Abstract
Interest in the role of serotonin (5-HT) in the therapeutic effects of atypical antipsychotic drugs originated from the observations that: (1) clozapine and other atypical drugs have a high affinity for 5-HT2A relative to D2 receptors; and (2) 5-HT2A receptors mediate the central effects of psychedelic hallucinogens. Recently, we found that 5-HT evokes a focal release of glutamate in the apical dendritic field of layer V pyramidal cells in prefrontal cortex, measured electrophysiologically by an increased frequency of spontaneous excitatory postsynaptic potentials/currents (EPSPs/EPSCs). An atypical mode of transmitter release (termed asynchronous release) seems to be involved because EPSC induction is tetrodotoxin (TTX)-sensitive but is not dependent on impulse flow and is supported by Sr2+ in the absence of external Ca2+. The 5-HT-induced increase in spontaneous EPSCs is blocked completely by the selective 5-HT2A antagonist M100907 (MDL 100,907). M100907 also blocks the enhancement by hallucinogens of a late, asynchronous component of electrically evoked EPSPs/EPSCs. Group II/III metabotropic glutamate agonists, which act downstream from 5-HT2A receptors at presynaptic inhibitory autoreceptors, markedly suppress the 5-HT-induced release of glutamate. Subtype-selective group II/III agonists, such as the group II metabotropic agonist LY354740, are particularly interesting in terms of therapeutic potential, because they are able to suppress the 5-HT2A-induced EPSCs while sparing overall glutamatergic transmission. An analysis of the mechanisms by which 5-HT2A receptors induce glutamate release suggests new targets for the design of novel treatments for schizophrenia.
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In the late 1970s, using radioligand binding techniques, it was discovered that antipsychotic drugs interacted not only with dopamine receptors but also with serotonin (5-HT) receptors, particularly in the frontal cortex (Leysen et al. 1978). Shortly thereafter, using radiolabeled 5-HT and the hallucinogen LSD (d-lysergic acid diethylamide) as ligands, at least two distinct populations of 5-HT receptors, termed 5-HT1 and 5-HT2, were described in the brain (Peroutka and Snyder 1979). Based on this classification, it was determined that some antipsychotic drugs, such as clozapine, interacted more potently with the 5-HT2 than D2 receptor; however, clinical potency appeared to correlate only with affinity for the D2 receptor (Peroutka and Snyder 1980). Only later, when antipsychotic drugs were grouped separately according to whether they had “typical” or “atypical” characteristics, did a high affinity for 5-HT2 relative to D2 receptors emerge as a distinguishing feature of the drugs in the atypical category (Altar et al. 1986; Meltzer et al. 1989).
Antipsychotic drugs are generally classified as atypical if they have reduced extrapyramidal side effects and/or an enhanced spectrum of antipsychotic efficacy, particularly with regard to negative symptoms. An early clinical study suggested that a drug, setoperone, with high affinity for 5-HT2 relative to D2 receptors, in addition to having relatively low extrapyramidal side effects, may have enhanced efficacy in the treatment of negative symptoms (e.g., emotional withdrawal, blunted affect) (Ceulemans et al. 1985). It is noteworthy that part of the rationale given in the latter study for testing the antipsychotic properties of 5-HT2-antagonist drugs was their ability to block certain effects of LSD in animal model systems (Colpaert and Janssen 1983). The hypothesis that 5-HT2 receptor blockade contributes to the favorable profile of atypical antipsychotic drugs led to the development of a new generation of agents with a high 5-HT2A to D2 ratio, some of which (e.g., risperidone) have now become accepted for clinical use in the treatment of schizophrenia (for reviews, see: Breier et al. 1997; Lieberman et al. 1998; Meltzer and Nash 1991).
Meanwhile, a large body of evidence has accumulated that 5-HT2 receptors may be involved in the mechanism of action of psychedelic hallucinogens. Originally, this idea was based on the demonstration of a high correlation between hallucinogenic potency in humans and the affinity of both phenethylamine (e.g., mescaline) and indoleamine (e.g. LSD and psilocybin) hallucinogens for 5-HT2 receptors (Glennon et al. 1984; Titeler et al. 1988). Indeed, among all known 5-HT receptor subtypes, affinity for 5-HT2 receptors is the only one shared by both the indoleamine and phenethylamine classes of hallucinogens. There is now abundant evidence from biochemical (Sanders-Bush et al. 1988), electrophysiological (Marek and Aghajanian 1996), and animal behavioral (Glennon 1990) studies that the effects of hallucinogens involve a partial agonist action at 5-HT2 receptors, particularly of the 5-HT2A subtype. Very recently, studies on the role of 5-HT2 receptors in the action of hallucinogens have been extended to human subjects. As predicted by the preclinical studies, the psychotomimetic effects of the indoleamine hallucinogen psilocybin have now been shown to be blocked completely by the preferential 5-HT2A antagonist ketanserin, the atypical antipsychotic risperidone, but not the typical antipsychotic haloperidol (Vollenweider et al. 1998). However, it remains to be determined whether 5-HT2A antagonism alone is sufficient for the treatment of schizophrenia or whether a threshold level of D2 antagonism may be required for full antipsychotic efficacy (Farde et al. 1992; Kapur et al. 1999). The resolution of these issues will require the completion of clinical testing with highly selective 5-HT2A antagonists such as M100907 (also referred to as MDL 100,907).
