ABSTRACT
Introduction
Material and methods Subjects
Results
Discussion
Author: J. L. ZELGER, Hj. X. SCHORNO, E. A. CARLINI
Pages: 67 to 81
Creation Date: 1980/01/01
The effect of khat (Catha edulis Forsk., family Celastraceae), a plant used for its stimulant effects in eastern Africa and southern Arabia, has until recently been attributed to the pharmacological action of d-norpseudoephedrine, also known as cathine. The isolation in 1975 of cathinone revived an earlier suggestion that the fresh leaves contained a substance more potent than cathine. The pharmacological assays reported on in this paper appear to confirm the higher stimulant capacity of cathinone. This substance produces qualitatively similar locomotor stimulation in mice and comparable stereotypy in rats as amphetamine does, although it is approximately half as active. The results obtained after pre-treatment with reserpine or alpha-methyl- p-tyrosine, which interfere with the catecholamine system, strongly suggest that cathinone interacts with brain catecholamines by an indirect mechanism and, most probably, by affecting neurotransmitter release of the labile pool.
Catha edulis Forsk., popularly known as khat or quat, is a plant widely used in parts of eastern Africa and southern Arabia. Its fresh leaves and tops are chewed or, less frequently, dried and consumed as tea, in order to attain a state of euphoria and stimulation. This custom is of great social importance in those areas and is probably older than coffee use (Emboden, 1972).
*Work partially financed by FINEP (Financiadora de Estudos e Projetos) and AFIP (Associacao Fundo Incentivo à Psicofarmacologia). A preliminary account of the results was presented at the V Brazilian Symposium of Medicinal Plants, September 1978. São Paulo. The manuscript was received on May 1979.
The stimulant effect of the plant was attributed to norpseudoephedrine or cathine (Alles et al., 1961; Hoffmann et al., 1955), a phenylalkylamine-type compound (figure I) isolated from the plant by several authors (Stockmann, 1913; Wolfes, 1930; Paris and Moyse, 1957; Winterfeld and Bernsmann, 1960). However, the attribution was disputed by reports showing that plant extracts from fresh leaves contained an unknown compound more active than norpseudoephedrine, also known as cathine (Brücke, 1941; Brilla, 1962; Friebel and Brilla, 1963) and a search was begun for substances with greater activity than cathine. In 1975, a new substance named cathinone (L(S)-(-)-alpha-aminopropiophenone) was isolated (United Nations, 1975) and its absolute configuration was definitively established in 1978 (Schorno and Steinegger, 1978). Cathine and cathinone are phenylisopropylamine derivatives which resemble the amphetamine structure (figure I). Since the pharmacological properties of cathinone have not yet been sufficiently investigated, it was decided to compare its activity to cathine, amphetamine, apomorphine and nomifensine, using rats and mice. The last three drugs are well known examples of drugs which interfere with the catecholamine systems of the brain. For a better understanding of the mechanism of the action of cathinone, experiments were also carried out with rats previously treated with alpha-methyl- p-tyrosine, reserpine and haloperidol.
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Experiment I:
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Male albino mice, 2 months old, weighing 25-35 g, from our own colony
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Experiment II :
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Male Wistar rats, 3-4months old, weighing 250-350g, from our own colony
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The drugs used were the following: d-amphetamine-sulphate and dl-amphetamine-sulphate (Sigma) apomorphine HCl (Sandoz) cathine (d-norpseudoephedrine HCl) (Knoll), kindly supplied by Cooper S. A., Fribourg, Switzerland nomifensine (8-amino-2-methyl-4-phenyl- 1,2,3,4-tetrahydroisoquinoline hydrogen maleinate) (Hoechst) reserpine (Serpasil®ampoules, Ciba) haloperidol (Johnson) dl-alpha-methyl-p-tyrosine methyl ester HCl (alpha-MpT) (Sigma) dl-cathinone oxalate and dl-cathinone HCl, prepared in the laboratory of the Department of Pharmacognosy and Phytochemistry at the University of Berne, by a procedure described earlier (Schorno and Steinegger, 1978).
