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Behavioural effects of acute and chronic β-phenylethylamine administration in the rat: Evidence for the involvement of 5-hydroxytryptamine
Nrurophura,mlcy.v Vol. 20. pp. Prmted in Great Britain
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lxm-3908/81/111067-06M2.00/0 Pergamon Press Ltd
1981
BEHAVIOURAL EFFECTS OF ACUTE AND CHRONIC /3-PHENYLETHYLAMINE ADMINISTRATION IN THE RAT: EVIDENCE FOR THE INVOLVEMENT OF 5-HYDROXYTRYPTAMINE C.
T.
DOURLSH
Psychiatric Research Division, University Hospital, Saskatoon. Saskatchewan S7N 0X0, Canada (Accepted 22 June 1981) Summary-The behavioural consequences of daily /3-phcnylethylamine (PEA) administration for a period of 6 weeks have been examined. Rats first showed signs of the 5-HT behavioural syndrome after a single injection of PEA (50 mg/kg) or 7 daily injections of PEA (25 mg/kg). The syndrome reached peak intensity after 3 weeks treatment and was prevented by pre-treatment with the 5-HT antagonists mianserin and methysergide or the neuroleptic clozapine, but relatively unaffected by pre-treatment with haloperidol. These data provide strong evidence for an effect of PEA on brain 5-HT mechanisms. Because of the similarity between PEA and amphetamine and the suggestion that PEA may be involved in the aetiology of schizophrenia it is proposed that the mechanisms of action of PEA be reassessed taking into account its ability to affect 5-HT systems in addition to catecholaminergic systems.
fi-Phenylethylamine (PEA) is an endogenous compound that is similar in structure to amphetamine lacking only the z-methyl group of amphetamine. /I-Phenylethylamine has been detected in all tissues analysed to date (see reviews by Boultott, 1976, 1979) but its precise function is unknown. It is uncertain at present whether PEA functions as a neurotransmitter in its own right, or as a synaptic activator associated with one of the conventional aminergic neurotransmitters (Boulton, 1979). The behavioural effects of PEA in rodents have been reported to be qualitatively similar to those of amphetamine and include hyperactivity (Jackson, 1971, 1972; Ho, 1978) and stereotypy (Randrup and Munkvad, 1966; Moja Staff, Gillin and Wyatt, 1976). Chronic amphetamine abuse in non-schizophrenic individuals produces a syndrome closely resembling paranoid schizophrenia (Connell, 1958; Ellinwood, 1976) and exacerbates symptoms when given acutely to schizophrenics (Janowsky and Davis, 1974). Amphetamine-induced stereotypy in rodents closely resembles the compulsive behaviour observed in addicts who consume large amounts of the drug (Snyder, Banerjee, Yamamura and Greenberg, 1974). Consequently amphetamine-induced stereotypy has been proposed as an animal model for schizophrenia (Snyder, 1973). Recently it has been suggested that PEA-induced stereotypy mimics the amphetamine model of schizophrenia (Borison, Havdala and Diamond, 1977; Borison and Diamond, 1978). These authors have suggested that stereotypy produced by chronic administration of PEA, unlike that induced Key words: /I-phenylethylamine. nic treatment, sensitization.
5-HT syndrome, chro-
by amphetamine, does not depend so greatly on neostriatal dopaminergic (DA) mechanisms, and may therefore represent a better animal model of schizophrenia. Although a large body of evidence implicates brain DA pathways in psychosis (Snyder, 1973; Meltzer and Stahl, 1976), recent research also suggests a possible role for brain S-hydroxytryptarnine (5HT) in the actions of paranoia-inducing drugs such as amphetamine and L-DGPA. At high dose levels these drugs have been found to induce a conspicuous behavioural syndrome by releasing endogenous 5-HT (Sloviter, Drust and Connor, 1978a; Lees, Fernando and Curzon, 1979). Interestingly, acute injections of PEA at high dose levels (60-80 mg/kg) also induced the 5-HT behavioural syndrome (Sloviter et al., 1980a) and this has been attributed to a direct agonistic effect of PEA on S-HT receptors in the brain. It is not known whether repeated administration of PEA at moderate dose levels (12.5-50 mg/kg) can induce the S-HT behavioural syndrome although there is evidence that chronic PEA treatment can produce behavioural sensitization of stereotypy at a dose of 50 mg/kg (Borison et al., 1977). The present study examined the behavioural consequences of single and repeated administration of a range of doses of PEA in an attempt to determine whether chronic administration of PEA induces a sensitization of the 5-HT behavioural syndrome and. in addition, whether the behavioural effects of the compound could be inhibited by 5-HT or DA receptor antagonists. The effects of individual or group testing were also examined since it has been reported that PEA increases activity in grouped mice but not in isolated mice (Jackson, 1978).
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METHODS
The subjects were 50 male SpragueDawiey rats (Canadian Breeding Labs, La Prairie, Quebec) housed in group cages with food and water ad libitum. Lighting operated on a 12 hr dark 12 hr light cycle (lights on 6a.m.) and temperature was maintained at 20-23°C. Animals weighed 200-210g at the start of the experiments.