Because of their possible involvement in the action of psychedelic hallucinogens and atypical antipsychotics there has been much interest in the location and function of 5-HT2A receptors in the central nervous system. Autoradiographic studies show 5-HT2A receptor binding in several regions of the brain, but the bulk of these receptors are found in the cerebral cortex (Lopez-Gimenez et al. 1997; Pazos and Palacios 1985). A correspondingly high density of 5-HT2A receptor mRNA has been found by in situ hybridization in the cerebral cortex (Mengod et al. 1990; Wright et al. 1995). Recent immunocytochemical studies have demonstrated a particularly high density of 5-HT2A receptors within the apical dendrites of cortical pyramidal cells (Hamada et al. 1998; Jakab and Goldman-Rakic 1998; Willins et al. 1997). This postsynaptic localization is consistent with electrophysiological studies on cortical pyramidal cells showing direct depolarizing effects mediated by 5-HT2 receptors (Aghajanian and Marek 1997; Araneda and Andrade 1991; Sheldon and Aghajanian 1990; Tanaka and North 1993).
The focus of this review is on the physiological role of 5-HT2A receptors in the medial prefrontal and anterior cingulate regions of the cerebral cortex, particularly in relation to their ability to enhance certain kinds of glutamatergic transmission by indoleamine and the phenethylamine hallucinogens. These electrophysiological effects are discussed in relation to the NMDA antagonist class of psychotomimetics, which, surprisingly, have now been reported to induce an increase in glutamate release in the cerebral cortex. Finally, potential new targets for antipsychotic drug design based on a hyperglutamatergic model of psychotomimetic drug action are discussed.
5-HT2A RECEPTORS ENHANCE GLUTAMATE RELEASE IN NEOCORTEX
Electrophysiological actions of hallucinogens, acting via 5-HT2 receptors, have been described in several subcortical regions of the rat (Aghajanian 1980; Garratt et al. 1993; McCall and Aghajanian 1980; Rasmussen and Aghajanian 1986). However, because hallucinogens characteristically alter higher-level processes, such as cognition, perception, and mood, studies on their effects in the cerebral cortex are receiving increasing attention. One of the most striking effects of 5-HT is an increase in spontaneous postsynaptic potentials (PSPs) in various cortical regions. Originally, recordings from pyramidal cells in brain slices from rat piriform cortex, a paleocortical region, showed that 5-HT induces mostly inhibitory postsynaptic potentials (IPSPs) (Sheldon and Aghajanian 1990). However, more recent studies have shown that in layer V pyramidal cells of the neocortex, 5-HT-induced synaptic events consist mostly of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) (Figure 1 ), shown in part by the fact that they are blocked by the AMPA/kainate glutamate receptor antagonist LY293558 but not the GABAA antagonist bicuculline (Aghajanian and Marek 1997). The 5-HT-induced EPSCs are antagonized by low concentrations of the highly selective 5-HT2A antagonist M100907 (Figure 2 ), indicating that they are mediated by 5-HT2A receptors (Aghajanian and Marek 1997; Marek and Aghajanian 1999). The 5-HT-induced increase in EPSCs is most pronounced in frontal regions such as the medial prefrontal cortex (Aghajanian and Marek 1997), where the density of 5-HT2A receptors is increased relative to more posterior regions (Lopez-Gimenez et al. 1997; Pazos and Palacios 1985). Norepinephrine (NE), via α1 adrenoceptors, also induces an increase in EPSPs in layer V pyramidal cells, but, at least in the rat, to only a fraction of that produced by 5-HT (Marek and Aghajanian 1999).
Quantitatively, the most pronounced effect of 5-HT in prefrontal cortex is to increase the frequency of EPSCs (Figure 1). Changes in the frequency of synaptic currents or potentials are generally regarded as being indicative of a modulation of presynaptic function. Accordingly, the relatively nonspecific group II/III metabotropic glutamate receptor agonist (1S, 3S)-ACPD (Aghajanian and Marek 1997) (Figure 3 ) or the selective group II metabotropic agonist LY354740 (Marek et al. 1999), acting at presynaptic inhibitory autoreceptors located on glutamatergic nerve terminals, suppresses the 5-HT-induced increase in the frequency of EPSCs in prefrontal cortex. These findings are consistent with the idea that activation of 5-HT2A receptors increases the release of glutamate onto layer V pyramidal cells through a presynaptic mechanism. However, this presynaptic effect might be mediated indirectly through a retrograde messenger, because, as discussed below, 5-HT2A receptors appear predominantly to have a postsynaptic localization (Hamada et al. 1998; Jakab and Goldman-Rakic 1998). 5-HT also produces a small but significant increase in the amplitude of spontaneous EPSCs, an effect that may involve a postsynaptic amplification mechanism (Aghajanian and Marek 1997). Such a postsynaptic effect is consistent with the finding of a high density of 5-HT2A receptor immunoreactivity in the apical dendrites of cortical pyramidal cells (Jakab and Goldman-Rakic 1998; Willins et al. 1997).
