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changes Hargreaves

in sleep WA:

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pathology. Arch Gen 30.

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Nature nursing

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Meltzer HY, Dorus man plasma creatine hication) Dubo H,

nase 33.

34. 35.

37.

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DC,

Pennington

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et al:

injury

and

Serum

phosfor Psy-

creatine

meningitis.

hypothesis evidence.

ki-

Lancet

of affective disAm J Psychiatry

122:509-522, 1965 Sack RL, Goodwin FK: Inhibition of dopamine-/3-hydroxyhase in manic patients: a clinical trial with fusaric acid. Arch Gen Psychiatry 31:649-654, 1974 Osterholm JL: Noradrenergic mediation of traumatic spinal Mendell

JR.

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Murphy

Life DL,

Sci [I] 14:1363-1384, Engel

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of creatine

B, compound

and

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of Duchenne

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Parker JM, imipramine 104. 1974

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KIun B: Spinal fluid injuries. J Neurosurg

44.

Meltzer HY, Engel WK: Histochemical abnormalities tal muscle in patients with acute psychoses: part Psychiatry 23:492-502, 1970

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JR:

Proximal Duchenne

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dystrophy.

1972 myopathy dystrophy.

Nature

induced Nature

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by 5-HT247:103-

activity

in brain of skeleArch Gen

II.

Meltzer HY: Central core fibers in an acutely psychotic Arch Gen Psychiatry 27:125-132. 1972 Mehtzer HY, Crayton JW: Neuromuscular abnormalities major mental illnesses: II. Muscle fiber in subterminal nerve abnormalities, in Biology ofthe Major Psychoses: parative

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2:743-748, 1967 Cao A, DeVirgilis S. Lippi C, et al: Creatine kinase isoenzymes in serum of children with neurological disorders. Chin Chim Acta 23:475-478, 1969 Snyder SH, Banerjee SP, Yamamura HI, et al: Drugs, neurotransmitters and schizophrenia. Science 184: 1243-1253, 1974 forming 1973

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of Schizophrenia:

Focus

on the

Receptor H. SNYDER,

M.D.

THE

Alleviation ofschizophrenic symptoms by phenothiazines and butyrophenones is associated with blockade ofdopamine receptors while exacerbation ofsymptoms by amphetamines appears to result from enhanced synaptic activity ofdopamine and/or norepinephrine The author suggests that biochemical labeling ofthe dopamine receptor with 3H-dopamine and 3H-haloperidol may clarif’ mechanisms of drug effects on the dopamine receptor.

DOPAMINE

inition found

HYPOTHESIS

supported anything

by no direct conclusively

ofschizophrenia evidence. abnormal

is by defNo one has about dopa-

,

.

Presented

at the

Association,

128th

Anaheim,

annual Calif.

,

meeting of the American May 5-9. 1975.

Snyder is Professor, Department mental Therapeutics, and Professor, Behavioral Sciences, Johns Hopkins Dr.

cine,

725

North

Wolfe

St.

of Pharmacology and ExperiDepartment of Psychiatry and University School of Mcdi-

Baltimore,

Am J Psychiatry

Psychiatric

133:2,

Md.

21205.

Februa

/976

197

DOPAMINE

HYPOTHESIS

mine (DA) in body fluids on brains of schizophrenics. but the indirect evidence is impressive. The symptoms of schizophrenia can be selectively exacerbated or relieved by the use ofdrugs. When phanmacologists dccipher the neurochemical mechanisms ofthcse drugs. all evidence points to DA.

DOPAMINE

In most areas ofthe brain, DA, one ofthe two principal catecholamines in the brain, is merely the precursor of noncpinephrinc (NE). It is transformed into NE by the enzyme dopamine hydroxylase; however, some parts of the brain lack dopamine hydnoxylase, and DA is the presumed neurotnansmitten (1-3) in these areas. The best known DA neuronal pathway has cell bodics in the substantia nigra of the brain stem with nerve terminals in the corpus striatum. the caudate nucleus, and the putamen. This pathway degenerates in patients with idiopathic Parkinson’s disease. The resultant DA depletion is causally related to the symptoms of the disease because replacing the missing DA by treatment with its amino acid precursor L-dopa dramatically alleviates symptoms. Thus in Parkinson’s discase a dopaminc hypothesis of causation has been translated into proof. A DA pathway important to endocrinology has cell bodies in the arcuate nucleus of the hypothalamus and nerve terminals synapsimg on the portal vessels in the median eminence that convey releasing factors from the hypothalamus to the pituitary gland. DA in these neurons regulates releasing facton activity and subsequent endocrine effects. Other DA pathways may be more related to the symptoms of schizophrenia. Pathways with cell bodies close to the substantia nigna project to the nucleus accumbens and olfactory tubencle, both components of the limbic system of the brain that regulates emotional behavior. Recently described DA pathways with cell bodies in the same areas project to parts ofthe frontal, cingulate, and entonhinal cerebral cortex, phylogenetically older parts of the cerebral cortex functionally nelated to the limbic system.

