Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Biochemical Factors in Schizophrenia Solomon H. Snyder To cite this article: Solomon H. Snyder (1977) Biochemical Factors in Schizophrenia, Hospital Practice, 12:10, 133-140, DOI: 10.1080/21548331.1977.11707215 To link to this article: http://dx.doi.org/10.1080/21548331.1977.11707215
Published online: 06 Jul 2016.
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Date: 11 March 2017, At: 08:31
Biochemical Factors in Schizophrenia soLoMoN H. s N yo E R
Johns Hopkins University
Many false trails have been followed over the years in attempts to associate schizophrenia with biochemical anomalies. Recently it has been found that there is a close correlation between the efficacy of certain neuroleptic agents in the management of the disease and their ability to block CNS receptor sites activated by dopamine. It is suggested that this may be a clue to one of many genetic bases of schizophrenia.
Almost since schizophrenia was first defined in the midnineteenth century, psychiatrists and others have speculated on possible biochemical factors in the disease. The severe and generalized nature of its symptoms su,.ggested the operations of some toxic process, a view that was strengthened by the discovery, around the turn of the twentieth century, that the severe neuropsychiatric disorder general paresis has an organic cause: syphilitic infection of the brain. Perhaps the first systematic work on the biochemistry of schizophrenia involved attempts to isolate abnormal substances in the blood or urine of patients. Thus, for example, a group at Tulane University reported the discovery in the serum of schizophrenics of a protein they called taraxein that was supposedly not present in normal individuals and that could cause hallucinations when injected into normal volunteers. Subsequent attempts to duplicate these findings, however, were unsuccessful: the blood proteins of schizophrenics turned out to be identical with those of normal individuals, apart from changes that could be most easily accounted for by chronic illness and institutionalization. Moreover, the hallucinatory reactions ascribed to taraxein could equally well be produced by a placebo if the latter were given in a similar experimental situation where such effects were suggested to the subjects. Another apparently false lead turned up a few years later, with the discovery of a chromatographic abnormality in the urine of schizophrenics, called, from its staining properties, the pink spot. Some researchers tentatively identified the compound giving rise to the spot as 3,4-dimethoxyphenylamine, a substance related both to the neurotransmitter dopamine and the hallucinogenic drug mescaline. Further work, however, showed that the pink spot was in fact composed of many compounds, its major components being metabolites of the drugs that the patients were taking. The failure of these attempts to demonstrate biochemical abnormalities in schizophrenics strengthened the view
of some psychiatrists - notably, those of the psychodynamic or psychoanalytic school - that the disease was entirely functional in its etiology. More recently, however, the whole question has been reopened with the demonstration that the disease possesses a strong hereditary component. Whether, and to what extent, patterns of behavior or tendencies to behave in a particular way can be transmitted genetically in man or other animals is still a matter of debate. What is not in dispute is thatthe mechanism of transmission must be chemical: the passing from parent to offspring of certain compounds (nucleic-acid sequences) that control the biosynthesis of other compounds (proteins). Inherited abnormalities of either physiology or behavior, in short, imply abnormalities somewhere in the body's protein complement. In the case of behavioral abnormalities, the obvious place to look for aberrant biochemistry is the CNS. Abnor· mal metabolites produced elsewhere in the body can, in· deed, sometimes affect the brain, but many such sub· stances are ruled out of consideration by the blood-brain barrier, which tends to protect the brain from physiologic perturbations elsewhere in the organism. Unfortunately, even limiting our search to the CNS does not help much, since that system - like most others - contains many thou· sands of different chemical species, many still unidentified or of unknown or little-known function. One must therefore approach the problem indirectly and by inference. Attempts to seek clues to abnormalities of the brain by examining the urine are not likely to be productive, since much experimental work has shown that most brain chemicals have little access to the urine. One potentially profitable line of approach is through investigation of the effects ot drugs, notably those that exert selective effects on
Dr. Sn1Jder '' Dtatmguished Servlce Profeuor of PsiJch,atru and PharmacologiJ, The Johns Hopk,ns Un,veraUIJ School of Med'· cme, BalUmore, Md. Hospital Practice Cktol¥r 1977
13]
NH2 CH-COOH CH2
0 OH
OH
OH
OH
Tyrosine
3-hyd roxytyrosi ne (dopa)
Dopamine
Norepinephrine
Diagram• ahow structural similarity of precursors and a break· down product, homo vanillic acid, to dopamine and norepinephrine, the two principal catecholamlnes found in the brain. In ltudlea of biochemical factors that may underlie schizophrenia,
schizophrenic behavior. If a drug can indeed relieve the symptoms of schizophrenia - and only those symptoms then there is at least a fair chance that by learning how the drug works we can secure clues to the biochemical lesion involved in the disease. As is-well known, a number of drugs do selectively relieve symptoms of schizophrenia. These so-called neuroleptic agents are of different molecular structures but fall mainly into two chemical families: the phenothiazines and the butyrophenones. When Jean Delay and Pierre Deniker introduced chlorpromazine, the first of the phenothiazines, into clinical practice in 195%, they expected merely that it would sedate hyperactive patients. They found, howt>·•er, that it could also activate witl.ur&wn schizophrenics and, accordingly, suggested that it was acting selectively on the fundamental schizophrenic abnormality, w.hatever that was. For many years, American physicians treated this conclusion with considerable skepticism. Eventually, however, the two French clinicians' conclusions were confirmed by a number of well-controlled, multi-hospital studies in the Veterans Administration and elsewhere. When the neuroleptics were compared with many other agents that affect mental functioning (notably, sedatives and antianxiety drugs), they proved to be the only compounds that could produce significant overall improvement in schizophrenic behavior and thought. Sedatives could reduce hyperactivity or violent behavior but had no effect on the disordered thinking associated 1 '34
Hospital Practice Cktober 1977
Homovanillic Acid
much emphasis has been given to dopamine because of strong correlations between the clinical effectiveness of many neuroleptic drugs with their ability to block receptor sites in the brain that are activated by dopamine.