The 5-HT-induced EPSCs are blocked by bath application of the fast sodium channel blocker tetrodotoxin (TTX) or perfusion of the slice with a solution containing no added calcium (”0” calcium) (Aghajanian and Marek 1997). Ordinarily, TTX sensitivity or Ca2+ dependence would suggest that 5-HT had activated glutamatergic cells located within the slice, leading to an impulse-flow dependent release of glutamate. However, several lines of evidence argue against this conventional interpretation. First, rarely were neurons within the confines of the brain slice induced to fire by bath application of 5-HT. Second, none of the recorded pyramidal cells (a potential source of intracortical excitatory inputs) was depolarized sufficiently by 5-HT to reach threshold for firing. Third, EPSCs could be induced by the microiontophoresis of 5-HT onto “hotspots” along the apical dendrites of layer V pyramidal cells, but no cell firing could be detected in the same locations while recording extracellularly through the microiontophoretic electrode (Aghajanian and Marek 1997). Together, these experiments suggest that 5-HT induces EPSCs in neocortical cells through a focal action involving a Ca2+-dependent mechanism that does not require impulse flow.
5-HT2A RECEPTORS AND ASYNCHRONOUS TRANSMISSION IN THE CEREBRAL CORTEX
Recently, we have begun to investigate possible atypical mechanisms by which 5-HT, in the absence of an increase in afferent impulse flow, could induce a focal, TTX-sensitive/Ca2+-dependent release of glutamate. Previously, it has been reported that mildly depolarizing agents, such as the K+ channel blocker 4-aminopyridine (4-AP), can induce a TTX-sensitive release of glutamate from isolated cortical synaptosomes; whereas, the increase in glutamate release produced by strongly depolarizing concentrations of KCl (sufficient to activate voltage-gated Ca2+ channels) is not TTX-sensitive (Tibbs et al. 1989). Notably, 4-AP preferentially enhances the “slow” rather than the “fast” component of glutamate release from cortical synaptosomes; this slow component has been hypothesized to represent the asynchronous mode of release, because it is supported by Sr2+ in the absence of Ca2+ (Herrero et al. 1996). Sr2+ substitutes for Ca2+ at the high-affinity Ca2+ sensor synaptotagmin III, which is believed to be responsible for slow, asynchronous transmitter release; in contrast, Sr2+ is ineffective at the low-affinity Ca2+ sensor synaptotagmin I thought to be essential for fast, synchronous transmitter release (Figure 4 ) (Geppert et al. 1994; Goda and Stevens 1994; Li et al. 1995). It has been proposed that the formation of a multi-molecular complex, consisting of synaptotagmin I together with synaptic core complex proteins, interacts with the segment II/III intracellular loop of Ca2+ channels (Tobi et al. 1998), forming the basis for rapid Ca2+-triggered transmitter release (for review, see Stanley 1997). Thus, if coupling to the synaptic protein interaction site of Ca2+ channels is prevented, fast synchronous transmitter release is impaired; whereas, late asynchronous release remains intact (Mochida et al. 1996).
In various regions of brain, including cerebral cortex (Araneda and Andrade 1991; Sheldon and Aghajanian 1990; Tanaka and North 1993), the effects of 5-HT2A-receptor activation resemble those of 4-AP in producing a slow depolarization through a reduction in K+ channel conductance. By analogy with 4-AP, it is possible that 5-HT induces an a TTX/Ca2+-sensitive focal increase in spontaneous EPSCs through an increase in the Sr2+-supported asynchronous mode of glutamate release. To test this possibility, we have examined the ability of Sr2+ to substitute for Ca2+ in supporting 5-HT-induced spontaneous EPSCs. We have found that the 5-HT-induced increase in the frequency of spontaneous EPSCs is fully supported by Sr2+ in the absence of added Ca2+, suggesting mediation by the asynchronous rather than synchronous mode of transmitter release (Figure 5 ). In contrast, the amplitude of spontaneous EPSCs is not fully supported by Sr2+ in the absence of Ca2+, consistent with the importance of Ca2+ in the postsynaptic amplification of glutamatergic inputs to apical dendrites of layer V pyramidal cells (Schiller et al. 1997).
