2j.nn
Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia It has been more than 35 years since it was first noted that phencyclidine (PCP, or Sernyl) induces psychotomimetic reactions in normal humans (1). Since that time, increasing usage of PCP as a psychedelic drug by humans has provided more insights regarding PCP as a behavioral and neurological model of schizophrenia, but as of yet, the critical neurobiological effects of PCP underlying the induction of schizophrenic-like behavior remain unknown. PCP induces several distinct behavioral effects in humans and animals that appear to represent schizophrenia-like symptomatology. In humans, acute PCP exposure can induce both positive and negative symptoms of schizophrenia (2). These acute effects, however, are usually transient. In contrast, repeated exposure to PCP in humans can lead to enduring presentation of both negative and positive symptoms of schizophrenia (2).Thus, repeated PCP administration may induce neurobiological defects that mimic those present in the brain of patients with schizophrenia. Despite the vast amount of data suggesting that PCP models the primary behavioral symptoms of schizophrenia, it is still unclear what pathophysiology underlies the PCP-induced behavior. Several plausible possibilities exist. First, PCP’s primary pharmacological action is noncompetitive antagonism of the Nmethyl-D-aspartate (NMDA)-sensitive glutamate receptor; thus, a hypoglutamatergic mechanism has been posited to underlid these effects (3). A second possible mechanism responsible for PCP-induced psychosis involves the anatomically distinct neuropathological effects of this drug. Neurons within the corticolimbic axis appear to be sensitive to PCP, undergoing pathological changes or even necrosis following acute or repeated administration. This pattern of neural damage has been suggested to roughly parallel that observed in 810
Advances in Pharmacology, Volume 42 Copyright Q 1998 by Academic Press. All rights of reproduction in any form reserved. 1054-3589/98 $25.00
Dysregulation of Mesoprefrontal DA Neurons by PCP Administration
8I I
schizophrenia (4). A final substrate by which PCP can induce psychotic-like symptoms in humans is dysregulation of mesotelencephalic dopamine (DA) systems. Acute PCP administration has been shown to activate the rnesoprefrontal DA system in the rat ( 5 ) . In this chapter, we will discuss some of our recent studies on the effects of acute and repeated PCP administration on the rodent and nonhuman primate DA systems and how these neurobiological effects may underlie the psychotomimetic properties of PCP. Finally, we will evaluate the relevance of DAergic dysfunction for the hypoglutamatergic and neuropathological hypotheses of PCP's effects. We have replicated the finding that PCP markedly increases prefrontal cortex (PFC) and nucleus accumbens DA metabolism in the rodent (Fig. 1) and have extended those findings by demonstrating that the isomers of 3amino-1-hydroxypyrrolid-2-one(HA966) and the az-noradrenergic receptor agonist clonidine, which can block stress-induced increases in PFC DA metabolism, can also prevent the activation of mesoPFC DA neurons after acute PCP without altering DA turnover in that area on their own. These data suggest
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PFC
4
Monkey Dorsolateral PFC
FIGURE I Acute PCP administration increases while subchronic PCP exposure decreases DA turnover in the rat PFC cortex (left) and monkey dorsolateral PFC (right).In addition, the effects of an acute PCP challenge dose on PFC DA turnover is reduced in the rat and eliminated in the monkey after subchronic PCP administration. Significantly increased versus salinelsaline: " p < .05; " * p < .01. tSignificantly reduced versus saline/saline: p < .05.