with them - and made withdrawn schizophrenics even more withdrawn. The antianxiety agents such as diazepam (Valium) and chlordiazepoxide (Librium), by contrast, proved to be considerably more effective than the neuroleptics in relieving anxiety but exerted no clear beneficial effect on schizophrenia. This latter finding, ill'cidentally, seriously weakened the theory, suggested by some psychologists, that the immediate cause of schizophrenia is an overwhelming "pan-anxiety." Ascertaining the mode of action of neuroleptic drugs, however, has been difficult, since these substances, like many other drugs, are highly reactive and can influence large numbers of biochemical processes not merely in the brain but elsewhere in the body. They can, for example, alter energy metabolism and protein turnover, as well as brain levels of a number of compounds that serve as neurotransmitters. How, then, does one determine which of these effects accounts for the drugs' therapeutic actions in patients with schizophrenia and which are simply irrelevant? One way of tackling this problem is to evaluate a large number of chemically related drugs. The phenothiazines, for example, include numerous agents of similar structure that have been tested in patients; some have proved highly effective in relieving schizophrenic symptoms, some totally ineffective, with many falling into the middle ground between the two extremes. If, then, a given chemical action of these drugs is exerted most potently by the most clinically efficacious
compounds and is least marked in the ineffective ones, one can feel reasonably confident that the action in question is related to the drugs' therapeutic effect. Conversely, if a given chemical action is shared by drugs of widely varying clinical potency, it seems unlikely that it will have much relevance to the biochemistry of schizophrenia. The second principle enables us to exclude a large number of chemical effects. For example, promethazine is closely related in structure to chlorpromazine but is devoid of antischizophrenic activity (it is an effective antihistamine). Yet most of chlorpromazine's biochemical effects are elicited just as potently by promethazine and, therefore, cannot represent chlorpromazine's therapeutic mode of action. This technique of elimination has over the years revealed only one biochemical action that consistently correlates closely with the clinical effects of large numbers of neuroleptics: the apparent ability of some neuroleptics to blockade receptor sites in the brain that are activated by the neurotransmitter dopamine. To evaluate these findings, however, we must first consider what dopamine is and what, so far as we know, it does. Dopamine is one of the body's three principal catecholamines (catechol referring to a benzene ring with two attached hydroxyl groups and amine referring to the presence of an amino [- NH,] group in the molecule), the other two being norepinephrine and epinephrine. Only dopamine and norepinephrine are found in the brain to any great extent, epinephrine exert-
ing its activity mainly on the peripheral nervous system. The ultimate (dietary) progenitor of dopamine in the body is the amino acid tyrosine, which is transformed successively into dihydroxyphenylalanine (dopa) and then into dopamine itself. In most parts of the brain, dopamine is then further transformed into ~orepinephrine by the action of the enzyme dopamine hydroxylase. In some areas, however, the enzyme is missing, meaning that dopamine rather than norepinephrine must serve as the neurotransmitter. The best known of these areas involves neurons in the substantia nigra with axonal terminals in the corpus striatum, which includes the caudate nucleus and putamen; the neurons act by releasing dopamine at the terminals. The neurons are selectively destroyed (by unknown causes) in patients with idiopathic Parkinson's disease. As is well known,.parkinsonian symptoms can be dramatically alleviated by administering the dopamine precursdr, L-dopa, indicating that dopamine depletion is causally related to the disease. Significantly, the neuroleptic drugs themselves can produce extrapyramidal, parkinsonianlike symptoms, but presumably by blocking the dopamine receptors rather than by engendering the depletion of dopamine. Other dopaminergic pathways are probably more important in schizophrenia. We know, for example, that pathways with neurons close to the substantia nigra project to the nucleus accumbens and the olfactory tubercle; both of these are components of the limbic system of the brain, which, significantly, regulates emotional behavior. Other, more recently described, dopaminergic pathways run from the same area to parts of the frontal, cingulate, and entorhinal cortex, which, though anatomically part of the brain's cortical associative centers, have been functionally linked to the limbic system. It is reasonable, therefore, that abnormalities in these dopaminergic pathways would induce emotional abnormalities that neuroleptic drugs, by further changing the pathways' functioning, would alleviate or abolish. But how does one demonstrate that neuroleptics do in fact act on the dopaminergic system? Specifi-
cally, can it be shown that they bind to dopamine receptor sites on the target neurons? The earliest findings in this area were obtained by the Swedish pharmacologist Arvid Carlsson. Frc>m a number of animal experiments with neuroleptic drugs, he had concluded that the behavioral changes observed seemed most consistent with a depletion of dopamine. However, when he measured brain levels of dopamine breakdown products (e.g., homovanillic acid), he found that the neuroleptic 4rugs actually increased these levels, implying an increase rather than a decrease in dopamine. To reconcile this finding with the animal behavioral data, Carlsson hypothesized that the rise was a secondary effect, resulting from biochemical feedback ..That is, the drugs blocked dopamine receptors, which in turn stimulated the dopamine-releasing cells to fire more frequently, thereby producing the ob-
served excess of the neurohumor. Many subsequent experiments, both pharmacologic and neurophysiologic, have demonstrated conclusively that the neuroleptics do indeed accelerate the firing of dopamine-releasing neurons. Demonstrating that they also block the receptor sites, however, has proved much more difficult, and for a long time much of the evidence was indirect. There was, for example, the matter of the extrapyramidal (parkinsonian) side effects frequently seen with neuroleptics, which it has become increasingly clear must be due to interference with some dopaminergic pathway. And since the drugs were clearly not blocking dopamine production or release (as occurs in Parkinson's disease itself), the obvious alternative was that they were interfering with its reception. In this connection it has been observed that schizophrenic patients treated with neuroleptics who do not
Although dopamCne Is tranrformed to norepCnephnne In mod part.s of the brain, fn othlrs the conllertlng enzvme Ia ml11mg and dopamme Itself aerves ar neurotranrmiHer. The dopamlnergCc pathwav• thought mort llkel11 to be fnvollled fn rchlzophrenfa ore auauted mthe drawing; thev ore component• of, or lmked funcllonallv to, the Umble avrtem, which Ia known to plov a dgrdjicant I'IIUlatof!l role fn emotional behaiJior. Hospital Practice Oclobtr 1977
1 'J5
Support for concept that neurolepUc drugs ameliorate achb:ophren•a bv block,ng receptor~ /or dopamme, thw reducmg U•/unct•onallevel at certam bram sUes, comes also from the find•ng of an exacerbaUng effect on the dbease bv drugs, e.g., the amphetammll, that •Umulate dopamme release or preoent ''' reuptake bv the neroe term,nal. develop extrapyramidal side effects tend to have much higher levels of dopamine breakdown products in the spinal ftuid than those who show such effects. This suggests that the feedback effect that Carlsson postulated does indeed liberate excess dopamine, which in turn prevents the appearance of parkinsonian symptoms. One might then wonder, however, how it is that the patients respond at all to the -drugs. That is, if the excess dopamine liberated is sufficient to pre\'ent the extrapyramidal symptoms, why is it not also sufficient to cancel t 16