In layer V pyramidal cells of medial prefrontal cortex, when extracellular Ca2+ is removed, there is a loss of synchronous electrically evoked EPSCs; the subsequent addition of Sr2+ leads to the appearance of late asynchronous EPSCs in the continued absence of synchronous EPSCs (Figure 6 ) (Aghajanian and Marek 1999). A similar increase in late, nonsynchronous component electrically evoked EPSCs was observed during 5-HT washout (when 5-HT2A receptors are unopposed by non-5-HT2A actions of 5-HT) or application of the 5-HT2A/2C partial agonist DOI (Figure 7 ). M100907 is highly effective in reversing the DOI enhancement of the late component of the evoked EPSC, confirming that this effect is mediated by 5-HT2A receptors (Figure 8 ). The conventional interpretation of this late component would be that it represents polysynaptic or epileptiform activity. However, in several respects (e.g., refractory period) this late component of the evoked response is distinct from conventional polysynaptic evoked EPSCs that occur, for example, in the presence of the GABAA antagonist bicuculline (Aghajanian and Marek 1999). Therefore, we hypothesize that the late component of the EPSC enhanced by 5-HT2A receptors is mediated by the asynchronous mode of glutamate release at the nerve terminal rather than through a polysynaptic pathway.
PROPOSED MECHANISMS FOR 5-HT2A RECEPTOR-INDUCED ASYNCHRONOUS GLUTAMATE RELEASE
A mechanism by which 5-HT2A receptors, either directly or indirectly, could promote asynchronous EPSCs in layer V pyramidal cells would be by increasing residual Ca2+ in excitatory nerve terminals; thereby activating of synaptotagmin III (see Figure 4). There are a number of possible mechanisms through which the activation of 5-HT2A receptors could augment levels of residual Ca2+ (Figure 9 ). It is known that 5-HT2A receptors are coupled via the Gq family of G proteins to the phospholipase C/phosphoinositide second messenger pathway, one limb of which leads to the formation of inositol trisphosphate (IP3), a releasor of Ca2+ from intracellular stores (Conn and Sanders-Bush 1986). This has been demonstrated directly in C6 glioma cells where a 5-HT2A-receptor mediated release of intracellular Ca2+ has been shown to be mimicked by an increase in intracellular IP3 (Bartrup and Newberry 1994). Nevertheless, although an elevation of intraterminal Ca2+ levels may contribute to residual Ca2+ levels, the observed dependence on extracellular Ca2+ (or Sr2+) indicates that entry of extracellular Ca2+ is required for 5-HT2A-induced asynchronous EPSCs. In the case of electrically evoked EPSCs, Ca2+ entry through voltage-gated Ca2+ channels could synergize with Ca2+ released from intracellular stores. However, in the case of spontaneous EPSCs, it is more difficult to account for the entry of extracellular Ca2+ because, in the absence of an increase in impulse flow, voltage-gated Ca2+ channels would not be activated. Earlier, we reported that 5-HT enhances a subtheshold, TTX-sensitive persistent Na+ current in layer V pyramidal cells (Aghajanian and Marek 1997). We have proposed elsewhere, that, if 5-HT acts to induce an increase in a persistent subthreshold Na+ current in excitatory nerve terminals, the resulting increase in intracellular Na+ could activate reverse Na+/Ca2+ exchange (NCXr), resulting in increased Ca2+ influx (Marek and Aghajanian 1998). Figure 9 depicts how Ca2+ entry through voltage-gated channels, in conjunction with reverse Na+/Ca2+ exchange and IP3-induced release from internal stores, may increase residual Ca2+ levels thereby, enhancing asynchronous release.
The fact that 5-HT produces a marked increase in the frequency of spontaneous EPSCs points to the involvement of a presynaptic site of action. However, a recent electron immunocytochemical study has shown only a scattering of 5-HT2A-labeled nerve terminals in prefrontal cortex; whereas, the bulk of these receptors are located postsynaptically on pyramidal cell apical dendrites (Jakab and Goldman-Rakic 1998). Thus, although postsynaptic 5-HT2A receptors may serve to increase the amplitude of spontaneous EPSCs (Aghajanian and Marek 1997), there is no simple way to explain how such a postsynaptic action could result in a marked increase in the frequency of EPSCs. Given the evidence for a predominantly postsynaptic location of 5-HT2A receptors, there is a need to explain how interactions with presynaptic modulators may occur. One possibility would be that a retrograde messenger is generated through the action of 5-HT on postsynaptic 5-HT2A receptors, which then could have a presynaptic effect on excitatory nerve terminals. Inhibitory modulators could then suppress this retrograde effect through their separate presynaptic site of action. Nevertheless, it is still possible that the effect of 5-HT on asynchronous EPSCs is mediated through a direct presynaptic action upon the apparently small subset of 5-HT2A-positive terminals that have been demonstrated to exist by electron immunocytochemistry (Jakab and Goldman-Rakic 1998).
