German Journal of Psychiatry
This paper reviews the latest research in the field of the neurobiology of schizophrenia. Particular emphasis is placed on the microanatomical studies showing loss of dendritic spines and loss of neuropil and the studies implicating abnormal redox functions at the glutamate synapse. Particular attention is paid to ketamine and whether it acts as an indirect agonist or an antagonist at the NMDA receptor. There is evidence that oxidative stress plays a role in the disease. The role of catecholamine o-quinones derived from dopamine, noradrenaline and adrenaline in the brain is reviewed. One of these (adrenochrome) was demonstrated forty years ago to be a psychotomimetic agent. Thus these o-quinones may play a role in the illness.
(German J Psychiatry 1998; 1 (2): 24-40)
Received: July 2, 1998
Published August 26, 1998
key words; schizophrenia, glutamate, catecholamine
o-quinones, redox mechanisms, dendritic spines
In recent years research into the biological basis of schizophrenia has focused on anatomical damage and the biochemical mechanisms that may underlie this. At the macroanatomical level there is general agreement that many cases, particularly of type II schizophrenia show enlarged ventricles and cortical atrophy, especially in the temporal lobes and prefrontal cortex (Nopoulos et al, 1995; Lim et al, 1996; Marsh et al, 1997; Ziparsky et al, 1997; Sullivan et al, 1998). Dissenting opinions have been voiced by Dwork (1997: except for enlarged lateral ventricles) and Heckers (1997: no strong clinicopathological correlations). This atrophy appears to be progressive over time in certain cases (DeLisi et al, 1997; Nair et al, 1997; Rapoport, 1997; Gur et al, 1998). Similar changes have been found in the normal siblings of schizophrenic cases (Seidman et al, 1997). A loss of cells in the dorsomedial nucleus of the thalamus has been reported by some (Pakkenberg, 1990; Jones, 1997; Lewis, 1997) but denied by others (Lesch and Bogerts, ; Jernigan et al, 1991: and see Weinberger, 1997). Portas et al (1998) found reduced connectivity between the thalamus and the cortex.
At the microanatomical level the most consistent findings have been a reduction of the neuropil together with a reduction in the number of dendritic spines in the cerebral cortex and striatum (Garey et al, 1995; Glans and Lewis, 1995; Holinger et al, 1995; Selemon et al, 1995, 1998; Roberts et al, 1995; Roberts et al, 1996; Goldman-Rakic and Selemon, 1997; Hirsch et al, 1997; Zaidel et al, 1997). Reports concerning disordered cytoarchitecture in the hippocampus have been conflicting (present - Arnold et al, 1997; Jönsson et al, 1997: absent - Akil and Lewis, 1997; Krimer et al, 1997). Akil and Lewis (1995) also report a reduction in all cortical layers of catecholaminergic axons and terminal boutons in the entorhinal cortex and prefrontal cortex. These microanatomical changes have been described as subtle (Bogerts, 1997; DeLisi et al, 1997).
Earlier work in this field concentrated upon looking for abnormalities in the number or function of receptors for biogenic amines. Now the focus of studies has shifted towards the glutamate synapse and towards 'deeper' aspects of neuronal function such as post-synaptic cascades, the molecular mechanisms of synaptic formation, cohesion and elimination, transcription mechanisms, redox systems and others. Clearly the place to start looking today, in view of the microanatomical evidence listed earlier, is at the mechanisms that are responsible for synaptic growth and deletion, particularly on dendritic spines. It so happens that this system closely involves the glutamate synapse. Interest in the glutamate system arose because it was noted that drugs that act on the NMDA glutamate receptor, such as ketamine and PCP, at low dose produce a model schizophrenic-like psychosis. It would therefore be appropriate to start with an account of the relevant parts of this synapse.