AMPHETAMINE

ACTIONS

One way to link a drug to a particular illness is to show that the drug reproduces symptoms of the disease. LSD psychosis was once thought to be a “model schizophrenia’ ; however, one cannot accurately equate the effects of such psychedelic drugs as LSD with schizophrenic symptoms. Psychedelic drugs produce perceptual changes in the visual sphere, whereas schizophrenic hallucinations are usually auditory. Unden the influence of psychedelic drugs, people do not demonstrate classic schizophrenic disorders in affect or thought. Moreover, clinicians rarely mistakenly diagnose individuals under the influence of psychedel‘

198

Am

J Psychiatry

133:2,

February

1976

ic drugs as schizophrenics. By contrast, there are numerous reports of amphetamine psychosis being misdiagnosed as acute paranoid schizophrenia before the history of drug ingestion is obtained. Some psychiatrists studying individuals with amphetamine psychoses have felt that they manifested schizophrenic disorders of affect and thought (4, 5). but others disagree (6). Although the specifics of amphetamine psychoses may not exactly match those of schizophnenia, the mere fact that experienced psychiatrists cam mistake the two diagnoses indicates that amphetamine psychosis is probably the best current drug model of schizophrenia. Amphetamine psychosis is not simply a precipitation of a latent schizophrenia on a sleep deprivation psychosis, since psychosis has been elicited by amphetamine in individuals screened for the absence of any history of schizoid disorders; in some cases the psychosis has occurred within 24 hours (6). Like amphetamine, cocaine is a widely abused CNS stimulant that can, in high doses, provoke a psychosis that is clinically indistinguishable from acute paranoid schizophrenia. Indeed, most of the symptoms of cocaine psychosis are essentially identical to those of amphetamine psychosis. How does cocaine act? An abumdance of pharmacologic evidence indicates that cocaine’s behavioral effects result from its facilitation of catecholamime synaptic activities by blocking the reuptake inactivation of catecholamines. Very large doses (100-500 mg) of amphetamine are required to elicit amphetamine psychosis, but amounts prescribed therapeutically for dieting on stimulant effects rapidly and reproducibly exacerbate schizophnenic symptoms (7). Amphetamine and related drugs such as methylphenidate (Ritalin) do not superimpose a drug psychosis on the schizophrenia but instead worsen the patient’s own symptoms. This effect is selective-it is not elicited in depressed or manic patients. There is no other drug known that so specifically and dramatically exacerbates schizophrenic symptoms. How do amphetamines act? Behavioral effects of amphetamines are exerted via the catecholamines NE or DA. Amphetamines enhance the actions of catecholamines by directly releasing them into the symaptic cleft on by preventing their inactivation via neuptake into the nerve terminal that released them. Amphetamimes do not affect other neurotransmitter or biochemical systems in the brain so specifically and potently. Although it is difficult to make a clear-cut distimction, the actions of amphetamines in exacerbating schizophrenic symptoms and eliciting amphetamine psychosis probably involve brain DA more than NE. While the neurochemical effects of amphetamines and cocaine are similar, there are differences; cocaine apparently lacks the amphetamines’ capacity to directly release catecholamines. If amphetamines exacerbate schizophrenic symptoms by increasing synaptic DA, them other pharmacologic maneuvers that produce the same biochemical

SOLOMON

end product should also worsen schizophrenic symptoms. The simplest technique to determine this would be the administration of L-dopa, the precursor of DA. In the few studies in which i-dopa has been administered to schizophrenics, it worsened behavioral abnormalities in much the same way that amphetamines do (8, 9).

PHENOTHIAZINES

Clinical psychopharmacologists generally agree that phemothiazines exert a specific antischizophrenic action and act primarily on the fundamental symptoms of schizophrenia (10). Their effects are not merely sedative, since they activate withdrawn patients and calm hyperactive individuals. Many other psychotropic drugs, including potent sedatives and antianxiety agents, have failed to provide selective benefits in schizophrenia comparable to the impressive actions of phenothiazimes and related agents. Moreover, while phenothiazines are used in the treatment of mania and mamy other conditions, the relief they afford in schizophrenia appears to be far more specific than their effects in other emotional disturbances. Understanding the mechanisms of action of phenothiazimes might shed light on brain mechanisms in schizophrenia. Unlike the amphetamines, the phenothiazimes do not possess obvious chemical resemblamce to particular meurotransmitters (figure 1). However, these drugs probably act by blocking postsynaptic receptor sites for the neurotransmitter actions ofDA. This theory was first advanced by Cansson (12) on the basis of limited indirect biochemical data. Carlsson hypothesized that if phenothiazines block DA receptors, animal behavior which resembled that induced by the DA depletion after treatment with such drugs as reserpime would result. Postsynaptic

FIGURE

1 With the Side Chain “Tilted”

Phenothiazines

chlorpromazine with dopamine superimposed

Toward the A Ring*

triflu promazi

ne

H.