The behavioural syndrome caused by S-HT release or receptor stimulation was evaluated according to the following scale (adapted from Jacobs, 1976). The syndrome was considered present in an all-or-none fashion if the rats simultaneously exhibited at least four of the following six component signs at any time during observation: (I) resting tremor (especially of head and forelimbs): (2) rigidity or hy~rtonicity (assessed both by grasping the rat around the torso and by passively extending and flexing the hindlimbs); (3) reciprocal forepaw padding (rhythmic dorso-ventral movements of the forelimbs); (4) hindlimb abduction (a dramatic splaying out of the hindlimbs); (5) Straub tail; (6) lateral head weaving (slow side to side head movements). Procedure
For the first week after arrival in the laboratory, the animals were handled daily as a taming procedure. Rats were randomly allocated to one of four drug treatment groups including the control condition referred to as 0 mg/kg. The groups were PEA 0, 12.5, 25 and 50mgjkg. Each animal was weighed and injected intra~ritone~ly daily for 42 days with one of
the 3 doses of PEA or distilled water. Each day (with the exception of test days) the animals were immediately returned to the home cage following injection and observed for 30min. The rats were tested following the initial drug treatment (day 1) and at seven day intervals after the first test. In addition, on selected days (from 28-42) animaIs were tested after administration of PEA in combination with a 5-HT or DA antagonist. Mianserin and methysergide (20 or 30mg/kg), both presumed 5-HT antagonists (Bieger, Larochelle and Hornykiewicz, 1972; Maj, Sowinska, Baran, Gancarczyk and Rawkow, 1978). were injected 15min prior to PEA. Haloperidol (0.2 mg’kg) and clozapine (20 or 30 mg/kg), both DA antagonists (Janssen, Niemegeers, Scheellekens and Lanaerts, 1967; Niemegeers and Janssen, 1979), were injected 30min prior to PEA at non-cataleptic doses. On test days the animals were transferred to individual ~lycarbonate metabohc cages and allowed to habituate for 30 min prior to drug administration. Behavioural responses were monitored continuously for 2 hr after injection. The presence or absence of the 5-HT behaviourai syndrome was recorded using the procedure described above. Reactivity to auditory and tactile stimuli was assessed by tapping a pencil on the cage top or on the animal’s body. Reactivity to visual and olfactory stimulation was assessed by the presentation of a dish of food pellets. On a number of test days the effects of group testing (n = 3 or 5) were examined. Druys
&Phenylethylamine hydrochloride (Sigma Chemical CO.), methysergide hydrogen maleate (Sandoz), mianserin hydrochloride (Organon Inc.), clozapine
Table 1. Dose-response effectsof acute and chronic administration of fl-phenylethylamine in evoking the 5-HT behavioural syndrome in rats Number of days of b-phenylethyiamine treatment
Drug dose (mgikg)
No. of rats tested
Dbof rats displaying the 5-HT syndrome
1 (Acute injection)
0 12.5 25 50
10 5 15 20
0 0 0 60
7
0 12.5 25 50
10 5 :;
0 0 60 100
14
0 12.5 25 50
10 5 IO 10
0 0 80 100
0 12.5 2.5 50
10 5 10 10
0 0 100 100
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Behavioural effects of /?-phenylethylamine
1
7
14
21
28
35
42
0-
1
7
14
21
20
35
42
Number of PEA Injections
Number of PEA Injections
a
b
Fig. 1. (a) Latency to onset (min) of the 5-HT behavioral syndrome in rats givena series of daily injections of /?-phenylethylamine for 42 days at a dose of 25 mg/kg (0) or 50 mg/kg (0). (b) Duration (min) of the 5-HT behavioural syndrome in rats given a series of daily injections of r!?-phenylethylamine for 42 days. Conventions are as described for Fig.l(a).
(Sandoz) and haloperidol
(Janssen, Beerse, Belgium)
were used. Drugs were dissolved in distilled water,
except for haloperidol and clozapine which were first dissolved in 100~1 of glacial acetic acid and then diluted 40-50 times with distilled water. Doses of each drug were calculated in terms of the salt and all injections were administered via the intraperitoneal route. RESULTS
The dose-response effects of single and repeated administration of PEA in evoking the S-HT behavioural syndrome are shown in Table 1. /I-Phenylethylamine (50mg/kg) induced the syndrome in 60% of animals tested after a single injection. The latency to onset of the syndrome was 10min (Fig. la) and the duration of the response 15 min (Fig. lb). /?-Phenylethylamine (25 mg/kg) first induced the syndrome after one week of daily injections (see Table 1); latency to onset was 6 min (Fig. la) and duration was 8 min (Fig. lb). The observed components of the syndrome were: piloerection, Straub tail, head weaving splayed hind-limbs, rigidity, tremor, forepaw padding, hyperreactivity and excessive salivation. The initial signs of the syndrome included a general disruption of motor activity accompanied by a flattened or hunched posture, piloerection, hyperreactivity and a marked splaying of the hind-limbs. Animals remained in one location for long periods displaying repetitive head movements and in most cases, forepaw padding. The animals were hyperthermic (i.e. elevated body temperature and rapid respiration were observed) and when lifted drew their hind-limbs toward the abdomen and remained rigid. Normal self-righting and limb-flexing reflexes were absent. The rats were inactive and insensitive to visual or olfactory stimulation but hyperreactive to tactile and auditory stimulation. There was no apparent difference in intensity of the’syndrome between animals tested individually or in groups of 3 or 5. After recovery from the syndrome all animals were hyperactive and excited and mounting was a common observation in group tests. The potency of PEA (25 and 50 mg/kg) in evoking NP2O.ll F
