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V0L5.N0 2,1979 Endorphins, , and Schizophrenia*

Jan Volavka, Leonard G. Davis, Abstract biochemical and pharmacological Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 and Yigal H. Ehrlich findings on the role of endorphins, The theory that alterations of cyclic nucleotides, and^rotein phos- dopaminergic synaptic transmission phorylation in the regulation of may play a role in the pathogenesis neuronal function. The presumed re- of schizophrenia is widely accepted. lationships are summarized in A more recent theory links the en- figure 1. dorphin system to the etiology of schizophrenia. We propose that Dopamine Hypothesis of these two theories may be combined Schizophrenia into a single model. Recent neuro- chemical and pharmacological find- Much research on the role of dopa- ings have indicated close functional mine in schizophrenia has been relationships between the endorphin done; a recent review provides a criti- and dopamine systems. Endorphins cal summary (Carlsson 1978). modulate dopaminergic synaptic Briefly, the dopamine hypothesis sug- transmission by exerting both pre- gests that in schizophrenia the synaptic and postsynaptic effects. cells that use dopamine as a neuro- On the molecular level, this modu- transmitter are hyperactive. This lation may involve the activity of hypothesis has been formulated nucleotide cyclases and protein phos- within the framework of the classical phorylation systems. Thus, the do- description of neuronal transmission: paminergic neuronal hyperactivity, A is synthesized currently believed to be related to and released from the presynaptic cell schizophrenia, may be caused by a to impinge on specific postsynaptic primary alteration in the endorphin receptors, resulting in a continuity of system. Several hypotheses about neuronal information transfer. The the nature of that alteration have hypothesis derives its primary sup- been advanced and tested in thera- port from pharmacological and thera- peutic experiments with schizo- peutic studies. The most effective phrenic patients. These experiments drugs (neuroleptics) in the treat- have not yet yielded definitive ment of schizophrenia have been results. found to be powerful blockers (antagonists) of the cellular receptors for dopamine (Snyder 1976). More- Endorphins ("endogenous over, the clinical efficacy of different ") have become one of the neuroleptics parallels their competi- most popular research topics in be- tive ability in binding to these recep- havioral sciences, , tors (Creese, Burt, and Snyder 1976). neurochemistry, and a number of Additional support is derived from other fields. Reviews of the neuro- the observation that the antipsy- chemistry and pharmacology of chotic effects of the neuroleptic opiate receptors and endorphins are drugs are potentiated by alpha- available elsewhere (e.g., Snyder methyl-para-tyrosine (Walinder et 1978). We have recently reviewed the al. 1976), an inhibitor of a key en- implications of the endorphin re- zyme (tyrosine hydroxylase) in the search for psychiatry (Verebey, biosynthesis of dopamine. These re- Volavka, and Clouet 1978). The pur- pose of this article is to focus on the 'Reprint requests should be addressed implications for schizophrenia and Dr. Volavka at Missouri Institute of Psy- to relate the dopamine hypothesis chiatry, 5400 Arsenal St., St. Louis, MO of schizophrenia to the more recent 63139. 228 SCHIZOPHRENIA BULLETIN