Activation of the NMDA receptor opens a calcium channel which starts a number of post-synaptic cascades. Ca + ions activate a number of neurodestructive proteases and nucleases. They also activate the enzyme phospholipase A2 which converts membrane phospholipids into arachidonic acid (AA). AA in turn activates the enzyme prostaglandin H synthase, the rate-limiting step in prostaglandin synthesis. This activation releases a large amount of reactive oxygen species (ROS) including the superoxide anion and the freely diffusable molecule hydrogen peroxide. Ca++ also activates the enzyme nitric oxide synthase, which process also releases large quantities of ROS and freely diffusible nitric oxide, which, in its dominant nitric oxide radical form, is a pro-oxidant. The free diffusion of H2O2 and NO back into the glutamate synapse would have pro-oxidant neurotoxic effects if it were not balanced by antioxidant defenses. The principle antioxidant defenses at the glutamate synapse are (i) ascorbate which is released into the synapse by the Na+/K+ ATPase-dependent glutamate transporter in exchange for glutamate during the reuptake process which terminates glutamate action, (ii) carnosine which is released together with glutamate from the synaptic vesicle and (iii) probably glutathione. There is also a redox sensitive site on the NMDA receptor protein which upon oxidation down regulates the NMDAr thus serving as protective negative feedback to shut off the source of ROS and RNS. Thus an important factor in the plasticity of the synapse (i.e. whether it grows or is deleted) may be the redox balance inside the synapse between neurotoxic pro-oxidants and neuroprotective antioxidants.
Another important component of the redox balance is likely to be dopamine released from adjacent dopamine boutons-en-passage and diffusing into the glutamate synapse (Smythies, 1997a,b). Dopamine is a potent antioxidant as are all catecholamines. The antioxidant mechanism entails redox cycling between dopamine and dopamine quinone driven by free radical scavenging in one direction and reduction of the dopamine quinone by ambient antioxidants, such as ascorbate and glutathione, in the other direction. This may constitute a basic mechanism underlying learning and neural computation since dopamine release is contingent upon positive reinforcement being received by the organism. Thus dopamine release would tilt the redox balance towards the neuroprotective reductive side and would result in synaptic growth. Lack of dopamine would have the opposite effect. Another mechanism whereby dopamine can alter the redox balance of neurons is the fact that D2 receptor activation leads to increased synthesis of antioxidant proteins -probably superoxide dismutase (Sawada et al, 1998). It is of interest that one effect of nerve growth factor (also involved in synaptic plasticity) is to increase the antioxidant defenses of the neuron by three mechanisms (i) inducing the activity of the antioxidant enzymes glutathione peroxidase and catalase (Goss et al, 1997; Sampath and Perez-Polo, 1997), (ii) lowering ROS production by inhibiting mitochondrial respiration and arachidonic acid metabolism -both potent sources of ROS production (Dugan et al. 1997), and (iii) by inhibiting ROS production by a carpase-linked mechanism (Schulz et al, 1997).
However, the entry of dopamine into the glutamate synapse would carry a risk because, in conditions of reduced antioxidant cover, dopamine can be easily oxidized further than dopamine quinone, either spontaneously or by peroxynitrite (produced by the interaction of NO and the superoxide anion) to form cyclized dopamine o-quinones including the highly toxic free radical o-semiquinone (Smythies, 1997a,b; Smythies and Galzigna, 1998). This also applies to other catecholamines in the brain, namely noradrenaline and possibly adrenaline. The noradrenergic neurons in the locus coeruleus and the C1-C3 neurons in the medulla both contain neuromelanin (Bogert, 1981; Saper and Petito, 1982). However, Gai et al (1993) claim that it is mainly the non-adrenergic pigmented neurons (that presumably contain some other catecholamine) in the C1-C3 group that contain the neuromelanin. But this work was carried out in patients with advanced Parkinsonís disease and needs to be repeated with normal brains. So we can infer that the noradrenergic and dopamine neurons in the brain contain o-quinones, which are obligatory metabolic precursors of neuromelanin. But further work needs to be done on the adrenergic system before we can say that adrenochrome occurs in brain. It is of course possible that adrenaline may be oxidized in brain tissue to form adrenochrome but for some reason this does not lead to neuromelanin formation. One explanation for this may be that a major metabolite of adrenochrome is adrenolutin in which the 3 -OH group is replaced by =O. This cannot form dihydroxyindole which is the necessary precursor for neuromelanin formation. Adrenolutin (but not adrenochrome) has been reported to be present in normal plasma (Dhalla et al. 1989) but no one as yet has looked for it in the brain.