Hospital Prat:tice October
1977
any therapeutic effect of the drugs elsewhere in the brain? Delay and Deniker, in fact, postulated just such a relationship; they believed that unless the patient showed a neurologic (extrapyramidal) response to the drug, he would derive no therapeutic benefit. Subsequently, however, it has become clear that this relationship between therapeutic benefit and side effects need not obtain - that the neurologic and emotional effects of the drugs do not correlate perfectly. The reason has to do with various other pharmacologic properties of the drugs that
we do not have space to detail here. One might note, however, that an overcompensation to neuroleptics, by release of excess dopamine, may explain why some schizophrenics fail to respond to the drugs. Another line of evidence on the mode of action of the neuroleptics came from studies of other, quite different, drugs. If the neuroleptics control schizophrenia by blocking dopamine receptors, thereby functionally reducing dopamine levels at certain sites in the brain, one would expect that drugs that increased dopamine levels at these sites would exacerbate the disease. As it happens, the amphetamines exert their clinical actions by increasing the amount of both norepinephrine and dopamine in the synaptic cleft. It has been found that even in very low doses these stimulants can dramatically exacerbate the symptoms of schizophrenic patients. Yet they do not exert such effects on patients with other emotional disorders (e.g., mania, depression)· nor on normal individuals at low doses. Experiments using different amphetamine analogues, with differential effects on the dopamine and norepinephrine systems, indicate that the exacerbation is more likely to be mediated through the former rather than the latter. One would expect, too, that L-dopa, which is used routinely in parkinsonian patients to raise dopamine levels, would also worsen schizophrenic symptoms, and in fact several clinical studies have shown that it does. It is important to note, by the way, that neither the amphetamines nor Ldopa in any way superimpose a different psychosis on the schizophrenic; rather, they exacerbate the pll!tient's own constellation of symptoms: a he, bephrenic patient becomes more hebephrenic, a catatonic more catatonic, and so on. If amphetamines and L-dopa can exacerbate the symptoms of schizophrenics by engendering an excess of dopamine, one might expect that in large enough doses they could induce psychotic symptoms even in nonschizophrenic individuals. So far as the amphetamines, at least, are concerned, this is the case. Amphetamine addicts - especially the "speed freaks"
who take the drug intravenously - often administer themselves doses of up to 500 mg, or 50 times the normal therapeutic dose. Such individuals will almost invariably, at one time or another, develop acute paranoid psychosis that can be clinically indistinguishable from acute paranoid schizophrenia. There are, indeed, numerous reports of individuals admitted to psychiatric hospitals with a diagnosis of schizophrenia that had to be revised when the history of drug abuse became known. Cocaine, which is believed to facilitate the actions of the catecholamines, can produce a very similar type of psychosis - an observation summed up by a famous jazz musician as, "If you aren't crazy before you take it, you're crazy afterward." The use of amphetamine or cocaine psychosis as a model for schizophrenia has been attacked on the ground that such individuals do \lot display all the abnormalities of thought and action typical of schizophrenia. Moreover, amphetamine psychosis is invariably paranoid in form, whereas paranoid schizophrenia is merely one type of the disease. Such objections do not seem to me necessarily fatal. For one thing, one can see the pathology of amphetamine psychosis as similar to that of schizophrenia without regarding them as identical. For another, the fact that amphetamine is acting in a nonschizophrenic who "knows" that the episode is likely to be transient should in itself make for major differences. The schizophrenic, by contrast, has been experiencing a more or less abnormal mental state for months or (usually) years, with littl~ or no hope of major relief. Nonetheless, all these lines of indirect evidence, while ·certainly persuasive, fall considerably short of hard proof that schizophrenia is linked to some disorder in the brain's dopaminergic pathways. For this reason, I and my associates Ian Creese and David Burt have attempted to obtain more direct evidence by studying the binding of neuroleptic dru~s to dopaminebinding sites in brain tissue. As is well known, many hormones, neurotransmitters, and other physiologically active substances produce their effects by binding to specific sites on the exterior (plasma) membranes
Caudal Caudate
Rostral Caudate
Globus Pallid us
Anterior Putamen
Olfactory Tubercle
Evidence that the dopamine receptor e:dsts in two states (i.e., with selective affinitv, respectivelv, for agonist and antagonist compounds of a given tvpe) was obtained in binding experiments. As seen in graph above, testing sections of calf brain with labeled dopamine and a labeled antagonist, haloperidol, showed that the .tame brain areas bind both subatances and do so in similar proportion• (in other parta of the brain neither (I bound). At the same time, testing the abilitv of agonist and antagonbt to inhibit binding of each other indicated that thev do not btnd to the same lite~ within the given locus. Graph below shows that dopamine tnhtblts dopamine btndtng much more than haloperidol bindIng, and vtce versa. Apomorphine, an agonist, has similar effects to dopamine's; fluphenazine, an antagonist, has effect• similar to haloperidol's. The mb:ed agonirt· antagonist, d-LSD, inhtbtts binding of both dopamine and haloperidol. 1,000 t• Dopamine
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Hoapital Practice Octobtr 1977
137
of their target cells, by which process they activate other processes in the cell interior by means of a "second messenger" substance such as cyclic AMP. Often the action of these substances can be antagonized by other compounds which, by themselves binding to the same membrane sites, block the action of the active, or agonist, substance. Such systems are often visualized in terms of a "lock-andkey" model: the binding site is the lock, the agonist compound the key, while the antagonist is an "incorrectly cut" key that cannot turn the Jock, but by filling the keyhole can prevent insertion of the correct key. Identification of neurotransmitter receptors is a very young science, dating only from about 1970, when several groups succeeded in isotopically labeling a particular type of acetylcholine receptor in certain invertebrates. Further progress in the area was hampered by the fact that both neurotransmitters and their antagonists are rather loosely bound to the receptor sites, meaning that it is hard to distinguish specific binding there from nonspecific adsorption. Only recently has this problem been overcome - by using low concentrations of binding substance with high levels of radioactivity plus rapid but vigorous washing of the tissues to remove the nonspecifically bound molecules. A number of exp~riments using this technique have indicated that for many brain receptor sites, at least, the lock-and-key model is an oversimplification. Rather, it appears that the receptor site exists in two states, one with selective affinity for agonist compounds of a given type, the other with similar affinity for the appropriate antagonists. The evidence supporting this view is too complex to detail here, but It includes, for example, the observation that the physiologic potency of antagonists of a particular class often doe1 not correlate well with their capacity to displace an agonist from the binding tite (as would be the case in the simple lock-and-key model), though it correlates very well with their capacity to displace other antagoni•ts. The two-state model also explains how compounds with no structund similarity to the agonist can still act as antagonists, and how other l J8