figure 1. Interactions of endorphins, cyclic nucieotldes, and phrenics, but that might be an effect Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 phosphoprotelns In neuronal processes related to schizophrenia of neuroleptic treatment rather than an intrinsic feature of schizophrenia. More recent findings on the regu- lation and modulation of synaptic neurotransmission have resulted in ^NDORPHINS, clinically important extensions of this classical system. Two recent clin- ical reports exemplify the application of the increased understanding of basic synaptic function to patient OPIATE treatment. Apomorphine, like RECEPTORS dopamine, is reportedly a stimulator () of the dopamine postsyn- aptic receptors (Anden et al. 1967; Ernst 1967), and thus should be ex- pected to worsen psychotic symp- S N toms (Yaryura-Tobias, Diamond, CYCLIC- PROTEIN and Merlis 1970). At lower concen- .NUCLE0TIDES7 ^PHOSPHORYLATION, trations, however, apomorphine ap- parently acts selectively on pre- synaptic dopamine receptors, which then inhibit dopamine release (Kehr (DOPAMINERGIC) et al. 1972; Nagy et al. 1978). These SYNAPTIC-TRANSMISSION presynaptic receptors are involved in monitoring the amount of dopamine so as to prevent further transmitter release. Using this information about the possible dual action of apomorphine, Smith, Tamminga, and Davis (1977) and Tamminga et V al. (1978) treated a small group of schizophrenics with low doses of SCHIZOPHRENIA apomorphine. These patients showed clinical improvement. The authors attributed the effectiveness ports indicate that the dopamine sys- for the dopamine hypothesis has of apomorphine to the suppression tem needs to be suppressed for suc- been obtained by characterizing the of dopamine action through these cessful treatment of schizophrenic composition of body fluids or post- presynaptic mechanisms. In a differ- patients. Other support is provided mortem of schizophrenics. ent approach, Alpert and Friedhoff by studies in which the dopamine The chemical investigation of dopa- (1976) have treated tardive dys- system is activated—for example, by mine and its metabolites in urine, kinesia patients with incremental amphetamines—which results in an blood, and particularly cerebrospinal doses of L-dopa, a precursor of increase of psychotic symptoms fluid has provided meager support at dopamine. The dyskinesia got (Angrist and Gershon 1970). As im- best for an increased dopamine ac- worse, presumably because more pressive as the above observations tivity in schizophrenics (Bowers dopamine was made. However, fol- are in their support of a hyperactive 1974; Farley, Price, and Hornykie- lowing abrupt discontinuation of dopamine system in schizophrenia, wicz 1977; Post et al. 1975). Recent L-dopa, the dyskinesia markedly the fact is that not all patients re- evidence (Lee et al. 1978) indicates improved, indicating the possibility spond positively to neuroleptic treat- that dopamine receptors are indeed of receptor modification (Friedhoff ment. Moreover, no direct evidence increased in the brain of schizo- 1977). VOL 5, NO. 2,1979 229

Biochemistry of Dopamlnergic determines the specificity in the mitter release from presynaptic ' Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 Transmission multiple actions of accumulated terminals (DeLorenzo 1976). Thus, > cyclic AMP? A large body of evi- the phosphorylation of proteins can In the preceding section, we have dence (for recent reviews, see regulate important steps in the presented evidence indicating that Greengard 1976; Rubin and Rosen processes that determine the alterations in dopaminergic synaptic 1975) supports the suggestion (Kuo ,. "supply" of presynaptically transmission may account, at least and Greengard 1969) that all the originating dopamine. The'efficacy in part, for some of the symptoms of physiological functions of this cyclic of dopaminergic synapses is deter- schizophrenia. An understanding of nucleotide are mediated and mined not only by the amount of the molecular mechanisms that play specified through a class of enzymes released dopamine, but also by the a role in this transmission process named cyclic AMP-dependent pro- degree of sensitivity of postsynaptic may shed light on molecular events tein kinases. Protein kinase trans- receptors to stimulation by possibly involved in bringing about fers a phosphate from ATP onto a dopamine. On the molecular level, schizophrenic symptoms. We shall protein to form a phosphoprotein. this can be determined by the mag- therefore briefly present here some This process is called protein nitude of the adenylate cyclase re- aspects of the biochemistry of phosphorylation. When certain sponse to dopamine stimulation. dopaminergic synaptic transmission, enzymes are phosphorylated, they Gnegy, Uzunov, and Costa (1976) with special emphasis on recent convert from an inactive to an active have demonstrated that an increase findings implicating cyclic adenosine form "or vice versa. Cyclic AMP act- in the phosphorylation of membrane- 3',5'-monophosphate (AMP) and ing through protein kinases can thus bound proteins results in a specific phosphoproteins in this induce changes in cellular activities decreased response of adenylate process. The efficacy of the trans- by regulating or activating key cyclase to dopamine activation. mission process depends on two enzymes that play a role in various Thus, the phosphorylation of pro- main events: first, the metabolism of cellular functions. Many different teins can regulate a multiplicity of dopamine and its release into the • proteins can serve as substrates for presynaptic and postsynaptic events synaptic cleft, and second, the con- protein kinases in neural tissue that are each intimately involved in sequences of the interaction of (Ehrlich et al. 1977fc). It was the mechanism of action of dopamine with its postsynaptic re- therefore suggested that the dopaminergic synapses (figure 2). It ceptors. The information provided specificity in the responses of a cell is possible, therefore, that some of by the neurotransmitter-receptor to various inputs can be determined / the aberrations in dopaminergic interaction is conveyed into the cell by the existence of numerous phos- synaptic transmission (believed to be by "second messengers." Kebabian, phoproteins that differ in their associated with schizophrenia) result Petzold, and Greengard (1972) have phosphorylative response to from abnormalities in enzymatic^ ' demonstrated that the interaction neurohumoral stimulation (Ehrlich systems that are involved in the between dopamine and its receptors et al. 1977n; Ehrlich, Rabjohns, and phosphorylation of specific proteins. in the peripheral and central Routtenberg 1977c; Ehrlich and There is some evidence that, in addi- nervous systems results in the ac- Routtenberg 1974). tion to cyclic nucleotides, neuroac- tivation of the enzyme adenylate Protein phosphorylative activity tive in general, and cyclase. The adenylate cyclase is a has been directly implicated in endorphins in particular, may also membrane-bound enzyme that several mechanisms involving be involved in the regulation of the converts adenosine triphosphate dopaminergic transmission. Tyro- events in the phosphorylation sys- (ATP) to cyclic AMP. Cyclic AMP sine hydroxylase, mentioned above tem. Such evidence has begun to accumulates intracellularly and is as the rate-limiting enzyme in the emerge from studies on the role of therefore considered the "second synthesis of dopamine, can be opiates and opiate receptors in messenger" in the process of activated by a phosphorylation dopaminergic mechanisms. dopaminergic synaptic transmission. process (Goldstein et al. 1976; Cyclic AMP has been shown to Lovenberg, Bruckwik, and Hanbauer The Opiate Receptor and act as a second messenger not only 1975). Recent studies have im- Endorphins for dopamine, but for a variety of plicated specific membrane-bound catecholamine phosphoproteins in the mechanisms The breakthrough in the investiga- and . What then of calcium-dependent neurotrans- tion of the mode of action of nar- 230 SCHIZOPHRENIA BULLETIN