EFFECTS OF PSYCHOTOMIMETIC NMDA ANTAGONISTS ON GLUTAMATE RELEASE: COMPARISON WITH PSYCHEDELIC HALLUCINOGENS
Recently, it has been reported that many effects of psychotomimetic NMDA antagonists, such as phencyclidine and ketamine, may be mediated through excess glutamate acting at non-NMDA (i.e., AMPA/kainate) receptors. Microdialysis techniques show that systemic administration of ketamine enhances the release of glutamate in prefrontal cortex (Moghaddam et al. 1997). Parallel behavioral studies have shown that the systemically active AMPA/kainate antagonist LY293558 ameliorates the cognitive deficits produced by ketamine, suggesting that NMDA antagonists may disrupt cognitive function by increasing the release of glutamate thereby, stimulating non-NMDA receptors (Moghaddam and Adams 1998). Moreover, a group II metabotropic glutamate agonist, LY354740, which prevented excessive release of glutamate, reduced the cognitive and motor effects of phencyclidine. The mechanism by which NMDA antagonists induce an increase in glutamate release appears to be distinct from that of 5-HT2A agonists, because bath application of phencyclidine to brain slices does not result in an increase in EPSCs in layer V pyramidal cells of prefrontal cortex (Marek and Aghajanian unpublished data). This lack of a direct effect suggests a requirement for the activation of intact afferent systems for NMDA antagonists to induce an increase in glutamate release. In any case, the precise mechanisms by which psychedelic hallucinogens and NMDA antagonists cause an increase in glutamate release are likely to differ. The evidence for an increase in glutamate transmission for both the psychedelic hallucinogens and the NMDA antagonists raises the possibility that there is a convergent or common final glutamatergic pathway that may account for overlapping aspects of their psychotomimetic effects. On the other hand, the effects of the two classes of drugs would not be expected to be identical, because the psychedelic hallucinogens do not block NMDA receptors.
Brain-imaging studies in human subjects also reveal similarities in the effects of psychedelic hallucinogens and NMDA antagonists. Representatives of the two major classes of psychedelic hallucinogens, the indoleamine psilocybin (Vollenweider et al. 1997b) and the phenethylamine mescaline (Hermle et al. 1992), have been shown to produce metabolic hyperfrontality in the anterior cingulate and other frontal regions. Interestingly, psychotomimetic doses of ketamine have been shown to produce a similar pattern of hyperfrontality, both in healthy volunteers (Breier et al. 1997; Vollenweider et al. 1997a) and schizophrenic patients (Lahti et al. 1995). In rat studies, the metabolic activation produced by ketamine in prefrontal cortex and other regions is blocked by clozapine but not haloperidol, perhaps because of the 5-HT2A antagonist properties of clozapine, which are not shared by haloperidol (Duncan et al. 1998). Regardless of differences in specific mechanisms, it is possible that an increased release of glutamate underlies the hyperfrontality seen with both psychedelic hallucinogens and ketamine.
In contrast to the hyperfrontality seen in the drug studies, the results of brain-imaging studies in schizophrenic patients have been mixed. Some studies, particularly in acutely psychotic, unmedicated, or drug-naive patients, have reported a hyperfrontal pattern similar to that produced by psychotomimetic drugs (Cleghorn et al. 1989; Ebmeier et al. 1993; Parellada et al. 1994). However, other studies, even those conducted in unmedicated or drug-naive schizophrenic patients (Andreasen et al. 1997; Haznedar et al. 1997), did not find a hyperfrontal pattern. A more consistent finding in schizophrenic subjects, regardless of whether they display hypofrontality (Andreasen et al. 1992; Buchsbaum et al. 1992; Weinberger et al. 1986) or hyperfrontality (Parellada et al. 1994) under resting conditions, is a diminished ability to respond with prefrontal activation when challenged with cognitive tasks. Interestingly, this deficit in task-related prefrontal activation is mimicked by the administration of psilocybin to normal human volunteers (Gouzoulis-Mayfrank et al. 1999).
NEW TARGETS FOR ANTIPSYCHOTIC DRUGS BASED ON PSYCHOTOMIMETIC DRUG MODELS
If hyperglutamatergic states play a role in the pathogenesis of schizophrenia, as they do in the psychotomimetic drug models, then treatments that limit or suppress glutamate release may be therapeutic or prophylactic in this disease. However, because glutamate is the main excitatory transmitter in the central nervous system, a generalized block of glutamatergic transmission would not be useful. Our studies on 5-HT2A-receptor mediated glutamate release in the cerebral cortex reveal the highly localized nature of this process, which involves only a subset of glutamatergic afferents innervating the apical dendrites of layer V pyramidal cells. Thus, the selective 5-HT2A antagonist M100907 is able to achieve a high degree of specificity by blocking glutamate release at a restricted set of glutamatergic terminals regulated by this receptor. We also have found an increased release of glutamate mediated by α1 receptors, which, like 5-HT2A receptors, are coupled through the Gq/11/phosphoinositide pathway. It is possible that antagonists of other receptors that are coupled through the Gq/11/phosphoinositide pathway also have therapeutic potential.