Hoepital Practice Octolwr 1977
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Bmding studies have provided a method of rankmg antlschizophrenic drugs according to potencu. Graph on this page shows a correlation coefficient of .94 between affinttu for
compounds can exert both types of effect- antagonist and agonist- simultaneously. It appears that the two states can in many cases be converted into one another, though in most cases we do not know how or why conversion occurs. With the opiate receptor, however, it has been shown that it binds opiates (agonists) much more effectively in the absence of sodium ion, while opiate antagonists are bound selectively when the ion is present. Exactly how this two-state model should be visualized at the molecular level is still uncertain and will probably remain so until someone succeeds in actually determining the structure of a receptor site. It may involve a stereochemical change in the receptor, as is the case with, for example, the visual pigments in their response to light. Alternatively, it may involve two adjacent molecules or adjacent sites on the same molecule. One of these might selectively bind agonists, the other, antagonists, and the molecules could be so arranged that the occupation of either site (or molecule) desensitizes
the other to the action of "its" compound. Additional models are also possible, but in the present state of knowledge there seems little point in speculating about them. A good deal of evidence obtained in our laboratory indicates that the dopamine receptors operate according to the two-state model. To begin with, labeling experiments show clearly that both dopamine and its antagonists bind to the same portions of the brain and, moreover, that the amount of binding in different areas is in the same proportion. For example, when sections of calf brain are tested with labeled dopamine and a labeled antagonist, haloperidol (an antischizophrenic drug), the greatest amount of binding for both drugs is in the caudal caudate region. The next highest amount is in the rostral cimdate, with 76% (of the maximum caudal caudate level) for haloperidol and 90% for dopa· mine. Levels are lower in the globus pallidus, anterior putamen, and olfactory tubercle, which for both drugs show about 6o%, 50%, and 40% to 45% of the maximum, respectively.
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haloperidol binding sUes and phannacologlc effecttvenen in animala. Con-elatton wtth potencv in achtzophrenla is almost as high, .84 (graph above).
A second point is that the binding in question does not involve presynaptic dopamine receptors, though these are known to exist. This can be demonstrated by injecting the compound 6hydroxydopamine into the substantia nigra of the rat brain, thereby destroying nearly all the dopamine-releasing presynaptic nerve terminals. Such treatment does not reduce binding of either dopamine or haloperidol. Thus, it seems clear that both drugs bind in the same locus (postsynaptic receptors) in the same parts of the brain and in the same proportions. Yet when we test their ability to inhibit binding of each other, and of other agonists and antagonists, it seems equally clear that they are not binding to the same sites. Thus, dopamine inhibits dopamine binding 30 times more effectively than it does haloperidol binding, while haloperidol inhibits haloperidol binding far more effectively than it does dopamine binding. (The difference in the latter situation is on the order of 300 to 1.) Apomorphine, an agonist (i.e., its physiologic effects resemble those of dopamine),
inhibits dopamine binding more than it does haloperidol binding. Fluphenazine, an antagonist, inhibits haloperidol binding more effectively than dopamine binding. Finally, d-LSD, which physiologically shows both agonistic and antagonistic effects in relation to dopamine, inhibits binding of both compounds. On the basis of these findings, we have ranked a whole series of antis,:hiwphrenic drugs by their ability to inhibit haloperidol binding, by their ability to antagonize the action of apomorphine and amphetamine in animals, by the average clinical dose, and by their ability to inhibit dopamine binding. The in vivo animal potency of the drugs correlates almost perfectly with their haloperidol-binding inhibition, with correlation coefficients averaging .94, and the correlation is almost as good for the clinical potency (.84). Ranked against dopamine-binding inhibition, however, the correlation is only moderately good (. s8). (The nature of correlation coefficients makes this figure much "worse" than .94, considerably more so than the raw
numerical difference would suggest.) These findings, we believe, provide strong evidence that the brain's dopaminergic pathways are involved in the therapeutic effects of neuroleptics in schizophrenia, and also that the dopamine postsynaptic receptor indeed exists in the two-state form. The haloperidol-binding inhibition test, moreover, provides a quick and cheap method for screening new antischizophrenic drugs, requiring only a few micrograms of the drug and a few milligrams of brain tissue; up to 100 drugs can be screened in a morning. Thus, the two most clinically potent antischizophrenic drugs, spiroperidol and benperidol, rank first and second in hal~peridol-binding inhibition but 16th and ztst (out of zs) in dopaminebinding inhibition, while (+)-butadamol, the top drug for inhibiting dopamine binding, ranks only 15th in clinical potency. However, more efficient drug screening, though certainly a benefidal side effect of our experiments, was not the main goal of these studies, which was rather to elucidate the biochemistry of schizophrenia. As indicated above, the studies are consistent with the dopamine theory of schizophrenia but have by no means demonstrated that the brain defect in that disease in\'olves dopamine itself. This somewhat paradoxical conclusion may perhaps be clarified by an electrical analogy: the fact that a dangerous short circuit can be abolished by tripping the appropriate circuit breaker does not mean that the short is in the breaker - it may be anywhere in the circuit. Equally, the fact that schizophrenic symptoms can be ameliorated, by "breaking" the dopaminergic pathways of the brain (by administering dopamine antagonists) need not imply that the symptoms' primary cause is some defect in release or reception of that substance. One should emphasize that the dopamine mediation of the therapeutic actions of neuroleptics does not necessarily mean that dopamine synapses are disturbed in schizophrenia. Possible schizophrenic abnormalities might involve systems several steps distant, but which can be modulated by changes in dopamine transmission. If dopamine systems are in fact abHospit•l Practice Octobfr
lfl77
139
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ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Biochemical Factors in Schizophrenia Solomon H. Snyder To cite this article: Solomon H. Snyder (1977) Biochemical Factors in Schizophrenia, Hospital Practice, 12:10, 133-140, DOI: 10.1080/21548331.1977.11707215 To link to this article: http://dx.doi.org/10.1080/21548331.1977.11707215
Published online: 06 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [FU Berlin]
Date: 11 March 2017, At: 08:31
Biochemical Factors in Schizophrenia soLoMoN H. s N yo E R
Johns Hopkins University
Many false trails have been followed over the years in attempts to associate schizophrenia with biochemical anomalies. Recently it has been found that there is a close correlation between the efficacy of certain neuroleptic agents in the management of the disease and their ability to block CNS receptor sites activated by dopamine. It is suggested that this may be a clue to one of many genetic bases of schizophrenia.