All drugs were dissolved in distilled water. The quantity injected into mice was 0.1 ml per 10 g and the quantity injected into rats was 0.1 ml per 100 g except for alpha-MpT and reserpine, which were injected into rats at the dosage of 0.3 ml per 100 g. Control solutions consisted of distilled water.
The experiments were carried out in air-conditioned laboratories at a temperature of 23 + 1°C, corresponding to the temperature in the animal house. Each animal was used once.
Spontaneous locomotor activity was recorded by means of 10 identical light-beam cages, each 25 x 40 cm crossed by three light beams. In a pre-selection test, one day before the experiment, the mice were deprived of food and water in the morning and placed individually (between 1100 and 1200) in the cages, and the total number of light-beam interruptions were recorded after one hour. For the experiment animals that scored between 300-700 interruptions during this hour were used. Within this range the animals were equally distributed among the groups. On the experimental day the mice were again deprived of food and water and the experiment took place between 1200 and 1600. The animals were placed individually in the cages 5 min after i.p. drug administration, and the number of light-beam interruptions was recorded at 15-min intervals during the first hour and then at 30-min intervals for a further 2h. In each session different dosages of one drug were administered and at least one control animal was also run. At the end of the experiment there were three control groups, one for each of the drugs used (amphetamine, cathine and cathinone). For each compound and dosage at least 10 mice were used.
The amount of cathinone, cathine and d-amphetamine administered are expressed as the weight of the corresponding bases. The following quantities were injected (mg/kg): cathinone, 30, 15, 7.5, 1.875, 1.25, 0.625 and 0.9325.
Measure of stereotyped behaviour. The rats were injected i.p. with one of the drugs used (cathinone, 2.5, 5, 10, 20 mg/kg; cathine, 10, 20, 40, 80 mg/kg; d-amphetamine, 2.5, 5 mg/kg) and placed individually in wire cages measuring 30x20x15 cm with a wire distance of 2 cm. Stereotyped behaviour was recorded in seconds for sniffing and verticalization (or rearing) and in number of bites and licks on the wire cage (criterion was the touching of the cage with the tongue or the surrounding by the teeth). The behaviour was recorded during 5-min periods beginning 5, 30, 60, 120 and 180 min after drug administration. For every group of drugs 5 rats were used. Food and water were withdrawn during observation.
Pre-treatment with alpha-MpT. Groups of 4 rats were injected i.p. with 300 mg/kg alpha-MpT or control solution 12 h before testing with cathinone, 20 mg/kg; cathine, 80 mg/kg; d-amphetamine, 5 mg/kg; and apomorphine, 5 mg/kg. Stereotyped behaviour was recorded as above.
Pre-treatment with reserpine. Groups of at least 5 rats were injected i.p. with 7.5 mg/kg of reserpine or control solution 18 h before testing with cathinone, 20 mg/kg; cathine, 80 mg/kg; d-amphetamine, 5 mg/kg; and nomifensine, 30 mg/kg. Stereotyped behaviour was recorded as above.
Pre-treatment with haloperidol. Groups of 6 rats were injected i.p. with 0.125 mg/kg or 0.25 mg of haloperidol or control solution 4 h before testing with cathinone, 20 mg/kg; cathine, 80 mg/kg; dl-amphetamine, 10 mg/kg. Stereotyped behaviour was recorded as above.
The results are summarized in Figure II. The two doses of amphetamine which were included for purposes of comparison showed the expected increase in motor activity. Low doses of cathinone (up to 1.25 mg/kg) failed to provoke stimulation of locomotion; on the contrary small; but significant decreases were observed with 1.25 mg/kg after 30 min and with 0.62 mg/kg at the end of 3 h. Beginning with 1.87 mg/kg (only after 3 h) and at all other larger doses (either after 30 min or 3 h) cathinone consistently increased motor activity. Motility was 5 times normal with 15 mg/kg after 3 h. At 30 mg/kg dosage, the increase was not so marked because stereotyped behaviour interfered with motor activity.