An alternative way to normalize glutamatergic transmission would be to suppress glutamate release at sites downstream from the initial 5-HT2A or other Gq-coupled receptor. Such an approach would allow for the possibility that the site of pathology in naturally occurring psychoses may not be at the initial receptor but may be at one or more of the steps involved in the complex process of regulating glutamate release. The hallucinogen model suggests that one such target is the regulation of residual Ca2+ levels, which underlie the process of asynchronous release. Residual Ca2+ can be regulated both positively (e.g., through release from internal stores via the phosphoinositide/inositol trisphosphate pathway and reversal of Na+/Ca2+ exchange) and negatively (e.g., by presynaptic autoreceptors). In preliminary studies, we have shown that low concentrations of the group II metabotropic agonist LY354740 can reduce the late asynchronous EPSP while sparing the early synchronous EPSP (Marek et al. 1999). One possible basis for this selectivity is that metabotropic subtypes are differentially expressed in different afferents to layer V pyramidal cells. For example, mGluR2 receptor mRNA is expressed strongly by relay cells in the anterior and midline nuclei of thalamus (Ohishi et al. 1993), possibly contributing to the band of mGluR2 receptor protein corresponding to the terminal regions of the thalamocortical pathway, which can be seen in the mid-layer of the cerebral cortex (Ohishi et al. 1998). Interestingly, this is the same layer that has been implicated in 5-HT2A-induced EPSCs (Marek and Aghajanian 1998).
As described above, pharmacological manipulations of glutamate transmission provide unexpected parallels between the hallucinogen and NMDA antagonists drug models of psychosis. Thus, the group II/III metabotropic agonist (1S, 3S)-ACPD and the preferential group II metabotropic agonist LY354740, which reduce the release of glutamate by acting upon presynaptic inhibitory autoreceptors, are able to block EPSCs induced by activation of 5-HT2A receptors in vitro (Aghajanian and Marek 1997; Marek et al. 1999). Similarly, LY354740 (which is active by the systemic route of administration [Schoepp et al. 1997]) has been shown to ameliorate certain cognitive deficits in rats produced by the NMDA antagonist phencyclidine in vivo (Moghaddam and Adams 1998). Taken together, these results suggest that metabotropic agonists would be useful in normalizing excesses in glutamate release, regardless of the cause. The availability of orally active metabotropic glutamate receptor agonists makes it feasible to test the hypothesis that excessive glutamate release, particularly in such critical sites as the prefrontal cortex, plays a role in the positive and/or negative symptoms of schizophrenia.
Clearly, there is need to explore new treatment approaches in schizophrenia, because even the best of therapeutic responses obtained with existing typical or atypical antipsychotic drugs are often delayed and not fully restorative (Tamminga 1998). As suggested above, a possible reason for this lack of full efficacy may be that the primary site of pathology in schizophrenia may lie downstream from the receptors (D2, 5-HT2A, etc.) that are targeted by currently available drugs.
References
Aghajanian GK . (1980): Mescaline and LSD facilitate the activation of locus coeruleus neurons by peripheral stimuli. Brain Res 186: 492–498
Aghajanian GK, Marek GJ . (1997): Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36: 589–599
Aghajanian GK, Marek GJ . (1999): Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825: 1–2, 161–171
Altar CA, Wasley AM, Neale RF, Stone GA . (1986): Typical and atypical antipsychotic occupancy of D2 and S2 receptors: An autoradiographic analysis in rat brain. Brain Res Bull 16: 517–525
Andreasen HC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, Cohen G, O'Leary DS . (1992): Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia: Assessment with xenon-133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiat 49: 943–958
Andreasen NC, O'Leary DS, Flaun M, Nopoulos P, Watkins GL, Boles Ponto LL . (1997): Hypofrontality in schizophrenia: Distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349: 1730–1734
Araneda R, Andrade R . (1991): 5-Hydroxytryptamine 2 and 5-Hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40: 399–412
Bartrup J, Newberry NR . (1994): 5-HT2A receptor-mediated outward current in C6 glioma cells is mimicked by intracellular IP3 release. NeuroReport 5: 1245–1248
Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D . (1997): Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiat 154: 805–811