Almost since schizophrenia was first defined in the midnineteenth century, psychiatrists and others have speculated on possible biochemical factors in the disease. The severe and generalized nature of its symptoms su,.ggested the operations of some toxic process, a view that was strengthened by the discovery, around the turn of the twentieth century, that the severe neuropsychiatric disorder general paresis has an organic cause: syphilitic infection of the brain. Perhaps the first systematic work on the biochemistry of schizophrenia involved attempts to isolate abnormal substances in the blood or urine of patients. Thus, for example, a group at Tulane University reported the discovery in the serum of schizophrenics of a protein they called taraxein that was supposedly not present in normal individuals and that could cause hallucinations when injected into normal volunteers. Subsequent attempts to duplicate these findings, however, were unsuccessful: the blood proteins of schizophrenics turned out to be identical with those of normal individuals, apart from changes that could be most easily accounted for by chronic illness and institutionalization. Moreover, the hallucinatory reactions ascribed to taraxein could equally well be produced by a placebo if the latter were given in a similar experimental situation where such effects were suggested to the subjects. Another apparently false lead turned up a few years later, with the discovery of a chromatographic abnormality in the urine of schizophrenics, called, from its staining properties, the pink spot. Some researchers tentatively identified the compound giving rise to the spot as 3,4-dimethoxyphenylamine, a substance related both to the neurotransmitter dopamine and the hallucinogenic drug mescaline. Further work, however, showed that the pink spot was in fact composed of many compounds, its major components being metabolites of the drugs that the patients were taking. The failure of these attempts to demonstrate biochemical abnormalities in schizophrenics strengthened the view
of some psychiatrists - notably, those of the psychodynamic or psychoanalytic school - that the disease was entirely functional in its etiology. More recently, however, the whole question has been reopened with the demonstration that the disease possesses a strong hereditary component. Whether, and to what extent, patterns of behavior or tendencies to behave in a particular way can be transmitted genetically in man or other animals is still a matter of debate. What is not in dispute is thatthe mechanism of transmission must be chemical: the passing from parent to offspring of certain compounds (nucleic-acid sequences) that control the biosynthesis of other compounds (proteins). Inherited abnormalities of either physiology or behavior, in short, imply abnormalities somewhere in the body's protein complement. In the case of behavioral abnormalities, the obvious place to look for aberrant biochemistry is the CNS. Abnor· mal metabolites produced elsewhere in the body can, in· deed, sometimes affect the brain, but many such sub· stances are ruled out of consideration by the blood-brain barrier, which tends to protect the brain from physiologic perturbations elsewhere in the organism. Unfortunately, even limiting our search to the CNS does not help much, since that system - like most others - contains many thou· sands of different chemical species, many still unidentified or of unknown or little-known function. One must therefore approach the problem indirectly and by inference. Attempts to seek clues to abnormalities of the brain by examining the urine are not likely to be productive, since much experimental work has shown that most brain chemicals have little access to the urine. One potentially profitable line of approach is through investigation of the effects ot drugs, notably those that exert selective effects on
Dr. Sn1Jder '' Dtatmguished Servlce Profeuor of PsiJch,atru and PharmacologiJ, The Johns Hopk,ns Un,veraUIJ School of Med'· cme, BalUmore, Md. Hospital Practice Cktol¥r 1977
13]
NH2 CH-COOH CH2
0 OH
OH
OH
OH
Tyrosine
3-hyd roxytyrosi ne (dopa)
Dopamine
Norepinephrine
Diagram• ahow structural similarity of precursors and a break· down product, homo vanillic acid, to dopamine and norepinephrine, the two principal catecholamlnes found in the brain. In ltudlea of biochemical factors that may underlie schizophrenia,
schizophrenic behavior. If a drug can indeed relieve the symptoms of schizophrenia - and only those symptoms then there is at least a fair chance that by learning how the drug works we can secure clues to the biochemical lesion involved in the disease. As is-well known, a number of drugs do selectively relieve symptoms of schizophrenia. These so-called neuroleptic agents are of different molecular structures but fall mainly into two chemical families: the phenothiazines and the butyrophenones. When Jean Delay and Pierre Deniker introduced chlorpromazine, the first of the phenothiazines, into clinical practice in 195%, they expected merely that it would sedate hyperactive patients. They found, howt>·•er, that it could also activate witl.ur&wn schizophrenics and, accordingly, suggested that it was acting selectively on the fundamental schizophrenic abnormality, w.hatever that was. For many years, American physicians treated this conclusion with considerable skepticism. Eventually, however, the two French clinicians' conclusions were confirmed by a number of well-controlled, multi-hospital studies in the Veterans Administration and elsewhere. When the neuroleptics were compared with many other agents that affect mental functioning (notably, sedatives and antianxiety drugs), they proved to be the only compounds that could produce significant overall improvement in schizophrenic behavior and thought. Sedatives could reduce hyperactivity or violent behavior but had no effect on the disordered thinking associated 1 '34
Hospital Practice Cktober 1977
Homovanillic Acid
much emphasis has been given to dopamine because of strong correlations between the clinical effectiveness of many neuroleptic drugs with their ability to block receptor sites in the brain that are activated by dopamine.