Adrenochrome has been shown to be a psychotomimetic agent (Hoffer et al, 1954, Schwartz et al, 1956; Taubman and Jantz, 1957; Grof, 1963). No such tests have yet been carried out on noradrenochrome or dopaminochrome. The C1-C3 group are thought to be concerned in stress responses and project to the medial thalamus (Phillipson & Bohn. 1994; Otake et al. 1995; Rico & Cavada. 1998) and substantia nigra (Nagatsu et al. 1998). Furthermore phenylethylanolamine N-methyl transferase activity in human brain was found to be high in the RF, hypothalamus and locus coeruleus, and intermediate in the SN, amygdala, septum, periacqueductal grey, and central thalamus (the medial thalamus was not looked at) in a report by Lew et al. 1977). Mefford et al (1978) report that adrenaline levels are high in the medial thalamus as well as the hypothalamus and septum. All this suggests that the medullary adrenergic system may not only be concerned with lower visceral functions in the brain as was once thought, but may powerfully modulate key limbic higher functions in particular those related to stress.
Direct evidence of catecholamine o-quinone production in brain is furnished by the detection of a metabolite of dopamine o-quinone -5-cysteinyl dopamine -by Carlsson et al, (1994). Levels of this compound are raised in the brain in schizophrenia indicating increased auto-oxidation of dopamine by the quinone pathway.
Intraventricular infusions of dopamine in humans every 3 weeks led to the development of paranoid delusions (but no hallucinations or thought disorder) that lasted 2 weeks after each infusion (Kulkarni et al., 1992). This may have been due to over-stimulation of dopamine receptors. It may also have been due to the neurotoxic effects of quinone metabolic products of the dopamine.
Postmortem studies of glutamate receptors have yielded conflicting results:
(i) mRNAs for AMPA receptors subunits R1 and R2 have been reported by one group to be reduced in the hippocampus (Eastwood et al, 1997a), medial temporal lobe (Eastwood et al, 1997b) and in the subiculum and parahippocampal gyrus (Kerwin and Harrison, 1995). The same group also report altered AMPA receptor desensitization kinetics (changes in flip-flop ratios) in remaining R2 subunits (Eastwood et al, 1997a). They conclude that subtle, progressive excitotoxic damage may be involved.í (Eastwood et al, 1997b).
(ii) The same group report an increase in mRNAs for NR1 and NR2A (but not NR2B) subunits of the NMDA receptor in the hippocampus (Beckwith et al. 1995b). Another group (Humphries et al, 1995; Humphries et al, 1996; Hirsch et al, 1997) report a decrease in mRNAs for the NMDA R1 subunit in the superior temporal cortex in cognitively impaired but not unimpaired schizophrenics. Goff and Wine (1997) found that NMDArs have raised levels of 2D subunits, which would result in higher sensitivity to glutamate. They also found more unedited AMPArs, which would increase Ca++ inflow. This data would support increased excitotoxic damage in the disease.
In contrast, Meador-Woodruff et al (1997b) failed to find any abnormality in mRNAs for ionotrophic glutamate receptors in the prefrontal cortex, hippocampus, septum and striatum in schizophrenic brains. A loss of glutamate terminals in the hippocampus and polar temporal cortex (Deakin and Simpson, 1997) and of non-NMDArs in the hippocampus (Beckwith et al, 1995a) have also been reported.
This anesthetic drug is usually described as an antagonist at the glutamate receptor. Therefore, since it produces psychotic reactions at sub-anesthetic doses, schizophrenia has been attributed to underactivity at glutamate synapses. However, glutamate excitotoxicity, which has also been linked to schizophrenia, involves overactivity at glutamate synapses. This led Olner and Farber (1995) to suggest that an early over-activity of glutamate synapses might destroy GABAergic neurons, or NMDArs on their surface, and so lead to disinhibition of glutamate systems downstream. This overlooks the fact that GABArs are continually being synthesized and so a local destruction would have to be continually maintained in order to result in a chronic disease.
However, there is a simpler explanation. Ketamine at subanesthetic doses leads to increased glutamate release and subsequent increased stimulation of AMPA receptors (which open channels that allow ingress of Ca++ as well as Na+) as well possibly of NMDArs not blocked by ketamine at this lower dose -in other words it would act as an indirect AMPA/NMDA agonist at this low dose (Moghaddam et al, 1997; Moghaddam, 1997). Hoffman and McGlashan (1997) also point out that that the dose used in animals (0.5-50 mg/kg) to demonstrate NMDAr antagonism is much larger than the psychotomimetic dose used in humans (0.05-0.1 mg/kg). They suggest that the lesion in schizophrenia may be reduced cortical connectivity rather than receptor dysfunction.