Effects of dl-cathinone, d -amphetamine (AMPH) and d -cathine on locomotor activity in mice. The columns represent the means of the cumulative activity count after 30 min (upper graph) and 3 h (lower graph) for each dosage (mg/kg), taking the means of the control groups as equal to 100. The actual means (± SD) of the control groups were, respectively, 222 ± 73, 224 ± 84 and 286 ± 76 counts after 30 min and 549 ± 283; 641 ± 419 and 719 ± 197 counts after 3 h. Asterisks indicate statistically significant differences from the control groups: *p < 0.05, **p < 0.01, ***p < 0.001 (Student's t-test, two-tailed).
Cathine, during the first 30 min. was less effective than cathinone. Significant differences from the control group were obtained only with 15 mg/kg and above. Furthermore, the maximum motility after 30 min was less than 3 times normal compared to 4 5 times with the however, cathine induced a proportionally larger increase in motility than cathinone, attaining with 30 mg/kg a value of 6 times the control value. This means that the cathine effect on motility persists during the 3 h of measurement, as can be better seen in figure III, where the time course curves of cathinone (3.75 - 30 mg/kg) and cathine (3.75 - 60 mg/kg) are plotted with those of the control groups and 1.87 mg/kg of amphetamine. The cathinone-treated animals (with the exception of the 30 mg/kg group in which the activity, followed by a rapid decline. The cathine groups, on the other hand, remained at a more constant dose-dependent level (attained after about 1 h) until the end of the test period. Therefore, the time course of the cathinone effect was similar to that of amphetamine, a fact that does not apply to cathine.
Dependence of locomotor activity of mice on time after treatment with dl-cathinone (upper graph) and d-cathine (lower graph), as compared to d-amphetamine- and control-treated animals. Each point represents the number of light-beam interruptions during a 15-min period. The symbols represent dosages as follows: Δ, 3.75 mg/kg; l, 7.5 mg/kg; Δ, 15 mg/kg; l, 30 mg/kg; Δ, 60 mg/kg; X, control groups with 95% confidence limit shown by the shadowed area. The dotted curve is for the dosage 1.87 mg/kg of d-amphetamine. Note that the cathinone and amphetamine curves peak at about 15-30 min and then decline rapidly in contrast to the cathine curves, which reach a plateau after about 60 min.
Measure of stereotyped behaviour. Figure IV summarizes the results. The doses 10 mg/kg of cathine and 2.5 mg/kg of cathinone are not represented as they were inactive. As it is seen, 20 mg/kg of d-cathine produced some but no continuous sniffing, and was practically inactive concerning verticalization and biting/licking; with 80 mg/kg, however, d-cathine was able to produce evident biting/licking which appeared after 2 h and persisted for at least another 2 h. The dl-cathinone induced marked sniffing beginning with 5.0 mg/kg, and biting/licking was clearly elicited with 20 mg/kg, an effect that started after 30 min.
For comparison purposes, figure IV shows also the effects of 2.5 and 5.0 mg/kg of apomorphine and d-amphetamine. Apomorphine acted almost immediately and reached its highest effect for sniffing, verticalization and biting after 30 min. Both doses of amphetamine were efficient in inducing sniffing for about 2 h but did not elicit marked verticalization; biting/licking were clearly observed only with the 5.0 mg/kg dosage. Therefore, both compounds from Catha edulis, being also weak elicitors of verticalization, approached more the effects of amphetamine than those of apomorphine. Furthermore, cathinone and also to some extent cathine elicited rapid head movements similar to those observed with amphetamine but not with apomorphine.
Pre-treatment with alpha-MpT. As seen in table 1, alpha-MpT completely abolished all types of stereotyped behaviour induced by 5.0 mg/kg of d-amphetamine and 20 mg/kg of cathinone. The blockade for the high dose of 80 mg/kg of cathine, although significant, was not complete for sniffing after 2 h (peak of the action of this drug), but verticalization and biting/licking were abolished. The apomorphine stereotypies were not affected at all by the pre-treatment; on the contrary, a significant intensification was observed.