SNYDER

neurons would respond to the receptor blockade by sounding an alarm calling for more dopamine. By a feedback system DA cells would then fire more frequently and release more DA. providing an excess of DA metabolites or breakdown products. Canlsson observed an increase in DA metabolites after phenothiazinc administration and showed that these biochemical effects ofphenothiazines were correlated with the clinical potency of the drugs. This is a crucial task in relating drug “effect” to “mechanism of clinical action.” Since phenothiazines are highly reactive chemicals, they produce many biochemical actions, most of which do not correlate with clinical effects. Thus the phenothiazine prornethazime (Phenergan) is a potent antihistamine, but it is totally ineffective in treating schizophrenia, although it exerts most phenothiazineinduced biochemical actionsjust as effectively as chlorpromazine. Canlsson showed that the increase in DA metabolites produced by chlonpromazine and other phenothiazines was in proportion to their milligram potency in treating schizophrenia, but promethazine was totally ineffective. Subsequently, other pharmacologists found that the increased formation of DA metabolites elicited by phenothiazimes derives from an increased synthesis and, presumably, release of DA (13, 14). Only recently did Aghajamian and Bunney (15) actually show that the DA neurons fire more frequently after phenothiazime administration and that phemothiazimes actually block the neurophysiologic effects produced by the injection of minute amounts of DA onto postsynaptic cells possessing DA receptors. Thus, at a neurophysiologic 1evci, one can now demonstrate the synaptic actions of DA, which appears to function as an inhibitory neurotransmitter, and the capacity of phemothiazimes to block these effects in proportion to their clinical efficacy. Because neurophysiologic studies are quite difficult to perform, only a limited number of drugs can be screened. It has been possible to monitor DA receptor activity biochemically via two techniques-an indirect and a more recent direct approach. Cyclic ademosine rnomophosphate (cAMP) is thought to be a second messenger mediating the actions of many hormones and meurotransmitters. Kebabian and associates (16) showed that a cAMP accumulating system. or adenylate cyclase. in areas of the brain rich in DA nerve tenminals responds selectively to DA and is affected much less by other catecholamimes (table 1). This DAsensitive adenylate cyclase is thus linked in some way to the DA receptor and provides an indirect reflection ofdopamine receptor activity that can be readily monitoned in vitro. As seen in table 1 phenothiazines inhibit the effects of DA on the adenylate cyclase in proportiom to their clinical potency (18, 20). Thus trifluoperazine (Stelazine) and fluphenazine (Prolixin, Permitil), two very potent phemothiazimes in clinical practice, are considerably more active on the DA-sensitive adenylate cyclase than chlorpromazine, which is clinically less potent. ,

trifluoperazine

*From

Feinberg

and Snyder

fluphenazine

(11).

AmJPs’,’chiatry

133:2,

Februa

1976

199

DOPAMINE

HYPOTHESIS

In order to directly measure the DA receptor biochemically we labeled neurotnansmitter receptors in the brain by binding radioactive forms of the neurotransmitter on its antagonists to synaptic membranes in brain homogenates (21-23). Using such procedures. we recently succeeded in biochemically identifying the DA receptor in the brain (17). DA receptor binding displays all the characteristics one would expect of the DA receptor. Of the various catccholamincs, DA has by fan the greatest affinity-it is almost 20 times more potent than NE and several thousand times more potent than isopotenenol. the catecholamine with greatest affinity for -adrcncngic receptors. The relative p0tencies of phenothiazines competing for DA receptor binding closely parallels their clinical potency and their effects upon the DA-sensitive adenylate cyclase.. Optical and geometrical isomers of phenothiazime-related drugs are uniquely valuable in the study of recepton specificity. Ifthc physical properties ofthe two isomers, especially the optical isomers, are essentially the same, any difference in pharmacologic potency must be related to the structure of the receptor sites. The isomeric specificity of the DA receptor binding sites for the isomers of butaclamol and flupenthixol parallels the influences of these isomers on the DAsensitive adenylate cyclase and their pharmacologic potency in intact animals (table 1). Interestingly. one group ofdrugs does not fit in panticularly well in either the DA-sensitive adenylate cyclase or DA receptor binding. Butyrophenones such as haloperidol (Haldol) are considerably more potent on a milligram basis than phenothiazines in vivo but arc not .

TABLE 1 Phenothiazine and Thioxanthene Drug Effects on Specific Dopamine Receptor Binding and a Dopamine-Sensitive Adenylate Cyclase

Relative in Competing

Hahoperidol

( + )-Butaclamoh a-Flupenthixol Fluphenazine Trifluoperazine Trifluproma.zine Perphenazine Chlorpromazine

Promazine )-Butachamoh

‘tPotency

Sensitive

Adenyhate

50

50

1200

728 4545

1087 250 -

100

27 8

are listed

in approximate

schizophrenia

in competing

the reciprocal

Potency in Dopamine-

Cychase of Rat Corpus Striatum***

625 465 181 214 125 100

(-

treating

for

Dopamine Receptor Binding**

Drug*

‘Dmgs

Relative Inhibiting

Potency

and

descending

eliciting

for binding

of the nanomolar

17