Low doses of ketamine increase 2-DG uptake in the limbic cortex and subcortex, whereas high doses reduce 2-DG uptake globally (Duncan et al, 1998). Low doses of ketamine also promote FOS-L1 induction in limbic cortex (but not in limbic subcortex), whereas high doses lead to a robust increase of FOS-L1 induction (Duncan et al, 1998). These workers suggest that ketamine may produce its psychotomimetic effect by two mechanisms (i) by the one suggested by Olney and Farber (1995) and (ii) by increasing glutamate release. Anesthetic doses of ketamine inhibit glutamate release. The hypothesis that the psychotomimetic effect of ketamine and PCP is due primarily to increased, not decreased, glutamatergic activity is supported by the observation that acute administration of PCP (i) increases the expression of COX-2 mRNA in rat retrosplenial cortex which indicates activation of the post-NMDAr cascade (COX-2 is a part of the PGH synthase complex) (Hashimoto et al, 1997). and (ii) increases the production of mRNA for glutamate dehydrogenase (Shimizu et al, 1997) which these authors suggest is compensatory for increased glutamate release. In monkeys PCP given acutely activates the mesoprefrontal dopamine system (Jentsch et al, 1998) due, these authors suggest, to a decrease in the inhibition of the dopamine system by glutamate. In contrast chronic administration of PCP inhibits DA turnover. Which of these effects is related to the psychotomimetic effects of PCP is unclear.
There is also data from research into the mode of action of antipsychotic drugs on this system to support the hypothesis of an initial over-activity of the glutamate system which could lead to subtle, progressive excitotoxic damage which would result to later underactivity of this damaged system. However, this damage is to replaceable spines and neuropil not to irreplaceable neurons. Lidsky et al (1997) state that low doses of antipsychotic drugs enhance NMDA activity possibly (a) because they block dopamine presynaptic D2 receptors, leading to an increase in extracellular dopamine, which in turn would block glutamate reuptake, resulting in increased intrasynaptic glutamate levels and (b) because dopamine acting post-synaptically at D1 receptors enhances glutamate activated G-protein linked adenylate cyclase activation. This group claims that antipsychotics are NMDA antagonists only at high doses (Lidsky et al, 1997). Bannerjee et al. (1996) state that haloperidol and clozepine are potent augmentors (rather than antagonists) at the NMDAr. In contrast Ilyin et al. (1996) state that haloperidol is an NMDAr blocker (by a direct allosteric effect on the receptor protein) and only at very low doses may potentiate NMDAr activity. Coughenour et al (1997) also support the claim that haloperidol is a non-competitive allosteric antagonist at the NMDAr. Clearly, if antipsychotic agents are NMDA receptor blockers (at the relevant dose), then ketamine is hardly likely to act as an NMDAr antagonist in the production of its psychotomimetic effect..
A complication is introduced by Halberstadt (1995) who claims that haloperidol does not bind to NMDArs but to sigma receptors. Sharp (1997) states that PCP binds to NMDArs (which does not lead to an induction of c-fos production) and to sigma receptors (which results in abundant c-fos production in the cingulate, parietal, and piriform cortex, midline thalamus, hypothalamus, but not in the hippocampus). Thus the binding to sigma receptors might appear to be more important. Sharp (1997) further states that there are no known endogenous ligands for the sigma receptor and its normal physiological function is also unknown. One additional interesting datum is that sigma receptor antagonists (such as rimcazole) block PCP-induced stereotyped behavior and inhibit PCP-induced c-fos production.
Further support for the hypothesis that psychotic reactions are associated, at least at some stage, by over-activity rather than under-activity at NMDA receptors is the reported successful use of the NMDAr antagonist amantadine in the treatment of catatonic schizophrenia (Northoff et al, 1997). Kornhuber et al (1997 and Kroemer et al (1998) have stressed the therapeutic promise of low-affinity uncompetitive NMDA antagonists like amantadine and memantine in protection against glutamate toxicity. Ketamine increases cortical blood flow in the anterior cingulate and right inferior frontal lobe in both schizophrenics and normals and decreases it in the left middle temporal cortex only in schizophrenics (Lahti et al, 1997).