the syndrome showed reverse tolerance (sensitization) during the first 21 days of injection and this observation was reflected in a decreased latency to onset and an increased duration of the response (see Fig. 1). The syndrome reached peak intensity after 21 days treatment (latency 30 set, duration 254Omin) and remained unchanged for a further three weeks of PEA administration. Treatment with a small dose of PEA (12.5 mg/kg) failed to produce the syndrome in any of the animals tested. These rats were active and displayed some weak autonomic signs including cardiovascular disruption (which was also evident at higher dose levels). However, the principal components of the syndrome were not observed in any of the subjects. Methysergide or mianserin (20 or 30 mg/kg; 15 min pre-treatment) prevented the 5-HT behavioural syndrome elicited by PEA (25 or 50mg/kg; Table 2). Instead of the usual inactivity accompanied by repetitive head and forepaw movements, the animals were extremely hyperactive and hyperreactive. Rats tested in a group tended to huddle together in a corner of the cage and then rushed around squeaking and jumping before returning to the group. There were also signs of increased aggression and the adoption of the “boxing” posture was a common observation. The hyperactive and hyperreactive responses were also evident in isolated rats and could be elicited by sound or movement near the cage but also occurred spontaneously. Control animals treated with mianserin or methysergide alone showed no signs of hyperactivity or hyperreactivity. Clozapine (20 or 30 mg/kg; 30 min pre-treatment) produced marked sedation and prevented the PEA-induced behavioural syndrome (Table 2). Smaller doses of the 5-HT antagonists (10 or 15 mg/kg) or clozapine (5 or 10 mg/‘kg) had no effect on the PEA induced response. Haloperidol (0.2 mg/kg; 30 min pre-treatment) failed to inhibit the 5-HT syndrome elicited by PEA. Although treatment with the DA antagonist caused mild sedation in control animals, the only apparent effect in PEA-treated rats was the disappearance of hyperreactivity and sali-
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C. T. DOURKH Table 2. Effects of pretreatment with S-HT or dopamine antagonists on the behavioural syndrome induced by chronic injection of /%phenylethylamine (25 or 50 mg/kg) Dose (mgikg)
Mianserin
20 or 30
5
Inhibition of all components except hyperreactivity in all rats
Methysergide
20 or 30
10
Inhibition of all components except hyperreactivity in all rats
Clozapine
20 or 30
10
Sedation and inhibition of all components in all rats
0.2
10
Inhibition of hyperreactivity and disappearance of headweaving in 4 out of 10 rats
Haloperidol
vation, and, in some animals, an inhibition weaving (see Table 2).
No. of rats tested
Effects on fi-phenylethylamine behavioural syndrome
Antagonist
of head
sensitization to its behavioural effects and this was reflected in a decreased latency to onset and an increase duration of the response (see Fig. 1). The observation of sensitization to the behavioural effects of DISCUSSION PEA stands in general agreement with the results of Borison et al. (1977) who reported an increase in The results of the present study indicate that some of the behavioural effects of PEA are mediated by intensity of stereotypy during chronic treatment with brain 5-HT mechanisms. This is consistent with a 50 mg/kg of PEA. The principal measures of stereonumber of previous findings that large doses of PEA, typy used by Borison’s group were inactivity, head substituted phenylethylamines and amphetamine bobbing and decreased responsiveness to stimulation. induce the 5-HT behavioural syndrome in rats and In addition, animals were observed to display inmice (Lees et al., 1979; Breese. Cooper and Mueller. creased autonomic signs including salivation and 1974; Sloviter et al., 1978a. 1980a; Chung Hwang and piloerection. A number of these behavioural signs are Van Woert, 1980). A single injection of PEA at a dose components of the 5-HT syndrome which may have of 50 mg/kg produced the S-HT syndrome in 60”/0of been misinterpreted as DA-mediated stereotypy. the animals tested. This is consistent with the results Additional evidence for 5-HT mediation of the of Sloviter et al. (1980a) who found that acute doses of chronic PEA behavioural syndrome is provided by 40 or 6Omgkg of PEA produced the syndrome in 50 the present results using antagonist pre-treatment (see Table 2). The 5-HT antagonists mianserin and methyand 75”, respectively of animals tested. However these findings are at variance with the results of Bori- sergide prevented all the components of the PEAson er al. (1977) who reported that 50mgkg of PEA, induced syndrome with the exception of hyperreactiadministered acutely, was a subthreshold dose for the vity and salivation and produced hyperactivity. The induction of behavioural effects (stereotypy). There is neuroleptic clozapine also prevented the syndrome and produced marked sedation. In contrast haloperino immediately apparent reason for this discrepancy since the same strain of rats was used in all three dol prevented hyperreactivity and attenuated head studies. The results also demonstrate that doses of weaving, but had no effect on any of the other components of the syndrome (see Table 2). This is in PEA (as small as 25 mg/kg) can induce the 5-HTagreement with the results of Sloviter et al. (1980a) syndrome in rats provided the drug is administered who found that mianserin and methysergide (both chronically. Since PEA, as a substrate for monoamine 10 mg/kg) inhibited the 5-HT syndrome induced by a oxidase, is oxidized extremely rapidly (Durden and Philips, 1980) it seems likely that if this oxidation was single large dose of PEA and produced marked hyperactivity and hyperreactivity. However, larger blocked by a suitable monoamine oxidase inhibitor, then much smaller doses of PEA could be used to doses of the 5-HT antagonists and clozapine were required to inhibit the PEA syndrome in the present produce this behavioural syndrome. There was no apparent difference in intensity of the study, and this may be due to the increased behavPEA syndrome between rats tested individually and ioural potency of PEA observed after repeated adminrats tested in groups of 3 or 5. These results do not istration (see Fig. 1; N.B. anatagonist studies took support the suggestion that PEA has a more potent place after 28-42 days of PEA treatment). These findstimulant effect in grouped animals (Jackson, 1978) ings are consistent with the suggestion (Jacobs, 1974, although this discrepancy may be due to a species 1976; Grahame-Smith, 1971; Deakin and Dashwood, difference. Repeated administration of PEA produced 1981) that hyperactivity and hyperreactivity, unlike