Pre-treatment with reserpine. The results are summarized in table 2. Reserpine pre-treatment significantly increased the intensity and shortened the latency of the stereotyped behaviour induced by dl-cathinone and d-amphet-amine in comparison to the control animals. Cathine induced normal or even increased initial stereotypies; however, unlike the controls the effects progressively wore off, so that 30 - 60 min after injection, pre-treated animals showed significantly less stereotyped behaviour. Reserpine produced the expected results in the case of nomifensine, that is, greatly diminishing its sniffing and biting/licking effects
Effects of d-cathine, dl-cathinone, apomorphine (APO), and d-amphetamine (AMPH) on three items of stereotyped behaviour. The columns represent the mean behaviour of a group of 5 rats, observed over the 5-min intervals 5-10, 30-35, 60-65, 120-125 and 180-185 min after injection.
Pre-treatment with haloperidol. The results in table 3 show that the biting/licking caused by cathine, cathinone and amphetamine was significantly reduced by haloperidol, although in the case of cathine the effects were not so pronounced. The neuroleptic induced only a little alteration in the sniffing behaviour induced by the three drugs, although there was a tendency to reduce this effect. On the other hand, haloperidol-treated animals showed a tendency to increase verticalization, especially with cathine and amphetamine, combined with an observed higher locomotion (increased number of crossings in the cages).
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Verticalization (mean time in seconds ± S D) |
Sniffing (mean time in seconds ± SD) |
Biting/licking (mean number ± SD) |
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|---|---|---|---|---|---|---|---|---|
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Substance
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Dosage (mg/kg)
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Time after injection (min)
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Control
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Alpha-MpT
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Control
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Alpha-MpT
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Control
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Alpha-MpT
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dl-Cathinone
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20 |
30-35
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48±96
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0±0
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300±0
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1±2***
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156±117
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0±0
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60-65
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75±150
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0±0
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300±0
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3±5***
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352±123
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0±0**
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d-Cathine
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80 |
30-35
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1±1
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0±1
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297±3
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20±23***
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0±0
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1±1
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60-65
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12±25
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0±0
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298±4
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11±15***
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3±6
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0±0
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||
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120-125
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22±42
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0±0
|
300±0
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120±136*
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131±103
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0±0*
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d-Amphetamine
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5 |
30-35
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54±85
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10±21
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298±4
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11±22***
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10±19
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0±0
|
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60-65
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73±87
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0±0
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291±12
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0±0***
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38±25
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0±0*
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Apomorphine
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5 |
30-35
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298±4
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157±166
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300±0
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300±0
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130±121
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263±104
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60-65
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95±139
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176±149
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104±135
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300±0*
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23±46
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312±108**
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Notes:
There were four animals in each group.
Asterisks indicate statistically significant differences from the respective control groups (* p≤0.05; ** p≤0.01; *** p≤0.001; Student's t-test, two-tailed)
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Verticalization (mean time in seconds ± S D) |
Sniffing (mean time in seconds ± SD) |
Biting/licking (mean number ± SD) |
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Substance
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Dosage (mg/kg)
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Time after injection (min)
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Control
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Reserpine
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Control
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Reserpine
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Control
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Reserpine
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dl-Cathinone
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20 |
5-10
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31±21
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64± 113
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247±53
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300±0
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0±0
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265±142
**
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30-35
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0±0
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166±152
*
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300±0
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300±0
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195±111
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360±125
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||
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60-65
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0±0
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165±152
*
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300±0
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300±0
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416±160
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397±118
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d-Cathine
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80 |
5-10
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9±15
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4±7
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141 ±78
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133± 100
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1±3
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36±74
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30-35
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24±68
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0±0
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297±4
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161±134
*
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0±0
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29±47
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||
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60-65
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33±73
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1±3
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299±3
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122±127
**
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2±4
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16±14
*
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120-125
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79±121
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4±11
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300±0
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49±59
***
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142±132
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13±21
*
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d-Amphetamine
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5 |
5-10
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52±64
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86±109
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203±83
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300±0
*
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0 |
230±154
**
|
|
30-35
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45±35
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116±142
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300±0
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300±0
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6±0
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485±60
***
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||
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60-65
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33±36
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121± 106
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300±0
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300±0
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36±66
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477±71
***
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Nomifensine
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30 |
5-10
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28±13
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19±24
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257±40
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118±73
**
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0±0
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3±6
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30-35
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1±2
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8±11
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295±11
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183±109
*
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158±129
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11±11
*
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60-65
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0±0
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4±5
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300±0
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48±35
***
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183±140
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8±6
*
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Notes:
There were five animals in each group except for d-cathine, in which there were eight
Asterisks indicate statistically significant differences from the respective Control groups (* p≤0.05; ** p≤0.01; *** p≤0.001; Student's t-test, two-tailed).