8 12
J. David Jentsch et of.
that PCP-stimulated PFC DA metabolism is dependent on increased impulse flow in mesoPFC DA neurons, a conclusion supported by in vivo microdialysis studies demonstrating that PCP-induced PFC DA release is tetrodotoxinsensitive (6),and that the enantiomers of HA966 and clonidine can selectively modulate stimulated states of these neurons. In the primate, acute PCP administration causes a selective activation of DA metabolism in the frontal cortex (see Fig. l),while sparing subcortical DA systems. In addition, as in the rodent, S-(-)HA966 blocks PCP-induced increases in DA turnover in the monkey frontal cortex (7). This finding demonstrates that the DAergic activation noted in rodent brain after PCP is conserved in the primate and that this effect can be pharmacologically modulated in a fashion similar to that observed in the rodent. These neurochemical effects of acute PCP exposure do have relevance to observed behavioral effects of PCP in humans. Research from our laboratory has already demonstrated that increased DA turnover in rodent and monkey PFC impairs spatial working-memory function (8). Thus, it is likely that the impairments in cognitive functioning observed in normal human subjects after acute PCP exposure are due to a hyperdopaminergic state of the PFC and that compounds that attenuate this increased DA-receptor activation in the PFC will ameliorate the cognitive deficits. The marked activation of mesoPFC DA systems after an acute PCP challenge is consistent with hypotheses involving hypoglutamatergic and neuropathological mechanisms in the PCP model of schizophrenia. First, there is developing evidence that NMDA receptors have a predominant role in regulating recurrent inhibition (RI)in the cortex (9)and that by blocking NMDA receptors, a preferential reduction in RI is lost, leading to increases in the firing of excitatory corticomesencephalic fibers. Thus, acute PCP may lead to a stimulation of DA neurons indirectly by activating cerebral cortical output circuits. This loss of R l in the cortex and stimulation of monoamine neuron firing may explain the almost paradoxical psychostimulant effects of this potent glutamatergic antagonist. Increases in DA transmission by acute PCP challenge may also explain the neuropathological effects of this compound. Interestingly, the antipsychotic drugs haloperidol and clozapine, both of which are DA-receptor antagonists, and the a2-noradrenergicagonist clonidine, which blocks the activation of PFC DA turnover after PCP exposure, all prevent the PCP-induced neural injury in rat brain ( 3 ) .This suggests that activation of DA systems by PCP may be involved in the development of neuropathology after acute PCP administration. Data from schizophrenics, however, support the idea that there is a hypoactivity, rather than hyperactivity, of the PFC DA innervation in schizophrenia. Interestingly, we have recently observed that subchronic PCP administration, a paradigm that induces enduring schizophreniform symptoms in humans, reduces basal DA turnover in the rat and monkey PFC (see Fig. 1).In addition, the response to an acute PCP challenge dose in the rat and monkey PFC is blunted after repeated PCP exposure (see Fig. 1).These data suggest that there is an inhibition of basal and stimulated DA metabolism in rat and monkey brain after repeated PCP administration (10).
Dysregulation of Mesoprefrontal D A Neurons by PCP Administration
8 13
To determine whether there are functional consequences to this DAergic depression, we tested monkeys on an object retrieval-detour task, the performance of which is sensitive to reductions in mesotelencephalic DA function. Successful performance of this task is dependent on the capacity for response inhibition and the absence of perseverative behavior. Normal, saline-treated monkeys perform almost perfectly on this task, while monkeys previously treated subchronically with PCP were significantly impaired, as measured by a significantly higher incidence of perseverative response than controls and increased context-specific inappropriate responses (10). Perseverative behavior and incapacity for response inhibition are behavioral deficits displayed by schizophrenics. Finally, we most recently observed that the cognitive deficits displayed by monkeys subchronically treated with PCP are partially ameliorated with the atypical antipsychotic drug clozapine (lo), as are the negative symptoms of