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Behavioural effects of /%phenylethylamine
the other components of the S-HT syndrome, may not be a reflection of specific serotonergic activity, and could be mediated by DA rather than 5-HT. Further, Jacobs (1974) reported that spiroperidol blocked the 5-HT syndrome induced by L-tryptophan, but pimozide was only effective against head weaving. This finding is again consistent with 5-HT mediation since there is evidence that spiroperidol may act on 5-HT and DA receptors whereas pimozide and haloperidol may be more specific for DA receptors (Leysen, Niemegeers, Tollenaere and Laduron, 1978). Interestingly, a number of authors have suggested a ratio of neuroleptic potency at DA and 5-HT receptors based on behavioural, biochemical and receptor binding data (Fernando, Lees and Curzon, 1980; Leysen et al., 1978) which is in the following order: pimozide < haloperidoi < metoclopramide < ol-flupenthixol < thioridazine < clozapine. The latter ratios are proposed to increase with increasing antagonism at 5-HT receptors relative to antagonism at DA receptors. These relationships may shed some light on the interpretation of the results of Borison et a/. (1977) who found that clozapine and thioridazine were the most potent antagonists of chronic PEA-induced stereotypy. The present results and those of others (Sloviter et ul.. 1980a; Lees et al., 1979; Fernando et al., 1980; Leysen et a/., 1978) indicate that neurloeptics like clozapine may inhibit the behavioural syndrome associated with chronic administration of PEA via the induction of sedation and possibly, by an action on 5-HT receptors, A considerable body of evidence suggests that PEA possesses cat~holaminergic properties (Braestrup and Randrup, 1978; Jackson, 1972, 1978; Moja et al., 1978) which appear to be particularly important in the locomotor stimulant effects of the compound (Jackson, 1978; Ho, 1978). The results of the present study indicate that PEA also possesses serotonergic properties in tire which may be mediated by the release of endogenous S-HT or by a direct agonist effect on brain 5-HT receptors. One recent result supports the latter explanation (Sloviter et al., 1980a). The serotonergic behavioural effects of PEA show sensitization after repeated administration and further experiments are required to determine the cause of this effect. According to Borison et al. (1977) chronic PEAinduced stereotypy is dependent on limbic DA systems and noradrenergic mechanisms (Borison and Diamond, 1978) and, as such, has been proposed as an animal mode1 for schizophrenia. The present results indicate that 5-HT mechanisms are also involved in the behavioural effects of chronically administered PEA and it is, therefore, suggested that this finding may be of importance in the interpretation and use of the PEA model of schizophrenia. Although it is known that large doses of amphetamine can produce a syndrome closely akin to paranoid schizophrenia (Connell, 1958), it has not been demonstrated that exogenous PEA can induce a para-
noid state in normal subjects. The results of the present study demonstrate that PEA, like other paranoia-inducing drugs such as amphetamine and L-DOPA and many hallucinogenic drugs (Sloviter et al., 1978b; Sloviter, Drust, Darniano and Connor, 198Ob; Jenner, Marsden aid Thanki, 19801, can induce an abnormal behavioural syndrome which is thought to be mediated by brain 5-HT mechanisms. The behavioural syndrome increases in intensity after repeated administration of PEA and does not show signs of tolerance. Since it has been claimed that urinary concentrations of PEA are higher in chronic paranoid schizophrenics than in chronic non-paranoid schizophrenics or normals (Potkin, Karoum, Chuang Cannor-Spoor, Phillips and Wyatt, 1979), it is possible that PEA may play a role in the paranoid state. Aek~~~e~ge~e~~s-The author wishes to thank Dr A. A. Boulton and Dr R. S. G. Jones for constructive criticism of the manusc~pt and the Medical Research Council of Canada and Saskatchewan Health for continuing financial support. Drugs were generously supplied by Sandoz Canada Ltd (clozapine and methysergide), Organon, New Jersey, U.S.A. (mianserin) and Janssen, Beerse, Belgium (haloperidot).
REFERENCES Bieger, D., Larochelle, L. and Hornykiewicz, 0. (1972). A model for the quantitative study of central dopaminergic and serotonergic activity. Eur. J. Pharmac. 18: 128-136. Borison, R. L. and Diamond, B. I. (1978). A new animal model for schizophrenia: Interactions with adrenergic mechanisms. Biot. Psychiat. 13: 217-225. Borison, R. L., Havdala, H. S. and Diamond, 8. I. (1977). Chronic phenyletbylamine-indu~d stereotypy: A new animal model for schizophrenia? L$e Sci. 21: 117-122. Boulton, A. A. (1976). Cerebral aryl alkyl aminergic mechanisms. In: Trace Amines and the Bruin (Usdin, E. and Sandier, M., Eds), pp. 21-39. Marcel Dekker, New York. Boulton, A. A. (1979). Trace amines in the central nervous system. In: International Reviews of Biochemistry Vol. 26: Physiological and Pharmacological Biochemistry (Tipton, K. F., Ed.), pp. 179-205. University Park Press, Baltimore. Braestrup, C. and Randrup, A. (1978). Stereotyped behaviour in rats induced by phenylethylamine, dependence on dopamine and noradrenaline, and possible relation to psychoses? In: Noneatecholic Phe~ylethy~ami~es, Part I. Phen~feth~~amine: Biolo~jcal ~eehanisms and Clinical Aspects. (Mosnaitn. A. D. and Wolf, M. E., Eds), pp. 245-270. Marcel Dekker, New York. Breese, G. R., Cooper, B. R. and Mueller, R. A. (1974). Evidence for involvement of 5-hydroxytryptamine in the actions of amphetamine. Br. J. Pharmac. 52: 307-314. Chung Hwang, E. and Van Woert, M. H. (1980). Comparative effects of substituted phenylethylamines on brain serotonergic mechanisms. J. Pharmac. exp. Ther. 213: 254-260. Connell, P. H. (1958). Amphetamine psychosis. Maudsley Monographs, 1st Edition No. 5. Oxford University Press,
Oxford. Deakin, J. F. W. and Dashwood, M. R. (1981). The differential neurochemi~al bases of the behaviours elicited by serotonergic agents and by the combination of a monoamine-_oxidase __ inhibitor and L-DOPA. ~europ~urmacaloq.~ZU: f23130.