with them - and made withdrawn schizophrenics even more withdrawn. The antianxiety agents such as diazepam (Valium) and chlordiazepoxide (Librium), by contrast, proved to be considerably more effective than the neuroleptics in relieving anxiety but exerted no clear beneficial effect on schizophrenia. This latter finding, ill'cidentally, seriously weakened the theory, suggested by some psychologists, that the immediate cause of schizophrenia is an overwhelming "pan-anxiety." Ascertaining the mode of action of neuroleptic drugs, however, has been difficult, since these substances, like many other drugs, are highly reactive and can influence large numbers of biochemical processes not merely in the brain but elsewhere in the body. They can, for example, alter energy metabolism and protein turnover, as well as brain levels of a number of compounds that serve as neurotransmitters. How, then, does one determine which of these effects accounts for the drugs' therapeutic actions in patients with schizophrenia and which are simply irrelevant? One way of tackling this problem is to evaluate a large number of chemically related drugs. The phenothiazines, for example, include numerous agents of similar structure that have been tested in patients; some have proved highly effective in relieving schizophrenic symptoms, some totally ineffective, with many falling into the middle ground between the two extremes. If, then, a given chemical action of these drugs is exerted most potently by the most clinically efficacious
compounds and is least marked in the ineffective ones, one can feel reasonably confident that the action in question is related to the drugs' therapeutic effect. Conversely, if a given chemical action is shared by drugs of widely varying clinical potency, it seems unlikely that it will have much relevance to the biochemistry of schizophrenia. The second principle enables us to exclude a large number of chemical effects. For example, promethazine is closely related in structure to chlorpromazine but is devoid of antischizophrenic activity (it is an effective antihistamine). Yet most of chlorpromazine's biochemical effects are elicited just as potently by promethazine and, therefore, cannot represent chlorpromazine's therapeutic mode of action. This technique of elimination has over the years revealed only one biochemical action that consistently correlates closely with the clinical effects of large numbers of neuroleptics: the apparent ability of some neuroleptics to blockade receptor sites in the brain that are activated by the neurotransmitter dopamine. To evaluate these findings, however, we must first consider what dopamine is and what, so far as we know, it does. Dopamine is one of the body's three principal catecholamines (catechol referring to a benzene ring with two attached hydroxyl groups and amine referring to the presence of an amino [- NH,] group in the molecule), the other two being norepinephrine and epinephrine. Only dopamine and norepinephrine are found in the brain to any great extent, epinephrine exert-
ing its activity mainly on the peripheral nervous system. The ultimate (dietary) progenitor of dopamine in the body is the amino acid tyrosine, which is transformed successively into dihydroxyphenylalanine (dopa) and then into dopamine itself. In most parts of the brain, dopamine is then further transformed into ~orepinephrine by the action of the enzyme dopamine hydroxylase. In some areas, however, the enzyme is missing, meaning that dopamine rather than norepinephrine must serve as the neurotransmitter. The best known of these areas involves neurons in the substantia nigra with axonal terminals in the corpus striatum, which includes the caudate nucleus and putamen; the neurons act by releasing dopamine at the terminals. The neurons are selectively destroyed (by unknown causes) in patients with idiopathic Parkinson's disease. As is well known,.parkinsonian symptoms can be dramatically alleviated by administering the dopamine precursdr, L-dopa, indicating that dopamine depletion is causally related to the disease. Significantly, the neuroleptic drugs themselves can produce extrapyramidal, parkinsonianlike symptoms, but presumably by blocking the dopamine receptors rather than by engendering the depletion of dopamine. Other dopaminergic pathways are probably more important in schizophrenia. We know, for example, that pathways with neurons close to the substantia nigra project to the nucleus accumbens and the olfactory tubercle; both of these are components of the limbic system of the brain, which, significantly, regulates emotional behavior. Other, more recently described, dopaminergic pathways run from the same area to parts of the frontal, cingulate, and entorhinal cortex, which, though anatomically part of the brain's cortical associative centers, have been functionally linked to the limbic system. It is reasonable, therefore, that abnormalities in these dopaminergic pathways would induce emotional abnormalities that neuroleptic drugs, by further changing the pathways' functioning, would alleviate or abolish. But how does one demonstrate that neuroleptics do in fact act on the dopaminergic system? Specifi-
cally, can it be shown that they bind to dopamine receptor sites on the target neurons? The earliest findings in this area were obtained by the Swedish pharmacologist Arvid Carlsson. Frc>m a number of animal experiments with neuroleptic drugs, he had concluded that the behavioral changes observed seemed most consistent with a depletion of dopamine. However, when he measured brain levels of dopamine breakdown products (e.g., homovanillic acid), he found that the neuroleptic 4rugs actually increased these levels, implying an increase rather than a decrease in dopamine. To reconcile this finding with the animal behavioral data, Carlsson hypothesized that the rise was a secondary effect, resulting from biochemical feedback ..That is, the drugs blocked dopamine receptors, which in turn stimulated the dopamine-releasing cells to fire more frequently, thereby producing the ob-
served excess of the neurohumor. Many subsequent experiments, both pharmacologic and neurophysiologic, have demonstrated conclusively that the neuroleptics do indeed accelerate the firing of dopamine-releasing neurons. Demonstrating that they also block the receptor sites, however, has proved much more difficult, and for a long time much of the evidence was indirect. There was, for example, the matter of the extrapyramidal (parkinsonian) side effects frequently seen with neuroleptics, which it has become increasingly clear must be due to interference with some dopaminergic pathway. And since the drugs were clearly not blocking dopamine production or release (as occurs in Parkinson's disease itself), the obvious alternative was that they were interfering with its reception. In this connection it has been observed that schizophrenic patients treated with neuroleptics who do not
Although dopamCne Is tranrformed to norepCnephnne In mod part.s of the brain, fn othlrs the conllertlng enzvme Ia ml11mg and dopamme Itself aerves ar neurotranrmiHer. The dopamlnergCc pathwav• thought mort llkel11 to be fnvollled fn rchlzophrenfa ore auauted mthe drawing; thev ore component• of, or lmked funcllonallv to, the Umble avrtem, which Ia known to plov a dgrdjicant I'IIUlatof!l role fn emotional behaiJior. Hospital Practice Oclobtr 1977
1 'J5
Support for concept that neurolepUc drugs ameliorate achb:ophren•a bv block,ng receptor~ /or dopamme, thw reducmg U•/unct•onallevel at certam bram sUes, comes also from the find•ng of an exacerbaUng effect on the dbease bv drugs, e.g., the amphetammll, that •Umulate dopamme release or preoent ''' reuptake bv the neroe term,nal. develop extrapyramidal side effects tend to have much higher levels of dopamine breakdown products in the spinal ftuid than those who show such effects. This suggests that the feedback effect that Carlsson postulated does indeed liberate excess dopamine, which in turn prevents the appearance of parkinsonian symptoms. One might then wonder, however, how it is that the patients respond at all to the -drugs. That is, if the excess dopamine liberated is sufficient to pre\'ent the extrapyramidal symptoms, why is it not also sufficient to cancel t 16