schizophrenia. Further, preliminary data suggest that a D4 mechanism is critically involved in the action of clozapine in this paradigm. These data suggest that subchronic PCP administration in the monkey induces a profound and chronic cognitive dysfunction similar to that manifested in schizophrenia and that the PCP-induced impairments respond to pharmacological treatment, as do the negative symptoms of schizophrenia. Taken together, our data indicate that repeated PCP administration may model the cognitive dysfunction of schizophrenia and suggest that this dysfunction may be due to an inhibition of DAergic function in the PFC. Further, this paradigm may represent a step forward in biological psychiatric research by offering a tool for evaluating the pathophysiology of the deficits of schizophrenia and a mechanism for the evaluation of novel agents that may be able to ameliorate the typically treatment-refractory negative symptoms in this debilitating disorders. Refeyences 1. Luby, E. D., Cohen, B. D., Rosenbaum, G., Gottleib, J. S., and Kelly, R. (1959). Study of a new schizophreniomimetic drug-Sernyl. Arch. NeuroZ. Psychiatry 81, 363-369. 2. Pearlson, G. D. (1981).Psychiatric and medical syndromes associated with phencyclidine (PCP) abuse. John Hopkins Med. J . 148, 25-33. 3. Olney, J. W., and Farber, N. B. (1995).Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 99 8- 1007. 4. Ellison, G. (1995). The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res. Rev. 20, 250-267. 5. Deutch, A. Y., Tam, S. Y., Freeman, A. S., Bowers, M. B., and Roth, R. H. (1987). Mesolimbic and mesocortical activation induced by phencyclidine: Contrasting pattern to striatal response. Eur. J. Pharmaiol. 134, 257-264. 6 . Nishijima, K., Kashiwa, A,, Hashimoto, A., Iwarna, H., Umino, A,, and Nishikawa T. (1996).Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striarum as revealed by in vivo dialysis. Synapse 22,304-312. 7. Jentscb, J. D., Elsworth, J. D., Redmond, D. E., and Roth, R. H. (1997). Phencyclidine increases monoamine turnover in rodent and monkey forebrain: Modulation by the isomers of HA966.J. Neurosci. 17, 1769-1776.
814
T. H.Svensson et 01.
8. Murphy, B. L., Arnsten, A. F. T., Goldman-Rakic, P. S., and Roth, R. H. (1996).Increased dopamine turnover in prefrontial cortex impairs spatial working memory in rats and monkeys. Proc. Natl. Acad. Sci. U.S.A. 93, 1325-1329. 9. Grunze, H. C., Rainnie, D. G., Hasselmo, M. E., Barkai, E., Hearn, E. F., McCarley, R. W., and Greene, R. W. (1996). NMDA-dependent modulation of CAI local circuit inhibition. J . Neurosci. 16, 2034-2043. 10. Jentsch, J. D., Redmond, D. E., Jr., Elsworth, J. D., Taylor, J. R., Youngren, K. D., and Roth, R. H. (1997). Enduring cognitive dysfunction and cortical dopamine deficits in monkeys after long-term phencyclidine administration. Science (in press).
T. H. Svensson, J. M. Mathe, G. G. Nomikos, B. Schilstrom, M. Marcus, and M. Fagerquist
Department of Physiology and Pharmacology Division of Pharmacology Karolinska lnstitutet S- I 7 I 77 Stockholm, Sweden
Interactions between Catecholamines and Serotonin: Relevance to the Pharmacology of Schizophrenia The glutamate-dopamine (DA)hypothesis of schizophrenia is largely based on indirect, pharmacological evidence. This includes the schizophrenomimetic effects of various N-methyl-D-aspartate (NMDA)-receptor antagonists, such as phencyclidine (PCP), MK-801, or ketamine, which can appear even with acute drug administration to healthy volunteers, as well as the fact that all approved antipsychotic drugs have one effect in common-to impair brain DA neurotransmission, mostly via DA-Dz-receptor antagonism-and that paranoid schizophrenics tend to worsen on administration of indirectly or directly acting DA-receptor agonists, as well as on PCP-like agents. However, although most neuroleptics, including selective Dz antagonists, in positron emission tomography studies display a D2-receptor occupancy of about 75% in clinically effective doses, the atypical antipsychotic drug clozapine shows only about 50% Dzreceptor occupancy in the human brain, in spite of superior clinical efficacy. Therefore, it is of considerable interest to find out how other properties of clozapine and other potentially atypical neuroleptics, such as a potent antagonistic action at central S-HT~A and al-adrenoceptors, may contribute to the antipsyAduances in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved. ioj4-3j89/98 $2j.nn