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Durden. D. A. and Philips, S. R. (1980) Kinetic measurements of the turnover rates of phenylethylamine and tryptamine in the rat brain. J. Neurochem. 34: 1725-1732.
Ellinwood. E. H. (1976). Amphetamine psychosis: 1. Description of the individuals and process. J: new. tnent. Dis. 144: 173-283.
Fernando, J. C. R., Lees, A. J. and Curzon, G. (1980). Differential antagonism by neuroleptics of backward-walking and other behaviours caused by amphetamine at high dosage. Neuropharmacoloyy 19: 549-553. Grahame-Smith. D. G. (1971). Studies in riro on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J. Neurothem. 18: 1053-1066. Ho. B. T. (1978). Behavioural effects of phenylethylamineneurochemical correlates. In: Noncarecholic Phenylrthylarninrs. Purt 1. Phenylethylamine: and Clinicul Aspects (Mosnaim,
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Jackson, D. M. (1972). The effect of /3-phenylethylamine upon spontaneous motor activity in mice: A dual effect on locomotor activity. J. Pharm. Pharmac. 24: 383389. Jackson. D. M. (1978). fi-Phenylethylamine: Studies on the mechanism of its stimulant effects. In: Noncatecholic Phen~~lethylaminrs, Mechunisms und
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pp. 317-338. Raven Press, New York. Janssen, P. A. J.. Niemegeers, C. J. E.. Schellekens, K. H. L. and Lenaerts, F. M. (1967). Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Arxeimitrrl-Forsch. 17: 841-854. Jenner. P.. Marsden. C. D. and Thanki, C. M. (1980). Behavioural changes induced by N.N-dimethyltryptamine in rodents. Br. J. Phurmac. 69: 69-80.
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Snyder, S. H. (1973). Amphetamine psychosis: A “model” schizophrenia mediated by catecholamines. Aln. J. Psychiuf. 130: 61-67. Snyder. S. H., Banerjee. S. P., Yamamura, H. I. and Greenberg, D. (1974). Drugs, neurotransmitters and schizophrenia. Science 184: 1243-1253.
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1981
BEHAVIOURAL EFFECTS OF ACUTE AND CHRONIC /3-PHENYLETHYLAMINE ADMINISTRATION IN THE RAT: EVIDENCE FOR THE INVOLVEMENT OF 5-HYDROXYTRYPTAMINE C.
T.
DOURLSH
Psychiatric Research Division, University Hospital, Saskatoon. Saskatchewan S7N 0X0, Canada (Accepted 22 June 1981) Summary-The behavioural consequences of daily /3-phcnylethylamine (PEA) administration for a period of 6 weeks have been examined. Rats first showed signs of the 5-HT behavioural syndrome after a single injection of PEA (50 mg/kg) or 7 daily injections of PEA (25 mg/kg). The syndrome reached peak intensity after 3 weeks treatment and was prevented by pre-treatment with the 5-HT antagonists mianserin and methysergide or the neuroleptic clozapine, but relatively unaffected by pre-treatment with haloperidol. These data provide strong evidence for an effect of PEA on brain 5-HT mechanisms. Because of the similarity between PEA and amphetamine and the suggestion that PEA may be involved in the aetiology of schizophrenia it is proposed that the mechanisms of action of PEA be reassessed taking into account its ability to affect 5-HT systems in addition to catecholaminergic systems.
fi-Phenylethylamine (PEA) is an endogenous compound that is similar in structure to amphetamine lacking only the z-methyl group of amphetamine. /I-Phenylethylamine has been detected in all tissues analysed to date (see reviews by Boultott, 1976, 1979) but its precise function is unknown. It is uncertain at present whether PEA functions as a neurotransmitter in its own right, or as a synaptic activator associated with one of the conventional aminergic neurotransmitters (Boulton, 1979). The behavioural effects of PEA in rodents have been reported to be qualitatively similar to those of amphetamine and include hyperactivity (Jackson, 1971, 1972; Ho, 1978) and stereotypy (Randrup and Munkvad, 1966; Moja Staff, Gillin and Wyatt, 1976). Chronic amphetamine abuse in non-schizophrenic individuals produces a syndrome closely resembling paranoid schizophrenia (Connell, 1958; Ellinwood, 1976) and exacerbates symptoms when given acutely to schizophrenics (Janowsky and Davis, 1974). Amphetamine-induced stereotypy in rodents closely resembles the compulsive behaviour observed in addicts who consume large amounts of the drug (Snyder, Banerjee, Yamamura and Greenberg, 1974). Consequently amphetamine-induced stereotypy has been proposed as an animal model for schizophrenia (Snyder, 1973). Recently it has been suggested that PEA-induced stereotypy mimics the amphetamine model of schizophrenia (Borison, Havdala and Diamond, 1977; Borison and Diamond, 1978). These authors have suggested that stereotypy produced by chronic administration of PEA, unlike that induced Key words: /I-phenylethylamine. nic treatment, sensitization.