Hospital Prat:tice October
1977
any therapeutic effect of the drugs elsewhere in the brain? Delay and Deniker, in fact, postulated just such a relationship; they believed that unless the patient showed a neurologic (extrapyramidal) response to the drug, he would derive no therapeutic benefit. Subsequently, however, it has become clear that this relationship between therapeutic benefit and side effects need not obtain - that the neurologic and emotional effects of the drugs do not correlate perfectly. The reason has to do with various other pharmacologic properties of the drugs that
we do not have space to detail here. One might note, however, that an overcompensation to neuroleptics, by release of excess dopamine, may explain why some schizophrenics fail to respond to the drugs. Another line of evidence on the mode of action of the neuroleptics came from studies of other, quite different, drugs. If the neuroleptics control schizophrenia by blocking dopamine receptors, thereby functionally reducing dopamine levels at certain sites in the brain, one would expect that drugs that increased dopamine levels at these sites would exacerbate the disease. As it happens, the amphetamines exert their clinical actions by increasing the amount of both norepinephrine and dopamine in the synaptic cleft. It has been found that even in very low doses these stimulants can dramatically exacerbate the symptoms of schizophrenic patients. Yet they do not exert such effects on patients with other emotional disorders (e.g., mania, depression)· nor on normal individuals at low doses. Experiments using different amphetamine analogues, with differential effects on the dopamine and norepinephrine systems, indicate that the exacerbation is more likely to be mediated through the former rather than the latter. One would expect, too, that L-dopa, which is used routinely in parkinsonian patients to raise dopamine levels, would also worsen schizophrenic symptoms, and in fact several clinical studies have shown that it does. It is important to note, by the way, that neither the amphetamines nor Ldopa in any way superimpose a different psychosis on the schizophrenic; rather, they exacerbate the pll!tient's own constellation of symptoms: a he, bephrenic patient becomes more hebephrenic, a catatonic more catatonic, and so on. If amphetamines and L-dopa can exacerbate the symptoms of schizophrenics by engendering an excess of dopamine, one might expect that in large enough doses they could induce psychotic symptoms even in nonschizophrenic individuals. So far as the amphetamines, at least, are concerned, this is the case. Amphetamine addicts - especially the "speed freaks"
who take the drug intravenously - often administer themselves doses of up to 500 mg, or 50 times the normal therapeutic dose. Such individuals will almost invariably, at one time or another, develop acute paranoid psychosis that can be clinically indistinguishable from acute paranoid schizophrenia. There are, indeed, numerous reports of individuals admitted to psychiatric hospitals with a diagnosis of schizophrenia that had to be revised when the history of drug abuse became known. Cocaine, which is believed to facilitate the actions of the catecholamines, can produce a very similar type of psychosis - an observation summed up by a famous jazz musician as, "If you aren't crazy before you take it, you're crazy afterward." The use of amphetamine or cocaine psychosis as a model for schizophrenia has been attacked on the ground that such individuals do \lot display all the abnormalities of thought and action typical of schizophrenia. Moreover, amphetamine psychosis is invariably paranoid in form, whereas paranoid schizophrenia is merely one type of the disease. Such objections do not seem to me necessarily fatal. For one thing, one can see the pathology of amphetamine psychosis as similar to that of schizophrenia without regarding them as identical. For another, the fact that amphetamine is acting in a nonschizophrenic who "knows" that the episode is likely to be transient should in itself make for major differences. The schizophrenic, by contrast, has been experiencing a more or less abnormal mental state for months or (usually) years, with littl~ or no hope of major relief. Nonetheless, all these lines of indirect evidence, while ·certainly persuasive, fall considerably short of hard proof that schizophrenia is linked to some disorder in the brain's dopaminergic pathways. For this reason, I and my associates Ian Creese and David Burt have attempted to obtain more direct evidence by studying the binding of neuroleptic dru~s to dopaminebinding sites in brain tissue. As is well known, many hormones, neurotransmitters, and other physiologically active substances produce their effects by binding to specific sites on the exterior (plasma) membranes
Caudal Caudate
Rostral Caudate
Globus Pallid us
Anterior Putamen
Olfactory Tubercle
Evidence that the dopamine receptor e:dsts in two states (i.e., with selective affinitv, respectivelv, for agonist and antagonist compounds of a given tvpe) was obtained in binding experiments. As seen in graph above, testing sections of calf brain with labeled dopamine and a labeled antagonist, haloperidol, showed that the .tame brain areas bind both subatances and do so in similar proportion• (in other parta of the brain neither (I bound). At the same time, testing the abilitv of agonist and antagonbt to inhibit binding of each other indicated that thev do not btnd to the same lite~ within the given locus. Graph below shows that dopamine tnhtblts dopamine btndtng much more than haloperidol bindIng, and vtce versa. Apomorphine, an agonist, has similar effects to dopamine's; fluphenazine, an antagonist, has effect• similar to haloperidol's. The mb:ed agonirt· antagonist, d-LSD, inhtbtts binding of both dopamine and haloperidol. 1,000 t• Dopamine
tt-
lc
t-
.,.'
~c
100
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• Apomorphine
fff-
:c g
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~
t=
e d-LSD
f-
0
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~
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...,::t .......
10
~ ff-
Haloperidol • I
1
I
I
I
I
I I I
10
I
I
I
I
I I II
• ~luph1en~i~e
100
1
1 11
1,000
[ 3H) Dopamine (Inhibition constant, nM)
Hoapital Practice Octobtr 1977
137
of their target cells, by which process they activate other processes in the cell interior by means of a "second messenger" substance such as cyclic AMP. Often the action of these substances can be antagonized by other compounds which, by themselves binding to the same membrane sites, block the action of the active, or agonist, substance. Such systems are often visualized in terms of a "lock-andkey" model: the binding site is the lock, the agonist compound the key, while the antagonist is an "incorrectly cut" key that cannot turn the Jock, but by filling the keyhole can prevent insertion of the correct key. Identification of neurotransmitter receptors is a very young science, dating only from about 1970, when several groups succeeded in isotopically labeling a particular type of acetylcholine receptor in certain invertebrates. Further progress in the area was hampered by the fact that both neurotransmitters and their antagonists are rather loosely bound to the receptor sites, meaning that it is hard to distinguish specific binding there from nonspecific adsorption. Only recently has this problem been overcome - by using low concentrations of binding substance with high levels of radioactivity plus rapid but vigorous washing of the tissues to remove the nonspecifically bound molecules. A number of exp~riments using this technique have indicated that for many brain receptor sites, at least, the lock-and-key model is an oversimplification. Rather, it appears that the receptor site exists in two states, one with selective affinity for agonist compounds of a given type, the other with similar affinity for the appropriate antagonists. The evidence supporting this view is too complex to detail here, but It includes, for example, the observation that the physiologic potency of antagonists of a particular class often doe1 not correlate well with their capacity to displace an agonist from the binding tite (as would be the case in the simple lock-and-key model), though it correlates very well with their capacity to displace other antagoni•ts. The two-state model also explains how compounds with no structund similarity to the agonist can still act as antagonists, and how other l J8