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Verticalization (mean time in seconds ± S D) |
Sniffing (mean time in seconds ± SD) |
Biting/licking (mean number ± SD) |
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|---|---|---|---|---|---|---|---|---|
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Substance
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Dosage
(mg/kg)
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Time
after
injection
(min)
|
Control
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Haloperidol•
|
Control
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Haloperidol•
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Control
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Haloperidol•
|
|
dl-Cathinone
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20 |
60-65
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79±120
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87±115
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300±0
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294±10
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237±144
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0±0
**
|
|
41±51
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287±29
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16±40 **
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d-Cathine
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80 |
120-125
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0±0
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94±116
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299±2
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291±10
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174±105
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47±81
*
|
|
1±2
|
284±38
|
48±93
|
||||||
|
dl-Amphetamine
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10 |
60-65
|
0±0
|
52±77
|
300±0
|
289±10
*
|
188±121
|
1±2
**
|
|
77±64
*
|
256±94
|
10±24
**
|
||||||
Notes:
There were six animals in each group.
Asterisks indicate statistically significant differences from the respective control groups (* P≤0.05; ** P≤0.01; Student's t-test two-tailed).
The first entry is for the smaller dosage (0.125 mg/kg), the second for the larger (0.25 mg/kg).
The results described above show that both cathine and cathinone possess central stimulant properties, but the properties differ quantitatively and qualitatively from each other.
In the case of locomotor stimulation cathinone acted almost like amphetamine, although a higher dosage was necessary to produce approximately the same activity. However, even working with dosages calculated as the bases of the compounds, a precise quantitative comparison is difficult, due to the use of the active d-form of amphetamine and the racemic form of cathinone, of which the l-form is more active (Schorno and Steinegger, 1978). If the ratio of activities of the two isomers of cathinone corresponds to that of amphetamine, l-cathinone would be almost half as active in producing locomotor stimulation as d-amphetamine. On the other hand, d-carbine, the naturally occurring form of the substance (Halbach, 1972), turned out to be much less active than d-amphetamine, confirming the data of Fairchild and Alles (1967). But while cathinone showed a similar locomotor activity vs. time curve as amphetamine, with its typical high initial stimulation and rapid decline, cathine produced a somewhat retarded increase in locomotion, attaining the maximum response after about one hour and persisting for at least one more hour.
A similar observation was made by Brilla (1962) with a non-identified khat component that produced a different dose-effect curve in comparison to d-nor-pseudoephedrine (cathine), the supposed active principle of Catha edulis Forsk. At that time this unknown component, present only in fresh leaves, was thought to be a labile precursor of cathine (Friebel and Brilla, 1963). It is very likely that this component was, or at least contained, cathinone. Cathinone seems to be contained only in young leaves (Schorno, personal communication), which would explain why only the tops of the plant are used by khat chewers. However, cathinone can be encountered also in dry plant material if the drying of young leaves is carefully done (Schorno and Steinegger, 1978) not just in fresh plant material, as supposed earlier (Friebel and Brilla, 1963; United Nations, 1975).