5-HT syndrome, chro-
by amphetamine, does not depend so greatly on neostriatal dopaminergic (DA) mechanisms, and may therefore represent a better animal model of schizophrenia. Although a large body of evidence implicates brain DA pathways in psychosis (Snyder, 1973; Meltzer and Stahl, 1976), recent research also suggests a possible role for brain S-hydroxytryptarnine (5HT) in the actions of paranoia-inducing drugs such as amphetamine and L-DGPA. At high dose levels these drugs have been found to induce a conspicuous behavioural syndrome by releasing endogenous 5-HT (Sloviter, Drust and Connor, 1978a; Lees, Fernando and Curzon, 1979). Interestingly, acute injections of PEA at high dose levels (60-80 mg/kg) also induced the 5-HT behavioural syndrome (Sloviter et al., 1980a) and this has been attributed to a direct agonistic effect of PEA on S-HT receptors in the brain. It is not known whether repeated administration of PEA at moderate dose levels (12.5-50 mg/kg) can induce the S-HT behavioural syndrome although there is evidence that chronic PEA treatment can produce behavioural sensitization of stereotypy at a dose of 50 mg/kg (Borison et al., 1977). The present study examined the behavioural consequences of single and repeated administration of a range of doses of PEA in an attempt to determine whether chronic administration of PEA induces a sensitization of the 5-HT behavioural syndrome and. in addition, whether the behavioural effects of the compound could be inhibited by 5-HT or DA receptor antagonists. The effects of individual or group testing were also examined since it has been reported that PEA increases activity in grouped mice but not in isolated mice (Jackson, 1978).
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T.
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METHODS
The subjects were 50 male SpragueDawiey rats (Canadian Breeding Labs, La Prairie, Quebec) housed in group cages with food and water ad libitum. Lighting operated on a 12 hr dark 12 hr light cycle (lights on 6a.m.) and temperature was maintained at 20-23°C. Animals weighed 200-210g at the start of the experiments.
The behavioural syndrome caused by S-HT release or receptor stimulation was evaluated according to the following scale (adapted from Jacobs, 1976). The syndrome was considered present in an all-or-none fashion if the rats simultaneously exhibited at least four of the following six component signs at any time during observation: (I) resting tremor (especially of head and forelimbs): (2) rigidity or hy~rtonicity (assessed both by grasping the rat around the torso and by passively extending and flexing the hindlimbs); (3) reciprocal forepaw padding (rhythmic dorso-ventral movements of the forelimbs); (4) hindlimb abduction (a dramatic splaying out of the hindlimbs); (5) Straub tail; (6) lateral head weaving (slow side to side head movements). Procedure
For the first week after arrival in the laboratory, the animals were handled daily as a taming procedure. Rats were randomly allocated to one of four drug treatment groups including the control condition referred to as 0 mg/kg. The groups were PEA 0, 12.5, 25 and 50mgjkg. Each animal was weighed and injected intra~ritone~ly daily for 42 days with one of
the 3 doses of PEA or distilled water. Each day (with the exception of test days) the animals were immediately returned to the home cage following injection and observed for 30min. The rats were tested following the initial drug treatment (day 1) and at seven day intervals after the first test. In addition, on selected days (from 28-42) animaIs were tested after administration of PEA in combination with a 5-HT or DA antagonist. Mianserin and methysergide (20 or 30mg/kg), both presumed 5-HT antagonists (Bieger, Larochelle and Hornykiewicz, 1972; Maj, Sowinska, Baran, Gancarczyk and Rawkow, 1978). were injected 15min prior to PEA. Haloperidol (0.2 mg’kg) and clozapine (20 or 30 mg/kg), both DA antagonists (Janssen, Niemegeers, Scheellekens and Lanaerts, 1967; Niemegeers and Janssen, 1979), were injected 30min prior to PEA at non-cataleptic doses. On test days the animals were transferred to individual ~lycarbonate metabohc cages and allowed to habituate for 30 min prior to drug administration. Behavioural responses were monitored continuously for 2 hr after injection. The presence or absence of the 5-HT behaviourai syndrome was recorded using the procedure described above. Reactivity to auditory and tactile stimuli was assessed by tapping a pencil on the cage top or on the animal’s body. Reactivity to visual and olfactory stimulation was assessed by the presentation of a dish of food pellets. On a number of test days the effects of group testing (n = 3 or 5) were examined. Druys
&Phenylethylamine hydrochloride (Sigma Chemical CO.), methysergide hydrogen maleate (Sandoz), mianserin hydrochloride (Organon Inc.), clozapine
Table 1. Dose-response effectsof acute and chronic administration of fl-phenylethylamine in evoking the 5-HT behavioural syndrome in rats Number of days of b-phenylethyiamine treatment
Drug dose (mgikg)
No. of rats tested
Dbof rats displaying the 5-HT syndrome
1 (Acute injection)
0 12.5 25 50
10 5 15 20
0 0 0 60
7
0 12.5 25 50
10 5 :;
0 0 60 100
14
0 12.5 25 50
10 5 IO 10
0 0 80 100
0 12.5 2.5 50
10 5 10 10
0 0 100 100
2142
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Behavioural effects of /?-phenylethylamine
1
7
14
21
28
35
42
0-
1
7
14
21
20
35
42
Number of PEA Injections
Number of PEA Injections
a
b
Fig. 1. (a) Latency to onset (min) of the 5-HT behavioral syndrome in rats givena series of daily injections of /?-phenylethylamine for 42 days at a dose of 25 mg/kg (0) or 50 mg/kg (0). (b) Duration (min) of the 5-HT behavioural syndrome in rats given a series of daily injections of r!?-phenylethylamine for 42 days. Conventions are as described for Fig.l(a).