Mediation Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021

cyclic AMP Peptidergic FndOrphins Neuron c •

Phospho- protein

Presynaptic Postsynaptic

Figure 2a. Hypothetical mechanisms of endorphin action—Endorphins as neurotransmitters (mediation)

Endorphin is released from the presynaptic terminal of a peptidergic neuron and interacts with a specific receptor located on an adjacent postsynaptic membrane. This receptor may be coupled with adenylate (or guanylate) cyclase. These cyclases form, respectively, cyclic AMP or cyclic GMP. These cyclic nucleotides regulate protein kinases, which in turn transfer phosphate to proteins. Phosphoproteins then regulate numerous cellular functions. cotic was made in 1973, high affinity for opiate agonists, and other laboratories appeared at when three laboratories (Pert and that an excellent correlation exists nearly the same time (Pasternak, Snyder 1973; Simon, Hiller, and between the binding affinity of Goodman, and Snyder 1975; Edelman 1973; Terenius 1973) opiates and their pharmacological Terenius and Wahlstrom 1975). simultaneously and independently potency. The discovery in brain of These naturally occurring opiate-like discovered stereospecific opiate- an endogenous substance with the compounds in mammalian tissues binding sites in rat brain homogen- capacity to bind competitively to were named "endorphins" as a con- ates. These three groups have opiate receptors and with biological traction of "endogenous morphines" demonstrated that the opiate- characteristics mimicking those of by Simon (1978, p. 126). Generically, binding sites in neuronal tissue are the opiates was first reported by all substances that are endogenous stereospecific, saturable, possess Hughes (1975). Similar reports from and bind to opiate receptors are re- VOL 5. NO 2,1979 231

Modulation Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021

Endorphins-

Protein

Dopaminergic Protein Neuron Kinase

Phospho- protein

Presynaptic Postsynaptic

Figure 2b. Hypothetical mechanisms of endorphin action—Endorphins as neuromodulators

The figure depicts a synapse in which the neurotransmitter is dopamine. The receptor in this case is coupled with adenylate cyclase. Endorphins act on the presynaptic receptor to inhibit dopamine release. This action may be mediated by protein kinase. Endorphins also act on a postsynaptic receptor to change the sensitivity of the dopamine receptor This effect may also be mediated by protein kinase. Adapted from Ehrlich (1979). f erred to as endorphins. Two of these peptide sequence that is in common of its sequence (as the met-enke- endorphins were purified from brain to part of a larger , beta- phalin constitutes part of beta-en- and were shown to be pentapeptides (figure 3). Another frag- dorphin) has been purified from brain (Hughes et al. 1975; Simantov and ment of lipotropin, amino acid #61- or pituitary (Rubenstein, Stein, and Snyder 1976); they have been des- 91, is referred to as beta-endorphin. Udenfriend 1978). However, leu-en- ignated met- and Ieu-enke- To date, no large endorphin-Iike dorphin was reportedly isolated from phalin. The met-enkephalin has a molecule with Ieu-enkephalin as part the dialysate of blood of schizo- 232 SCHIZOPHRENIA BULLETIN

