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Mediator mechanisms of cathinone effects on animal behaviour
31
Drug and Alcohol Dependence, 12 (1983) 3135 Elsevier Scientific Publishers Ireland Ltd.
MEDIATOR MECHANISMS BEHAVIOUR
E.A. BABAYAN,
N.K. BARKOV’
Serbsky All-Union (Received February
Research
OF CATHINONE
EFFECTS
ON ANIMAL
and A.I. MACHULA
Institute of General and Forensic
Psychiatry,
Moscow
(U.S.S.R.)
8th. 1983)
SUMMARY
The effect of cathinone on the visual differentiation of cats was investigated by the method of defense conditioned reflexes. It was found that cathinone decreases the differentiation of both the short-term and prolonged visual stimuli. These effects of cathinone increase when the serotoninergic system is activated and decrease under dopaminergic system activation.
Key words: Cathinone
-Visual
differentiation
- Animals
INTRODUCTION
Only a few reports deal with the biological effects of cathinone ((Yaminopropiophenone), an active compound of Khat (Cutha eduhs) 11,21. It was demonstrated that cathinone manifests effects similar to those of amphetamines in such tests as circular movement 131 and locomotor activity [4-61. There are some data showing that cathinone affects dopamine turnover [3]. Therefore its effects are produced at least partially, by interaction with monoaminergic systems. In this connection it seemed interesting to study the effect of chathinone on conditioned reflexes and the involvement of monoaminergic systems in the realization of these effects.
“To whom correspondence should be sent. Abbreviations: CR, conditioned reflex; DA, dopamine; DPS, differentiation of the prolonged stimulus of 3000 ms; DSS, differentiation of the short stimulus of 500 ms; 5-I-IT, serotonin; 5-HTP, 5-hydroxytryptophan; IR, interstimuli responses; LP, latent period; LPD, LP of conditioned reflexes for the differentiated stimuli; LPS, LP of conditioned reflexes for the single stimuli: L-MPT, L-methylparatyrosine; PCPA, parachlorphenylalanine. 03768716/83/$03.00 @ 1983 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland Ltd.
32 METHODS
Cats were trained by means of the defense conditioned reflex to distinguish between two differently orientated lines presented for 500 and 3000 ms. The training was considered to be completed when the differentiation of the visual stimuli at 3000 ms was accomplished correctly in the overwhelming majority of cases (approximating 100%). The correctness of the differentiation at 500 ms was at lower level (60-70%) irrespective of the length of training. Details of the methods used had been described by us previously [7]. The following parameters of the conditioned reflex (CR) were studied: differentiation of the short stimulus of 500 ms (DSS) and the prolonged stimulus of 3000 ms (DPS), latent period (LP) of the conditioned reflexes for the differentiated (LPD) and single stimuli (LPS), number of the inter-stimuli responses (IR). To analyze the effect of cathinone the following substances relative to three transmitted systems were used: (1) Serotoninergic. 1 mg/kg of methysergide (blocker of serotonin (5-I-IT)) receptors 45 min before cathinone administration; 20 mglkg of 5-hydroxytryptophan (5-HTP) - precusor of 5-HT - 1 h before cathinone administration; 200 mgfkg of parachlorphenylalanine (PCPA) -decreasing the synthesis of serotonin at the stage of the tryptophan hydroxylation -48 h before cathinone administration. (2) Dopaminergic. 20 mg/kg of L-DOPA - precusor of dopamine (DA) cathinone administration; 0.3 mg/kg of apomorphine -agonist of the DA receptors - 60 and 45 min respectively before cathinone administration. (3) Adrenergic. 2 mg/kg of phentolamine hydrochloride - cyadrenoblocker - and 3 mg/kg of propranolol - /?-adrenoblocker - 45 min before cathinone administration; 100 mg/kg of L-methylparatyrosine (LMPT) -blocker of the synthesis of catecholamines - 8 h before cathinone administration. All substances were administered intraperitoneally in the doses which did not alter the parameters of the conditioned reflexes. The cathinone dose was 1 mg/kg. The results of the experiments were processed statistically. RESULTS
In preliminary experiments it was demonstrated that the administration of cathinone 1 mg/kg led to the deterioration of the differentiation of the short and prolonged stimuli; did not alter the latent period of the conditioned reflex in response to differentiated stimuli; accelerated the conditioned reflex in response to a single stimulus, increased the number of interstimulus responses (Table I). In the experiments with the substances altering the activity of the mediator systems the following results were obtained. Methysergide removed the oppressive effect of cathinone on DPS, did not alter the effect of the latter on DSS and LPS and intensified its oppressive effect on IR.