(Sandoz) and haloperidol
(Janssen, Beerse, Belgium)
were used. Drugs were dissolved in distilled water,
except for haloperidol and clozapine which were first dissolved in 100~1 of glacial acetic acid and then diluted 40-50 times with distilled water. Doses of each drug were calculated in terms of the salt and all injections were administered via the intraperitoneal route. RESULTS
The dose-response effects of single and repeated administration of PEA in evoking the S-HT behavioural syndrome are shown in Table 1. /I-Phenylethylamine (50mg/kg) induced the syndrome in 60% of animals tested after a single injection. The latency to onset of the syndrome was 10min (Fig. la) and the duration of the response 15 min (Fig. lb). /?-Phenylethylamine (25 mg/kg) first induced the syndrome after one week of daily injections (see Table 1); latency to onset was 6 min (Fig. la) and duration was 8 min (Fig. lb). The observed components of the syndrome were: piloerection, Straub tail, head weaving splayed hind-limbs, rigidity, tremor, forepaw padding, hyperreactivity and excessive salivation. The initial signs of the syndrome included a general disruption of motor activity accompanied by a flattened or hunched posture, piloerection, hyperreactivity and a marked splaying of the hind-limbs. Animals remained in one location for long periods displaying repetitive head movements and in most cases, forepaw padding. The animals were hyperthermic (i.e. elevated body temperature and rapid respiration were observed) and when lifted drew their hind-limbs toward the abdomen and remained rigid. Normal self-righting and limb-flexing reflexes were absent. The rats were inactive and insensitive to visual or olfactory stimulation but hyperreactive to tactile and auditory stimulation. There was no apparent difference in intensity of the’syndrome between animals tested individually or in groups of 3 or 5. After recovery from the syndrome all animals were hyperactive and excited and mounting was a common observation in group tests. The potency of PEA (25 and 50 mg/kg) in evoking NP2O.ll F
the syndrome showed reverse tolerance (sensitization) during the first 21 days of injection and this observation was reflected in a decreased latency to onset and an increased duration of the response (see Fig. 1). The syndrome reached peak intensity after 21 days treatment (latency 30 set, duration 254Omin) and remained unchanged for a further three weeks of PEA administration. Treatment with a small dose of PEA (12.5 mg/kg) failed to produce the syndrome in any of the animals tested. These rats were active and displayed some weak autonomic signs including cardiovascular disruption (which was also evident at higher dose levels). However, the principal components of the syndrome were not observed in any of the subjects. Methysergide or mianserin (20 or 30 mg/kg; 15 min pre-treatment) prevented the 5-HT behavioural syndrome elicited by PEA (25 or 50mg/kg; Table 2). Instead of the usual inactivity accompanied by repetitive head and forepaw movements, the animals were extremely hyperactive and hyperreactive. Rats tested in a group tended to huddle together in a corner of the cage and then rushed around squeaking and jumping before returning to the group. There were also signs of increased aggression and the adoption of the “boxing” posture was a common observation. The hyperactive and hyperreactive responses were also evident in isolated rats and could be elicited by sound or movement near the cage but also occurred spontaneously. Control animals treated with mianserin or methysergide alone showed no signs of hyperactivity or hyperreactivity. Clozapine (20 or 30 mg/kg; 30 min pre-treatment) produced marked sedation and prevented the PEA-induced behavioural syndrome (Table 2). Smaller doses of the 5-HT antagonists (10 or 15 mg/kg) or clozapine (5 or 10 mg/‘kg) had no effect on the PEA induced response. Haloperidol (0.2 mg/kg; 30 min pre-treatment) failed to inhibit the 5-HT syndrome elicited by PEA. Although treatment with the DA antagonist caused mild sedation in control animals, the only apparent effect in PEA-treated rats was the disappearance of hyperreactivity and sali-
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C. T. DOURKH Table 2. Effects of pretreatment with S-HT or dopamine antagonists on the behavioural syndrome induced by chronic injection of /%phenylethylamine (25 or 50 mg/kg) Dose (mgikg)
Mianserin
20 or 30
5
Inhibition of all components except hyperreactivity in all rats
Methysergide
20 or 30
10
Inhibition of all components except hyperreactivity in all rats
Clozapine
20 or 30
10
Sedation and inhibition of all components in all rats
0.2
10
Inhibition of hyperreactivity and disappearance of headweaving in 4 out of 10 rats
Haloperidol
vation, and, in some animals, an inhibition weaving (see Table 2).
No. of rats tested
Effects on fi-phenylethylamine behavioural syndrome
Antagonist
of head
sensitization to its behavioural effects and this was reflected in a decreased latency to onset and an increase duration of the response (see Fig. 1). The observation of sensitization to the behavioural effects of DISCUSSION PEA stands in general agreement with the results of Borison et al. (1977) who reported an increase in The results of the present study indicate that some of the behavioural effects of PEA are mediated by intensity of stereotypy during chronic treatment with brain 5-HT mechanisms. This is consistent with a 50 mg/kg of PEA. The principal measures of stereonumber of previous findings that large doses of PEA, typy used by Borison’s group were inactivity, head substituted phenylethylamines and amphetamine bobbing and decreased responsiveness to stimulation. induce the 5-HT behavioural syndrome in rats and In addition, animals were observed to display inmice (Lees et al., 1979; Breese. Cooper and Mueller. creased autonomic signs including salivation and 1974; Sloviter et al., 1978a. 1980a; Chung Hwang and piloerection. A number of these behavioural signs are Van Woert, 1980). A single injection of PEA at a dose components of the 5-HT syndrome which may have of 50 mg/kg produced the S-HT syndrome in 60”/0of been misinterpreted as DA-mediated stereotypy. the animals tested. This is consistent with the results Additional evidence for 5-HT mediation of the of Sloviter et al. (1980a) who found that acute doses of chronic PEA behavioural syndrome is provided by 40 or 6Omgkg of PEA produced the syndrome in 50 the present results using antagonist pre-treatment (see Table 2). The 5-HT antagonists mianserin and methyand 75”, respectively of animals tested. However these findings are at variance with the results of Bori- sergide prevented