The mixed apoptotic/necrotic effect of chronic administration of PCP is prevented by pretreatment with clozepine (Johnson et al, 1998). The pattern of degeneration produced by PCP follows the distribution of mRNAs for the NR1 subunit of the NMDAr and of dopamine. These authors suggest that the toxic effects of PCP given chronically involves NMDAr overactivity.
To conclude this section, the evidence seems to support the hypothesis that schizophrenia, and the effects of psychotomimetic doses of ketamine, is associated with a shift in the balance of glutamate receptor function towards chronic local excitotoxic over-stimulation of the post-synaptic cascade, and/or the production of excessive amounts of ROS/neurotoxins by this cascade, leading to dynamic damage to the post-synaptic spines and their replacements and so a functional overall underactivity of the excitatory network results (loss of dendritic spines and functional synapses) (Benes, 1995). Based on neural net computer modeling Hoffman and McGlashan (1993) have pointed out that excessive pruning of dendritic spines and reduced cortical connectivity would lead to the formation of parasitic foci in the non-linear dynamical attractor networks of the brain. This leads to bizarre outputs, functionally autonomous sub-populations, and the locking of some modules into cognitive outputs independent of the input, all of which in a real brain could underlie the symptoms seen in schizophrenia. EEG support for this hypothesis has been provided by Lutzenberger et al (1995).
Studies of antioxidant systems in schizophrenia has produced the usual medley of conflicting results. In red blood cells SOD has been reported as lowered (Mahadik and Mukherjee, 1996) and raised (Abdalla et al, 1986; Reddy et al, 1991); GSHpx as lowered (Abdalla et al, 1986) and as normal (Mahadik and Mukherjee, 1996; Reddy et al, 1991); CAT as normal (Mahadik and Mukherjee, 1996) and as lowered (Reddy and Yao, 1996). Buckman et al (1990) report a strong negative correlation between brain atrophy and platelet GSHpx levels. They suggest the hypothesis that low GSHpx levels may constitute a vulnerability factor to oxidative stress. CAT activity in brain is low, and is located mainly in astrocytes. Therefore GSHpx (located mainly in neurons) is important. In the brain Loven et al (1996) found that Mn SOD activity was markedly raised (which would lead to excess production of hydrogen peroxide) in the temporal cortex and frontal cortex of a group of psychotic patients on neuroleptics, but there was no change in Cu/Zn SOD activity. Levels of the blood antioxidants albumin, uric acid and bilirubin are reduced (Yao et al, 1998a,b) and total antioxidant capacity is low (Yao et al, 1998c). These changes are correlated with the clinical severity of the disease. There is evidence that TBARS, a marker of lipid oxidation, is raised in schizophrenia (Mahadik et al, 1998) and that superoxide production by neutrophils is raised (Melamed et al, 1998) both indicating the presence of increased oxidative stress.
The suggestion that schizophrenia may be associated with synaptic malfunction or damage has led to studies of synaptic-associated proteins in post-mortem brains. Reduced levels of synaptophysin have been reported in the prefrontal cortex (Karson et al, 1997; Glantz and Lewis, 1997), and in association cortex (Perrone-Bizzozero et al, 1996) but also denied Browning et al (1993) who reported instead reduced levels of synapsin. Levels of mRNAs coding for synapsin 1A and 1B and synaptophysin have been reported to be raised in the left superior and middle temporal cortex Tcherepanov and Sokolov, 1997). Levels of the synaptic vesicle protein rab3a have been reported to be reduced in the left but not the right thalamus (Blennow et al. 1996) associated with decreased synaptic density. Levels of the neural cell adhesion molecule N-CAM 105-115-kDA are raised in the hippocampus and prefrontal cortex (Vawter et al, 1998). In a study of monozygotic twins discordant for schizophrenia (Poltorak et al, 1997), the schizophrenic twin showed higher CSF levels of N-CAM and lower levels of L1 antigen, with no change in contractin levels. Another study (Honer et al, 1997) N-CAM and syntaxin levels were both reported to be raised. As the latter is found only in conjunction with excitatory terminals, the authors suggest that this finding indicates increased glutamate activity in the cingulate cortex. Cotter et al (1997) report an increase in the expression of non-phosphorylated MAPs in the subiculum suggesting an abnormal assembly of cytoskeletal proteins. GAP-43 levels have been reported to be raised in association cortex (Perrone-Bizzozero et al, 1996) but their mRNAs reduced in selected areas (Eastwood and Harrison, 1998). This protein is involved in the initial establishment and later reorganization of synaptic connections. Similar complexities are revealed by Thompson et al (1998) who measured levels of the synaptosomal associated protein SNAP-25 and found levels to be decreased in the inferior temporal cortex and prefrontal cortex (area 10), increased in the prefrontal cortex (area 9) and normal in area 17.