The difference in action between carbine and cathinone must lie in the substitution on C 1 of the side chain. In a systematic comparison of derivatives of isopropylamine, van der Schoot et al. (1962) found that beta-hydroxy derivatives produced only minimal activity, while the beta-keto derivatives had a locomotor stimulating effect in mice. However, their potency was reduced in comparison to amphetamine. The more rapid and more intense action of cathinone could be due to the higher liposolubility of the keto group, facilitating access into the central nervous system.
Three of the possible mechanisms for the action of cathinone are:
Direct stimulation of the post-synaptic receptors Stimulation of the release of catecholamines (CA) stored in the pre-synaptic terminals
Inhibition of the re-uptake from the synaptic cleft of the released catecholamines
The last possibility can be excluded because all known drugs which inhibit the uptake of catecholamines do not elicit such a strong stimulation of motor activity. To study the first two possibilities, the stereotyped behaviour elicited by cathinone was compared to that of apomorphine, a dopamine agonist, and of d-amphetamine, which stimulates the liberation of CA (Carlsson, 1970).
The general profile of the stereotyped behaviour produced by cathinone, as well as by carbine, in high doses was shown to be very similar to that evoked by amphetamine and different from that of apomorphine. Thus, stereotyped behaviour elicited by both khat compounds and by amphetamine showed little verticalization and much head movement compared to apomorphine. Further-more, blocking the synthesis of CA by alpha-MpT completely abolished the stereotyped behaviour in cathine- and cathinone-treated animals, as observed with amphetamine. On the other hand, the action of apomorphine was increased, due probably to a hypersensibilization of post-synaptic receptors (Constantin et al., 1977). This result indicates that cathinone is implicated in the liberation of CA and does not act as a direct agonist.
The results of the experiment with reserpine pre-treatment illustrate the way cathinone (and also the drugs used for comparative purposes) acts on the release of CA. The effects of nomifensine, which, like methyl phenydate, acts by releasing CA from the fixed pool, which is largely depleted by reserpine (Braestrup and Scheel-Kruger, 1976), were blocked. The effects induced by cathinone, as well as those of amphetamine, were not affected by reserpine. These data, taken together with the results obtained with alpha-MpT, indicate that cathinone, like amphetamine, acts by stimulating the release of CA from the freshly synthesized pool. Furthermore, pre-treatment with reserpine increased the stereotyped behaviour induced by cathinone in a similar way to that observed for amphetamine, which has already been described (Smith, 1963; Morpurgo and Theobald, 1966; Stolk and Rech, 1967). For cathine, an interpretation of the results is difficult because initially the stereotyped behaviour was similar or more intense (for biting/licking) as compared to the non-pre-treated controls, but it diminished subsequently to near extinction after 2 h (peak-time of the controls).
The pre-treatment with 0.125 and 0.25 mg/kg of haloperidol reduced more specifically the biting/licking component than the other items of stereotyped behaviour (table 3). Locomotion and verticalization were even observed to increase. Haloperidol has been reported to influence certain items of stereotypy more than others (Ungerstedt et al., 1977). Such a qualitative shift in the stereo-type behaviour could be the result of a dopaminergic inhibition leading to a nor-adrenergic potentiation as suggested by Mogilnicka and Braestrup (1976). While cathinone again behaved like amphetamine, cathine seemed to be less affected by the neuroleptic, possibly in part because of the much higher dose of cathine injected.
In summary, cathinone, the newly isolated compound of Catha edulis Forsk., shows, as does amphetamine, a strong potency in stimulating the central nervous system and exhibits a similar mechanism of action. Contrary to the case of amphetamine, however, there are only a few reports of psychotic states after khat ingestion (Laurent, 1962; Le Bras and Fretillere, 1965; Halbach, 1972). This low incidence of ill-effects can probably best be explained by the self-limiting way in which khat is consumed in the areas concerned.
*The first entry is for the smaller dosage (0.125 mg/kg), the second for the larger (0.25 mg/kg).
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