1 Figure 3. Amlno acid sequence of human beta-lipotropin al. 1976). Cross-tolerance between Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 and met-enkephalin has 1 10 been demonstrated by measuring NH2- Glu-Leu-Thr-Gly-Gln-Arg-Leu-Arg-Gln-Gly- response to met-enkephalin administration with and without 20 morphine implants (Blasig and Herz Asp-Gly-Pro-Asn-Ala-Gly-Ala-Asn-Asp-Gly- 1976). Furthermore, beta-endorphin and met-enkephalin have been shown to produce dependence 30 similar to morphine (Loh et al. Glu-Gly-Pro-Asn-Ala-Leu-Glu-His-Ser-Leu- 19766; Wei and Loh 1976). These findings imply that endorphins inter- 40 act with the same receptor(s) as Leu-Ala-Asp-Leu-Val-Ala-Ala-Glu-Lys-Lys- morphine (the opiate receptor). However, recent evidence seems 50 to suggest the existence of two ACTH 4-10 (#47-53) Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-His-Phe- classes of receptors mediating the effects of morphine. Endorphins are the endogenous ligands for one 60 class; ACTH may be the ligand for Arg-Typ-Gly-Ser-Pro-Pro-Lys-Asp-Lys-Arg- the other class (Jacquet 1978). Endorphins and ACTH-like peptides 70 share the same precursor (pro-opi- Met-enkephalin (#61 -65) Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser- ocortin). Furthermore, they share some behavioral effects in animals, 80 such as excessive grooming (Gispen, Beta-endorphin (#61 -91) Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn- Van Ree, and DeWied 1977) and ex- tinction of active avoidance (DeWied et al. 1978). Watson et al. (1978neuropeptide between beta-endorphin and mor- shown (Barker et al. 1978n) that such fragments of lipotropin were effec- phine has been reported (Van Ree et peptides can alter the response of V0L5.N0 2,1979 233