In view of these conflicting results and the early state of this work it would be premature to try to draw any conclusions. However it is clearly a field of great promise.
NAA/creatine and NAA/choline ratios as obtained by proton magnetic resonance spectroscopy gives a measure of neuronal damage in the living human. These ratios have been reported to be reduced in various brain areas (Bertolino et al, 1996, 1998; Yurgelun-Todd et al, 1996). However, Lim et al (1998) found that in cortical grey matter the NAA signal was normal but the grey matter volume was reduced, whereas in cortical white matter it was the other way round. They suggested that their results indicated abnormal axonal connections.
There is considerable evidence that risk factors for schizophrenia include brain insults during gestation, such as maternal viral infections, starvation, obstetric complications, etc. (see excellent reviews by Wright et al, 1995; Chua and Murray, 1996; Wyatt 1996; and Turner, 1997). Schizophrenia is often accompanied by minor physical abnormalities and abnormal dermatoglyphics (Buckley, 1998).
The literature on alleged abnormalities of DA receptors in schizophrenia is vast and full of contradictions. Halberstadt (1995) says that there is no reliable evidence for the dopamine hypothesis. It seems that previously claimed increases in striatal D1 and D2 receptors were probably due to neuroleptic medication (Knable et al, 1994; Reynolds 1995; Hietala and Syvälahti, 1996), and that D3 and/or D4 receptors may be normal (Lahti et al, 1996; Reynolds and Mason 1994; Helmeste et al, 1996). Previous claims that D4 receptors are increased (Seeman et al, 1993; Marzella et al, 1997) have been criticized on methodological grounds (Meador-Woodruff et al, 1997a) One recent study (Joyce et al 1997) reported that D3 receptors in schizophrenic subjects drug free for one year were increased in the target area of the mesolimbic tract together with an altered laminar distribution of D2 receptors in the temporal lobe. One study actually reported a reduction of D1 receptors in the prefrontal cortex (but not the striatum) related to the severity of negative symptoms (Okubo et al, 1997). Meador-Woodfruff et al (1997a) found a marked reduction of mRNAs for D3 and D4 receptors in orbitofrontal cortex. Opeskin et al, 1996) found that D2 second messenger systems (PKC and adenylate cyclase) were not altered in the striatum in schizophrenia. Sigma receptors however may be reduced (Helmeste et al, 1996).
One group (Goldsmith et al, 1997; Joyce et al, 1997) has reported abnormal detailed cytoarchitectural pattern of D2 receptors in the perirhinal cortex and temporal lobe (but not hippocampus).
Since receptor molecules are continually being replaced, any chronic abnormality in receptor numbers or function is likely to reflect a disorder in the dynamic mechanism of receptor production and matching to loading, including protein synthesis, nuclear transcription, second messengers, etc. Furthermore, even if receptor numbers are found to be increased, or decreased, this may well represent secondary changes to a primary disturbance in some more basic mechanism.