Hoepital Practice Octolwr 1977
1,000
~------------.-------------.-----------~r------------,
Pipamperone •
j
• Promazine
~
0
[ 100b-----------~----------~----~-------r----------~ Sl
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·=
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J.nhlbltlon of [ 3H] Haloperidol Binding In Calf (inhibition constant, nM)
Bmding studies have provided a method of rankmg antlschizophrenic drugs according to potencu. Graph on this page shows a correlation coefficient of .94 between affinttu for
compounds can exert both types of effect- antagonist and agonist- simultaneously. It appears that the two states can in many cases be converted into one another, though in most cases we do not know how or why conversion occurs. With the opiate receptor, however, it has been shown that it binds opiates (agonists) much more effectively in the absence of sodium ion, while opiate antagonists are bound selectively when the ion is present. Exactly how this two-state model should be visualized at the molecular level is still uncertain and will probably remain so until someone succeeds in actually determining the structure of a receptor site. It may involve a stereochemical change in the receptor, as is the case with, for example, the visual pigments in their response to light. Alternatively, it may involve two adjacent molecules or adjacent sites on the same molecule. One of these might selectively bind agonists, the other, antagonists, and the molecules could be so arranged that the occupation of either site (or molecule) desensitizes
the other to the action of "its" compound. Additional models are also possible, but in the present state of knowledge there seems little point in speculating about them. A good deal of evidence obtained in our laboratory indicates that the dopamine receptors operate according to the two-state model. To begin with, labeling experiments show clearly that both dopamine and its antagonists bind to the same portions of the brain and, moreover, that the amount of binding in different areas is in the same proportion. For example, when sections of calf brain are tested with labeled dopamine and a labeled antagonist, haloperidol (an antischizophrenic drug), the greatest amount of binding for both drugs is in the caudal caudate region. The next highest amount is in the rostral cimdate, with 76% (of the maximum caudal caudate level) for haloperidol and 90% for dopa· mine. Levels are lower in the globus pallidus, anterior putamen, and olfactory tubercle, which for both drugs show about 6o%, 50%, and 40% to 45% of the maximum, respectively.
Chlorpromazine
e
e Penfluridol I e Trifluoperazine /Bromoperldol ' •• Haloperidol 0.1 1-----+--"". .n-Fiupenthixol--+--------t----------! ~' Trifluperldol \ Fluspirllene Clofuperol \ Benperldol Splroperldol Fluphenazine Pimozide
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Inhibition of [ 3H] Haloperidol Binding In Calf (inhibition constant, nM)
haloperidol binding sUes and phannacologlc effecttvenen in animala. Con-elatton wtth potencv in achtzophrenla is almost as high, .84 (graph above).
A second point is that the binding in question does not involve presynaptic dopamine receptors, though these are known to exist. This can be demonstrated by injecting the compound 6hydroxydopamine into the substantia nigra of the rat brain, thereby destroying nearly all the dopamine-releasing presynaptic nerve terminals. Such treatment does not reduce binding of either dopamine or haloperidol. Thus, it seems clear that both drugs bind in the same locus (postsynaptic receptors) in the same parts of the brain and in the same proportions. Yet when we test their ability to inhibit binding of each other, and of other agonists and antagonists, it seems equally clear that they are not binding to the same sites. Thus, dopamine inhibits dopamine binding 30 times more effectively than it does haloperidol binding, while haloperidol inhibits haloperidol binding far more effectively than it does dopamine binding. (The difference in the latter situation is on the order of 300 to 1.) Apomorphine, an agonist (i.e., its physiologic effects resemble those of dopamine),
inhibits dopamine binding more than it does haloperidol binding. Fluphenazine, an antagonist, inhibits haloperidol binding more effectively than dopamine binding. Finally, d-LSD, which physiologically shows both agonistic and antagonistic effects in relation to dopamine, inhibits binding of both compounds. On the basis of these findings, we have ranked a whole series of antis,:hiwphrenic drugs by their ability to inhibit haloperidol binding, by their ability to antagonize the action of apomorphine and amphetamine in animals, by the average clinical dose, and by their ability to inhibit dopamine binding. The in vivo animal potency of the drugs correlates almost perfectly with their haloperidol-binding inhibition, with correlation coefficients averaging .94, and the correlation is almost as good for the clinical potency (.84). Ranked against dopamine-binding inhibition, however, the correlation is only moderately good (. s8). (The nature of correlation coefficients makes this figure much "worse" than .94, considerably more so than the raw
numerical difference would suggest.) These findings, we believe, provide strong evidence that the brain's dopaminergic pathways are involved in the therapeutic effects of neuroleptics in schizophrenia, and also that the dopamine postsynaptic receptor indeed exists in the two-state form. The haloperidol-binding inhibition test, moreover, provides a quick and cheap method for screening new antischizophrenic drugs, requiring only a few micrograms of the drug and a few milligrams of brain tissue; up to 100 drugs can be screened in a morning. Thus, the two most clinically potent antischizophrenic drugs, spiroperidol and benperidol, rank first and second in hal~peridol-binding inhibition but 16th and ztst (out of zs) in dopaminebinding inhibition, while (+)-butadamol, the top drug for inhibiting dopamine binding, ranks only 15th in clinical potency. However, more efficient drug screening, though certainly a benefidal side effect of our experiments, was not the main goal of these studies, which was rather to elucidate the biochemistry of schizophrenia. As indicated above, the studies are consistent with the dopamine theory of schizophrenia but have by no means demonstrated that the brain defect in that disease in\'olves dopamine itself. This somewhat paradoxical conclusion may perhaps be clarified by an electrical analogy: the fact that a dangerous short circuit can be abolished by tripping the appropriate circuit breaker does not mean that the short is in the breaker - it may be anywhere in the circuit. Equally, the fact that schizophrenic symptoms can be ameliorated, by "breaking" the dopaminergic pathways of the brain (by administering dopamine antagonists) need not imply that the symptoms' primary cause is some defect in release or reception of that substance. One should emphasize that the dopamine mediation of the therapeutic actions of neuroleptics does not necessarily mean that dopamine synapses are disturbed in schizophrenia. Possible schizophrenic abnormalities might involve systems several steps distant, but which can be modulated by changes in dopamine transmission. If dopamine systems are in fact abHospit•l Practice Octobfr
lfl77
139
100=------------r------Promazine • Pipamperone
•
Chlor
Triflupromazine
( +)-Butaclamol
,._
e
e Fluanisone
e
:; 1.0 1::::----------+----------,,.jL---------+--:-:-------j C e Moperone
"B ·;: 0
cis-Thiothixene
e Trifluoperazine
t
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