neurons to the stimulatory effects dopaminergic ones. Examples of pep- cent of the dopamine cells degen- Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 of classical nonpeptide neurotrans- tidergic neurons modulating other erated after the lesion, or after a mitters. In this process the neuronal pathways have been pre- surgical cut of the pathway, only a endorphins play a modulatory role. viously indicated (Barker et al. 1978; 20-30 percent reduction of Such modulation could be carried Barker, Smith, and Neale 1978i). enkephalin binding to opiate recep- out on the molecular level via a The evidence for the modulatory tors was detected. This finding mechanism in which neuroactive role of endorphins is also provided certainly suggests that the enke- peptides induce changes in the by studies in which beta-endorphin phalin receptors occur on cells other properties of neuronal membranes. was applied to brain tissue. This than dopamine cells. Whether some Changes in the conformation of treatment resulted in an inhibition of these receptors could be on the membranes can result in altered ac- of the potassium-induced release of undegenerated postsynaptic cells is tivity of membrane-bound enzymes dopamine (Loh et al. 1976n). Besides not known. However, other evidence such as dopamine-sensitive adenyl- the modulation of dopamine release, (Bradley et al. 1976; Friedrickson ate cyclase, which are directly it appears that met-enkephalin ele- and Norris 1976; Gent and Wolsten- involved in neuronal function. The vates the rate of synthesis and turn- craft 1976; Hill, Pepper, and Mitchell phosphorylation and dephosphoryla- over of dopamine and its metabolites 1976) indicates that postsynaptic tion of membrane-bound proteins (Biggio et al. 1978). These effects influences of synaptic activity by have been reported to provide a could be blocked by indi- endorphins does occur. The key mechanism that can induce struc- cating that the modulation was question is whether receptors on the tural alterations in membranes through an opiate receptor rather various cell types might differ in (Gazit, Ohad, and Logter 1976). than a dopamine receptor. In an their specificity of interaction with Zwiers et al. (1976) have demon- earlier review (Lai 1976), evidence the different endorphins. In this con- strated that ACTH fragments have was presented that at least some of text, it has been shown (Gilbert and direct effects on the activity of the behavioral and physiological Martin 1976; Lord et al. 1977) that membrane-bound protein kinases effects of opiate agonists were pro- differences do exist between the two that phosphorylate specific proteins duced by indirect influences on classically studied opiate receptor in synaptic membranes. Recent dopaminergic synaptic transmission. systems, the mouse vas deferens observations (Davis and Ehrlich More recently, it has been shown and the guinea pig ileum. We have 1978) indicate that the phosphoryla- that morphine-induced central stim- mentioned studies suggesting that tion of these same proteins is also ulation can be antagonized by apo- the brain also contains more than effected by met- and leu-enkephalin. morphine, a dopamine receptor one class of morphine receptors agonist (Strombom and Svensson (Jacquet 1978; Jacquet et al. 1977; These in vitro experiments imply 1978). Further support for the in- Lord et al. 1977). Different receptor that the effects of neuroactive pep- volvement of opiate receptors in the types in brain must not be confused tides on protein phosphorylation modulation of the dopamine system with the same receptor in different may modulate synaptic function in was provided by the fact that the brain regions. For example, met- vivo (figure 2b). This suggestion is effect of enkephalin on dopamine enkephalin application to two differ- supported by the observations that metabolism was still observed after ent brain regions results in markedly the exposure of rats to stress (Ehr- kainic acid treatment, a chemical different behavioral responses, such lich, Rabjohns, and Routtenberg procedure to destroy dopamine as analgesia and seizures (Frenk, 1977) or to chronic morphine treat- receptors (Biggio et al. 1978). The McCarty, and Liebeskind 1978). ment (Ehrlich et al. 1978) elicits major evidence for a presynaptic in- These experiments point out the similar changes of protein phosphor- teraction of endorphins with regionality of specific functions in ylation. dopamine cells was provided by the brain and serve to emphasize the decrease in enkephalin-receptor markedly different roles in which Endorphins and the Dopamlne binding after specific chemical the same endogenous compound can System lesions of dopamine cells with participate. However, these authors 6-hydroxy-dopamine (Pollard, also suggested that different types It appears that neurons containing Llorens-Cortes, and Schwartz 1977), of receptors could exist in each brain endorphins may be involved in a a toxin to dopamine cells. It is impor- region since in their earlier studies modulatory role for the regulation tant to note that although 80 per- (Urea et al. 1977) both behaviors oc- of neuronal activities, particularly 234 SCHIZOPHRENIA BULLETIN