There have also been preliminary and often conflicting claims of malfunction in various other systems - serotonin receptors (Hashimoto et al, 1993; Simpson et al, 1996; Abi-Dargham et al, 1997; Burnet et al, 1996; Gurevich et al, 1997; Hernandez and Sokolov, 1997); the cholinergic system (Garcia-Rill et al, 1995; Dean et al, 1996; Leonard et al, 1996; Karson et al, 1996); mitochondria (Cavelier et al 1995; Whateley et al, 1996a,b); GABA systems (Beasley et al, 1997; Kalus et al, 1997); various polypeptides (e.g. CCK (Bachus et al, 1997), neurotensin (Wolf et al, 1995) and chromgranin (Miller et al, 1996)); melatonin (Monteleone et al, 1997): nitric oxide synthase (Karson et al, 1996); and phospholipids (Gattaz et al, 1987; Keshavan et al, 1993; Peet et al, 1994; George and Spence, 1996; Horrobin, 1996); Yao and Kammen, 1996; Katila et al, 1997; Ross et al, 1997; Volz et al, 1997). Much research has been directed at cytokines and possible autoimmune reactions. Naudin et al (1997) conclude that increased levels of IL-6 are widely accepted but the jury is still out on reported increased levels of TNF. This may reflect a genetic background (Naudin et al, 1997) or a non-specific stress response (Frommberger et al, 1997). Several reports on other cytokines await confirmation. There have also been some preliminary reports of abnormal neuromelanin in schizophrenic brains (see Smythies, 1996 for details). In view of the preliminary and inconsistent nature of all these reports, promising as they are, it is too early to evaluate them.
The transmethylation and one-carbon cycle hypotheses of schizophrenia and affective disorders have recently been reviewed elsewhere (Smythies et al, 1997). The key finding is that enzymes of the one-carbon cycle (MAT and SHMT) are impaired in schizophrenia that would be expected to lead to defective transmethylation mechanisms. It is noteworthy that O-methylation of catecholamine o-hydroquinones is a mechanism that prevents the formation of the toxic free radical o-semiquinone.
This review suggests that the most promising area for future research in schizophrenia are the mechanisms by which abnormal function at the glutamate synapse leads to excessive spine pruning, and loss of neuropil and inter-neural connectivity. These mechanisms may include oxidative stress, the production of neurotoxic catecholamine o-semiquinones, and the loss of trophic factors. These lesions may result in disorders in related mechanisms such as cell-adhesion factors, membrane lipids, receptors, etc.. The following risk factors are suggested (numbers (i)-(iii) have been reported to be present in schizophrenia): -
(i) Reduced antioxidant defenses leading to increased ROS attack on synaptic structures and increased oxidation of catecholamines to form neurotoxic o-quinones.
(ii) Impaired function of COMT leading to increased levels of neurotoxic catecholamine o-semiquinones.
(iii) Defects in the synthesis of neuromelanin.
(iv) Impaired function of the enzyme DT-diaphorase (Segura-Aguilar, personal communication), which converts aminochromes to the nontoxic o-hydroquinones and so inhibits the formation of the o-semiquinone..
(v) Excess action of the cytochrome P450 enzymes that synthesize catecholamine o-semiquinones.
Research programs suggested include studies on: -
(i) the status of neuromelanin in the catecholaminergic neurons in the SN, LC and C1-C3 groups of neurons in the brain in schizophrenia.
(ii) Determining in normal brains if the pigmented neurons of the C1 and C3 groups in the medulla are adrenergic or noradrenergic.
(iii) the details of where catecholamine o-quinones are synthesized in the brain and further details of the pathways involved.
(iv) a search for further metabolites on the neuromelanin pathway, particularly 5,6-dihydroxyindoles and their O-methylated metabolites, as well as 5-cysteinyl and 5-glutathionyl derivatives, in the brain and body fluids and their status in schizophrenia. If the C1 & C3 adrenergic neurons in the medulla do not produce neuromelanin, it would be worth while to see if they do or do not contain 5-cysteinyl adrenaline, or adrenolutin derived from adrenaline and any 0-methylated o-quinone metabolites.
(v) further studies on the enzymology, pharmacology, psychopharmacology, and physiology of catecholamine o-quinones and their metabolites.
(vi) further studies of redox mechanisms at the glutamate synapse and their possible role in normal and abnormal synaptic plasticity.
(vii) further exploration of the role of the adrenergic projection to the medial thalamus and its possible relationship to the action of neuroleptics at this site (Cohen and Wan, 1995).
(viii) further studies of the mechanism of the antioxidant properties of catecholamines.
It is further suggested that any clinical studies should be carried out according to the guide lines laid out by Stevens (1997).
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