Buchsbaum MS, Haier RJ, Potkin SG, Nuechterlein K, Bracha HS, Katz M, Lohr J, Wu J, Lottenberg S, Jerabek PA, Trenary M, Tafalla R, Reynolds C, Bunney WE . (1992): Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiat 49: 935–942
Ceulemans DLS, Gelders YG, Hoppenbrouwers M-LJA, Reyntjens AJM, Janssen PAJ . (1985): Effect of serotonin antagonism in schizophrenia: A pilot study with setoperone. Psychopharmacology 85: 329–332
Cleghorn JM, Garnett ES, Nahmias C, Firnau G, Brown GM, Kaplan R, Szechtman H, Szechtman B . (1989): Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiat Res 28: 119–133
Colpaert FC, Janssen PAJ . (1983): A characterization of LSD-antagonist effects of pirenperone in the rat. Neuropharmacology 22: 1001–1005
Conn PJ, Sanders-Bush E . (1986): Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5-HT2 binding site. J Neuroscience 6: 3669–3675
Duncan GE, Leipzig JN, Mailman RB, Lieberman JA . (1998): Differential effects of clozapine and haloperidol on ketamine-induced metabolic activation. Brain Res 812: 65–75
Ebmeier KP, Blackwood HR, Murray C, Souza V, Walker M, Dougall N, Moffoot APR, O'Carroll RE, Goodwin GM . (1993): Single-photon emission computed tomography with 99mTc-exametazime in unmedicated schizophrenic patients. Biol Psychiat 33: 487–495
Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G . (1992): Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: Relation to extrapyramidal side effects. Arch Gen Psychiat 49: 538–544
Garratt JC, Alreja M, Aghajanian GK . (1993): LSD has high efficacy relative to serotonin in enhancing the cationic current Ih: intracellular studies in rat facial motoneurons. Synapse 13: 123–134
Geppert M, Goda Y, Hammer RE, Li C, Rosahl TW, Stevens CF, Sudhof TC . (1994): Synaptotagmin I: A major Ca2+ sensor for transmitter release at a central synapse. Cell 79: 717–727
Glennon RA . (1990): Do classical hallucinogens act as 5-HT2 agonists or antagonists? Neuropsychopharmacology 3: 509–517
Glennon RA, Titeler M, McKenney JD . (1984): Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35: 2502–2511
Goda Y, Stevens CF . (1994): Two components of transmitter release at a central synapse. Proc Nat Acad Sci USA 91: 12942–12946
Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, Kovar K-A, Hermle L, Bull U, Sass H . (1999): Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. Neuropsychopharmacology 20: 565–581
Hamada S, Senzaki K, Hamaguchi-Hamada K, Tabuchi K, Yamamoto H, Yamamoto T, Yoshikawa S, Okano H, Okado N . (1998): Localization of 5-HT2A receptor in rat cerebral cortex and olfactory system revealed by immunohistochemistry using two antibodies raised in rabbit and chicken. Mol Brain Res 54: 199–211
Haznedar MM, Buchsbaum MS, Luu C, Hazlett EA, Siegel BV, Lohr J, Wu J, Haier RJ, Bunney WEJ . (1997): Decreased anterior cingulate gyrus metabolic rate in schizophrenia. Am J Psychiat 154: 682–684
Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach RA, Spitzer M . (1992): Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: Experimental psychosis as a tool for psychiatric research. Biol Psychiat 32: 976–991
Herrero I, Castro E, Miras-Portugal MT, Sanchez-Prieto J . (1996): Two components of glutamate exocytosis differentially affected by presynaptic modulation. J Neurochem 67: 2346–2354
Jakab RL, Goldman-Rakic PS . (1998): 5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Nat Acad Sci USA 95: 735–740
Kapur S, Zipursky RB, Remington G . (1999): Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiat 156: 286–293
Lahti AC, Holcomb HH, Medoff DR, Tamminga CA . (1995): Ketamine activates psychosis and alters limbic blood flow in schizophrenia. NeuroReport 6: 869–872
Leysen JE, Niemegeers CJE, Tollemaere JP, Lauduron PM . (1978): Serotonergic component of neuroleptic receptors. Nature 272: 168–171
Li C, Bazbek CL, Davletov A, Sudhof TC . (1995): Distinct Ca2+ and Sr2+ binding properties of synaptotagmins. J Biol Chem 270: 24898–24902
Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE, Kraus JE . (1998): Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiat 44: 1099–1117
Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT . (1997): Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn-Schmiedeberg's Arch Pharmacol 356: 446–454
Marek GJ, Aghajanian GK . (1996): LSD and the phenethylamine hallucinogen DOI are potent partial agonists at 5-HT2A receptors on neurons in the rat piriform cortex. J Pharmacol Exp Ther 278: 1373–1382
Marek GJ, Aghajanian GK . (1998): 5-HT-induced EPSCs in neocortical layer V pyramidal cell of prefrontal cortex: Suppression by m opiate receptor activation. Neuroscience 86: 485–497
Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK . (1999): Physiological antagonism between 5-hydroxytryptamine2A and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther, in press.