curred after a ventricular and a decreased phosphorylation of cess has received initial support Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 administration. membrane proteins (Ehrlich et al. from the reports of increased CSF Of the many behavioral effects of 1978), which are enkephalin-sensi- levels of endorphins in chronic endorphins in animals, one was tive (Davis and Ehrlich 1979). schizophrenic patients; these levels thought to be particularly important If a deficiency of endorphins decreased after neuroleptic treat- in its potential implications for occurs in schizophrenia, it may ment (Terenius et al. 1976). : Rigid immobility was cause the same net result: a hyper- antagonists were used to test the produced in rats by intracerebral ad- active dopamine system. This hyper- hypothesis of endorphin excess. ministration of beta-endorphin activity would develop through dif- Gunne, Lindstrom, and Terenius (Bloom et al. 1976; Jacquet and ferent biochemical mechanisms than (1977) have reported a therapeutic Marks 1976). The rat rigidity was described aboye. One might postu- effect of .4 mg naloxone I.V. The ef- seen as an analog of human cata- late an inability of the neurons to fect of low naloxone doses could not tonia (Bloom et al. 1976). Jacquet adjust to a deficiency of an be replicated (Davis et al. 1977; and Marks felt that the immobility inhibitory influence of endorphins. Janowsky et al. 1977; Volavka et al. in rats was similar to the extra- In essence, the system would always 1977), but doses around 10 mg may pyramidal rigidity elicited in patients be "on." The mechanism would be be effective in a subpopulation of by neuroleptics. Recent evidence in- different from receptor supersen- schizophrenics (Emrich et al. 1977; dicates that this similarity goes sitivity, but the ultimate effects Watson et al. 1978b). beyond the behavioral level: Beta- might be identical. Although consid- Another narcotic antagonist, endorphin-induced catalepsy was erable evidence links the endorphins , was also used in thera- shown to be mediated by metabolite and the dopamine system, effects of peutic experiments in schizophrenia alterations in nigrostriatal dopamine endorphins on other transmitter with negative results (Jackson and neurons (Berney and Hornykiewicz systems are also known. Volavka, in preparation; Mielke and 1977; Van Loon and Kim 1978). Gallant 1977; Simpson, Branchey, We hypothesize that deviations and Lee 1977). However, naltrexone of the dopaminergic transmission Endorphin Hypothesis of was found to possess clear postulated in schizophrenia may be Schizophrenia morphine-like effects in opiate- due to an alteration in the naive subjects (Volavka et al. 1979), endorphin system. If an endorphin Abnormality of the endorphin and these results therefore have no excess exists in schizophrenia, it system may be implicated in schizo- meaning for the hypothesis of en- could cause dopamine receptor su- phrenia. The hypotheses tested so dorphin excess. Thus, the hypothesis persensitivity. Elevated amounts of far deal with the potential abnormal- of endorphin excess is viable, and endorphins, in addition to inhibiting ity of the ligands (i.e., endorphins); more work is needed to identify the dopamine release (Loh et al. 1976n), an abnormality of the endorphin re- subpopulation of schizophrenics who can also cause a decreased phos- ceptors has also been considered may respond to high doses of phorylation of membrane proteins (Verebey, Volavka, and Clouet naloxone. (Davis and Ehrlich 1978; O'Cal- 1978). The hypotheses concerning The hypothesis of endorphin de- laghan, Williams, and Clouet, in the ligands can be classified into ficiency may be tested directly by press). Each of these events can lead three types: the first type postulates the administration of an endorphin. to receptor supersensitivity: De- endorphin excess in schizophrenia, Kline et al. (1977) claim therapeutic creased transmitter release can the second type postulates effects of beta-endorphin in schizo- cause a compensatory increase in endorphin deficiency, and the third phrenics. Several groups are now at- receptor activity (Friedhoff 1977), one postulates the presence of ab- tempting to replicate these results. while decreased membrane phos- normal endorphins. This third hy- Because of their fast rate of bio- phorylation can result in an in- pothesis may overlap with the first transformation, natural endorphins creased adenyl cyclase response to two hypotheses. An extensive re- or may not be suitable dopamine stimulation (Gnegy, view of this material was published substances for clinical use. Certain Uzunov, and Costa 1976). Long- recently (Verebey, Volavka, and molecular modifications retard that term morphine administration to Clouet 1978); a brief recapitulation rate (DeWied et al. 1978; Roemer et animals elicits dopamine receptor and update will be presented here. al. 1977), and at least one of these supersensitivity (Bonnet et al. 1978) The hypothesis of endorphin ex- new synthetic substances may be ef- VOL. 5. NO. 2,1979 235

fective in schizophrenia (Verhoeven receptor systems. That alteration spinal neurons. Brain Research, 154:

et al. 1978). If schizophrenia is re- may cause changes in the dopa- 153-158, 1978/.. Downloaded from https://academic.oup.com/schizophreniabulletin/article/5/2/227/1912938 by guest on 23 September 2021 lated to decreased opiate receptor minergic transmission, and ulti- Berney, S., and Hornykiewicz, O. occupancy (which may be a conse- mately schizophrenia (figures 1 and The effect of beta-endorphin and quence of endorphin deficiency), it 2). met-enkephalin on striatal dopamine may not matter whether endoge- We emphasize that there is a sub- metabolism and catalepsy: Com- nous or exogenous ligands are used stantial difference in the amounts of parison with morphine. Communica- to correct this situation (Verebey, data supporting the proposed hy- tions in , 1:597-604, Volavka, and Clouet 1978). That potheses. The dopamine hypothesis 1977. suggestion implies that the efficacy has received considerable support of opiate treatment for psychoses from pharmacological and clinical Biggio, G.; Casu, M.; Corda, M.G.; (which was common until World experiments. The role of endorphins DiBello, C; and Gessa, G.L. Stimula- War II) should be reevaluated. in schizophrenia is questionable, tion of dopamine synthesis in caudate nucleus by intrastriatal The hypothesis of abnormal however, and the links between en- enkephalins and antagonism by nal- endorphins in schizophrenia has dorphins and dopaminergic trans- oxone. Science, 200:552-554, 1978. received support from the recent mission have not been fully ex- work on hemodialysis. Wagemaker plored. The role of protein Blasig, J., and Herz, A. Tolerance and Cade (1977) have seen clinical phosphorylation in schizophrenia and dependence induced by improvement in schizophrenics after has not been studied. These hypoth- morphine-like pituitary peptides in hemodialysis. Palmour (in press) has eses can be tested, and we hope that rats. Naunyn-Schmiedebergs Archives of analyzed the dialysate and reported our review will stimulate experi- Pharmacology, 294:297-300, 1976. the isolation of leu-endorphin—a mental investigations. Bloom, F.E. Endorphins in mental ill- hitherto unobserved and presum- nesses. In: Melnechuk, T., ed. Cell ably abnormal compound, which Receptor Disorders. La Jolla, Calif.: might be a precursor of leu- References Western Behavioral Sciences enkephalin. However, according to Institute, 1978. pp. 134-152, Bloom (1978), Guillemin has also Alpert, M., and Friedhoff, A.J. Re- analyzed the dialysates provided by Bloom, F.; Segal, D.; Ling, N.; and ceptor sensitivity modification in the Guillemin, R. Profound behavioral Wagemaker and was "unable to find treatment of tardive dyskinesia. endorphin activity in any of them" effects in rats suggest new etiolog- Clinical Pharmacology and Therapeutics, ical factors in mental illness. Science, (p. 140). Obviously the exciting find- 19:103, 1976. ings of Wagemaker, Palmour, and 194:630-632, 1976. their colleagues require further Anden, N.E.; Rubenson, A.; Fuxe, Bonnet, K.A.; Branchey, L.B.; Fried- study. Several attempts to replicate K.; and Hokfelt, T. Evidence for hoff, A.J.; and Ehrlich, Y.H. Long- their clinical findings in controlled dopamine receptor stimulation by term narcotic exposure reduces cau- experiments are in progress. The apomorphine. Journal of Pharmacy and date cyclic nucleotide levels, protein hypothesis of abnormal endorphins Pharmacology, 19:627-629, 1967. kinase and tyrosine hydroxylase in schizophrenia needs more testing. Angrist, B.M., and Gershon, S. The activities. Life Sciences, 22:2003-2008, phenomenology of experimentally 1978. We have suggested that the mal- induced amphetamine psychosis: function underlying mental illness Bowers, M.B., Jr. Central dopamine Preliminary observations. Biological turnover in schizophrenic syn- may lie in the disordered relation- Psychiatry, 2:95-107, 1970. ship between different sets of opiate dromes. Archives of General Psychiatry, receptors (Verebey, Volavka, and Barker, J.; Neale, J.H.; Smith, T.G. 31:50-57, 1974. Clouet 1978). An altered interaction Jr.; and MacDonald, R.L. Opiate pep- Bradley, P.B.; Biggs, I.; Gayton, R.J.; between two classes of neuropeptide tide modulation of amino acid re- and Lampert, L.A. Effects of micro- receptor systems has recently been sponses suggests novel form of iontophoretically applied met- proposed as the cause of opiate ab- communication. Science, 199:1451- enkephalin on single neurons. stinence syndrome (Jacquet 1978). It 1453, 1978«. Nature, 261:425-426, 1976. is possible that further research will Barker, J.L.; Smith, T.G.; and Neale, Bu'scher, H.H.; Hill, R.C.; Roemer, reveal an alteration in the integra- J.H. Multiple membrane actions of D.; Cardinaux, P.; Closse, A.; tion of the neuromodulatory peptide enkephalin revealed using cultured Hauser, D.; and Pless, J. Evidence 236 SCHIZOPHRENIA BULLETIN

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Single copies of Special Report: Schizophrenia 1976 by Samuel J. Keith et al. are Special Report: available free of charge from the Center for Studies of Schizophrenia. Schizophrenia Multiple copies will also be supplied to requesters who wish to use the report for teaching purposes. The 58-page booklet summarizes recent research in schizophrenia, with special emphasis on work carried out by investigators who have received grant support from the National Institute of Mental Health. The major research areas covered in the report are Diagnosis, Genetics, Biology, Psychophysiology, Psychological Functioning, Family Studies, Studies of Populations at High Risk, Childhood Psychoses, Borderline Conditions, and Treatment. Requests for the report should be addressed to the Center for Studies of Schizophrenia, National Institute of Mental Health, 5600 Fishers Lane, Rm. 10C-26, Rockville, MD 20857.