all the components of the PEAson er al. (1977) who reported that 50mgkg of PEA, induced syndrome with the exception of hyperreactiadministered acutely, was a subthreshold dose for the vity and salivation and produced hyperactivity. The induction of behavioural effects (stereotypy). There is neuroleptic clozapine also prevented the syndrome and produced marked sedation. In contrast haloperino immediately apparent reason for this discrepancy since the same strain of rats was used in all three dol prevented hyperreactivity and attenuated head studies. The results also demonstrate that doses of weaving, but had no effect on any of the other components of the syndrome (see Table 2). This is in PEA (as small as 25 mg/kg) can induce the 5-HTagreement with the results of Sloviter et al. (1980a) syndrome in rats provided the drug is administered who found that mianserin and methysergide (both chronically. Since PEA, as a substrate for monoamine 10 mg/kg) inhibited the 5-HT syndrome induced by a oxidase, is oxidized extremely rapidly (Durden and Philips, 1980) it seems likely that if this oxidation was single large dose of PEA and produced marked hyperactivity and hyperreactivity. However, larger blocked by a suitable monoamine oxidase inhibitor, then much smaller doses of PEA could be used to doses of the 5-HT antagonists and clozapine were required to inhibit the PEA syndrome in the present produce this behavioural syndrome. There was no apparent difference in intensity of the study, and this may be due to the increased behavPEA syndrome between rats tested individually and ioural potency of PEA observed after repeated adminrats tested in groups of 3 or 5. These results do not istration (see Fig. 1; N.B. anatagonist studies took support the suggestion that PEA has a more potent place after 28-42 days of PEA treatment). These findstimulant effect in grouped animals (Jackson, 1978) ings are consistent with the suggestion (Jacobs, 1974, although this discrepancy may be due to a species 1976; Grahame-Smith, 1971; Deakin and Dashwood, difference. Repeated administration of PEA produced 1981) that hyperactivity and hyperreactivity, unlike
1071
Behavioural effects of /%phenylethylamine
the other components of the S-HT syndrome, may not be a reflection of specific serotonergic activity, and could be mediated by DA rather than 5-HT. Further, Jacobs (1974) reported that spiroperidol blocked the 5-HT syndrome induced by L-tryptophan, but pimozide was only effective against head weaving. This finding is again consistent with 5-HT mediation since there is evidence that spiroperidol may act on 5-HT and DA receptors whereas pimozide and haloperidol may be more specific for DA receptors (Leysen, Niemegeers, Tollenaere and Laduron, 1978). Interestingly, a number of authors have suggested a ratio of neuroleptic potency at DA and 5-HT receptors based on behavioural, biochemical and receptor binding data (Fernando, Lees and Curzon, 1980; Leysen et al., 1978) which is in the following order: pimozide < haloperidoi < metoclopramide < ol-flupenthixol < thioridazine < clozapine. The latter ratios are proposed to increase with increasing antagonism at 5-HT receptors relative to antagonism at DA receptors. These relationships may shed some light on the interpretation of the results of Borison et a/. (1977) who found that clozapine and thioridazine were the most potent antagonists of chronic PEA-induced stereotypy. The present results and those of others (Sloviter et ul.. 1980a; Lees et al., 1979; Fernando et al., 1980; Leysen et a/., 1978) indicate that neurloeptics like clozapine may inhibit the behavioural syndrome associated with chronic administration of PEA via the induction of sedation and possibly, by an action on 5-HT receptors, A considerable body of evidence suggests that PEA possesses cat~holaminergic properties (Braestrup and Randrup, 1978; Jackson, 1972, 1978; Moja et al., 1978) which appear to be particularly important in the locomotor stimulant effects of the compound (Jackson, 1978; Ho, 1978). The results of the present study indicate that PEA also possesses serotonergic properties in tire which may be mediated by the release of endogenous S-HT or by a direct agonist effect on brain 5-HT receptors. One recent result supports the latter explanation (Sloviter et al., 1980a). The serotonergic behavioural effects of PEA show sensitization after repeated administration and further experiments are required to determine the cause of this effect. According to Borison et al. (1977) chronic PEAinduced stereotypy is dependent on limbic DA systems and noradrenergic mechanisms (Borison and Diamond, 1978) and, as such, has been proposed as an animal mode1 for schizophrenia. The present results indicate that 5-HT mechanisms are also involved in the behavioural effects of chronically administered PEA and it is, therefore, suggested that this finding may be of importance in the interpretation and use of the PEA model of schizophrenia. Although it is known that large doses of amphetamine can produce a syndrome closely akin to paranoid schizophrenia (Connell, 1958), it has not been demonstrated that exogenous PEA can induce a para-
noid state in normal subjects. The results of the present study demonstrate that PEA, like other paranoia-inducing drugs such as amphetamine and L-DOPA and many hallucinogenic drugs (Sloviter et al., 1978b; Sloviter, Drust, Darniano and Connor, 198Ob; Jenner, Marsden aid Thanki, 19801, can induce an abnormal behavioural syndrome which is thought to be mediated by brain 5-HT mechanisms. The behavioural syndrome increases in intensity after repeated administration of PEA and does not show signs of tolerance. Since it has been claimed that urinary concentrations of PEA are higher in chronic paranoid schizophrenics than in chronic non-paranoid schizophrenics or normals (Potkin, Karoum, Chuang Cannor-Spoor, Phillips and Wyatt, 1979), it is possible that PEA may play a role in the paranoid state. Aek~~~e~ge~e~~s-The author wishes to thank Dr A. A. Boulton and Dr R. S. G. Jones for constructive criticism of the manusc~pt and the Medical Research Council of Canada and Saskatchewan Health for continuing financial support. Drugs were generously supplied by Sandoz Canada Ltd (clozapine and methysergide), Organon, New Jersey, U.S.A. (mianserin) and Janssen, Beerse, Belgium (haloperidot).
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Snyder, S. H. (1973). Amphetamine psychosis: A “model” schizophrenia mediated by catecholamines. Aln. J. Psychiuf. 130: 61-67. Snyder. S. H., Banerjee. S. P., Yamamura, H. I. and Greenberg, D. (1974). Drugs, neurotransmitters and schizophrenia. Science 184: 1243-1253.