Marek GJ, Aghajanian GK . (1999): 5-HT2A receptor or α1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367: 197–206
McCall RB, Aghajanian GK . (1980): Hallucinogens potentiate responses to serotonin and norepinephrine in the facial motor nucleus. Life Sci 26: 1149–1156
Meltzer HY, Matsubara S, Lee JC . (1989): Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2, and serotonin-2 pKi values. J Pharmacol Exp Ther 251: 238–246
Meltzer HY, Nash JF . (1991): Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43: 587–604
Mengod G, Pompeiano M, Martinez-Mir MI, Palacios JM . (1990): Localization of the mRNA for the 5-HT2 receptor by in situ hybridization histochemistry: Correlation with the distribution of receptor binding sites. Brain Res 524: 139–143
Mochida S, Sheng S-H, Baker C, Kobaysashi H, Catterall WA . (1996): Inhibition of neurotransmission by peptides containing the synaptic protein interaction site of N-type Ca2+ channels. Neuron 17: 781–788
Moghaddam B, Adams B . (1998): Stimulation of group II metabotropic glutamate receptors normalizes the cognitive and motoric effects of phencylidine. Science 281: 1349–1352
Moghaddam B, Adams B, Verma A, Daly D . (1997): Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with prefrontal cortex. J Neurosci 17: 2921–2927
Ohishi H, Neki A, Mizuno N . (1998): Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: An immunohistochemical study with a monoclonal antibody. Neurosci Res 30: 65–82
Ohishi H, Shigemoto R, Nakanishi S, Mizuno N . (1993): Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 53: 1009–1018
Parellada E, Catafau AM, Bernardo M, Lomena F, Gonzalez-Monclus E, Setoain J . (1994): Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: A resting and activation SPECT study. Psychiat Res Neuroimaging 55: 131–139
Pazos A, Palacios JM . (1985): Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346: 205–230
Peroutka SJ, Snyder SH . (1979): Multiple serotonin receptors: differential binding of 3H-serotonin, 3H-lysergic acid diethylamide and 3H-spiroperidol. Mol Pharmacol 16: 687–699
Peroutka SJ, Snyder SH . (1980): Relationship of neuroleptic drug effects at brain dopamine, serotonin, α-adrenergic, and histamine receptors to clinical potency. Am J Psychiat 137: 1518–1522
Rasmussen K, Aghajanian GK . (1986): Effects of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: Reversal by selective 5-HT2 antagonists. Brain Res 385: 395–400
Sanders-Bush E, Burris KD, Knoth K . (1988): Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J Pharmacol Exp Ther 246: 924–928
Schiller J, Schiller Y, Stuart G, Sakmann B . (1997): Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons. J Physiol Lond 505: 605–616
Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S, Cockerham SL, Burnett JP, Belegaje R, Bleakman D, Monn JA . (1997): LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology 36: 1–11
Sheldon PW, Aghajanian GK . (1990): Serotonin (5-HT) induces IPSPs in pyramidal layer cells of rat piriform cortex: Evidence for the involvement of a 5-HT2-activated interneuron. Brain Res 506: 62–69
Stanley EF . (1997): The calcium channel and the organization of the presynaptic transmitter release face. TINS 20: 404–409
Tamminga CA . (1998): Sertotonin and schizophrenia. Biol Psychiat 44: 1079–1080
Tanaka E, North RA . (1993): Actions of 5-hydroxytryptamine on neurons of the rat cingulate cortex. J Neurophys 69: 1749–1757
Tibbs GR, Barrie AP, Van Mieghem FJE, McMahon HT, Nicholls DG . (1989): Repetitive action potentials in isolated nerve terminals in the presence of 4-aminopyridine: Effects on cytosolic free Ca2+ and glutamate release. J Neurochem 53: 1693–1699
Titeler M, Lyon RA, Glennon RA . (1988): Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 94: 213–216
Tobi D, Wiser O, Trus M, Atlas D . (1998): N-type voltage-sensitive calcium interacts with syntaxin, synaptobrevin and SNAP-25 in a multiprotein complex. Receptors Channels 6: 89–98
Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J . (1997a): Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacology 7: 9–24
Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J . (1997b): Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 16: 357–372
Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Babler A, Vogel H, Hell D . (1998): Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9: 3897–3902
Weinberger DR, Berman KF, Zec RF . (1986): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiat 43: 114–125
Willins DL, Deutch AY, Roth BL . (1997): Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27: 79–82
Wright DE, Seroogy KB, Lundgren KH, Davis BM, Jennes L . (1995): Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain. J Comp Neurol 351: 357–373
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This article was prepared with support from the National Institute of Mental Health and the State of Connecticut. Supported by an unrestricted educational grant from Hoechst Marion Roussel.
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Aghajanian, G., Marek, G. Serotonin–Glutamate Interactions: A New Target for Antipsychotic Drugs. Neuropsychopharmacol 21 (Suppl 2), S122–S133 (1999). https://doi.org/10.1016/S0893-133X(99)00106-2
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DOI: https://doi.org/10.1016/S0893-133X(99)00106-2
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