I
DSS (%I DPS (%ng) LPD (S) LPS (S) IR WI
M t S.D.
*Difference substance:
53 f 3.34
82 t 4.26
9.6 IT0.065
7.3 t 0.045
2.1 f 0.095
95 it 2.25
9.5 -t 0.07
7.5 t 0.035
1.4 2 0.07
M -t S.D.
1 mgkg
Cathinone
72 t 3.8
Pi-e-Drug
P < 0.05.
*2.2 t 0.071
7.2 -t 0.055
9.7 c 0.033
“95 i 2.25
53 i 4.9
M 2 S.D.
1 mgkg M rt S.D. *66 2 2.13 *95 t 2.24 9.5 + 0.055 7.3 t 0.045 2.0 2 0.064
*42 2 3.076 “68 2 3.07 9.6 -t 0.041 7.3 + 0.063 2.1 t 0.07
20 mg/kg
Cathinone L-DOPA
M 2 SD.
+
+
*65 t 2.24 *97*2.11 9.5 i 0.095 7.2 2 0.08 2.1 r 0.095
‘72 2 3.076 *95 i- 2.24 9.6 + 0.054 “7.0 ? 0.063 “2.5 + 0.095
Cathinone + apomorphine 0.3 mg/kg M ITSD.
+
M lr S.D.
200 mglkg
Cathinone PCPA
M k S.D. *53 + 3.4 81+ 4.02 9.6 -t 0.065 7.2 2 0.055 2.1 1-0.16
‘43 + 2.11 “70 t 2.56 9.6 i 0.083 7.2 z 0.065 2.2 2 0.07
2 mgkg
Cathinone + phentolamine HCl
M 5 S.D.
+
2.2 t 0.65
7.2 -t 0.065
9.6 2 0.045
83 -+3.33
54 t 4.9
M t SD.
3 mg/kg
Cathinone propranolol
BY SUBSTANCES
plus interacting
REFLEX
Cathinone L-MPT lOOmg/kg
and cathinone
OF THE CONDITIONED
reflex after cathinone
PARAMETERS
of the conditioned
Cathinone 5-HTP 20 mgkg
of a given parameter
Cathinone + methysergide
between the mean quantity
ALTERATION OF THE CATHINONE EFFECT ON THE DIFFERENT INFLUENCING THE ACTIVITY OF THE MEDIATOR SYSTEMS
TABLE
34
5-HTP intensified the oppressive effect of cathinone on DSS and DPS, but did not alter its effect on IR and LPS. PCPA removed the oppressive effect of cathinone on DSS and DPS and intensified it on LPS and IR. L-DOPA decreased the effect of cathinone on DPS and DSS, and did not alter its effect on LPS and IR. Apomorphine produced the same effect. Propranolol and phentolamine hydrochloride (blockers of 6- and aadrenoreceptors) did not alter the cathinone effect. L-MPT intensified the effect of cathinone on DSS and DPS. Thus the experiments demonstrated a number of facts indicative of the heterogeneous interaction of cathinone with the monoaminergic systems. It was found that the oppressive effect of cathinone on the differentiation of the visual stimuli was modified by simultaneous interaction with the serotonin - as well as dopaminergic system. Activation of the serotoninergic system intensifies the effect of cathinone and activation of the dopaminergic system decreases it. The blockade of the serotonin receptors affected the cathinone effect only with respect to the prolonged stimuli whereas alteration of the serotonin level changed the cathinone effect on the differentiation of the prolonged as well as of short-term stimuli. A still greater difference was observed in the cases of alteration of the catecholamine level and blockade of the adrenoreceptors. DISCUSSION
The experiments demonstrated that cathinone deteriorates the diff erentiation of the visual stimuli. Zelger and Carlini [3] have shown that after cathinone administration the release of dopamine is increased and its reuptake inhibited, resulting in the activation of the dopaminergic system. It is also known [8-101 that the activation of this system leads to the improvement of the visual differentiation. In contrast to Zelger and Carlini we administered cathinone in a small dose. Taking into account its similarity to amphetamine it is not unlikely that in this dose it, like amphetamine [ll] reduces the activity of the dopaminergic system. It is therefore, quite natural that the agonists of DA, L-DOPA and apomorphine decrease the effect of cathinone. It was found that the substances inhibiting the activity of 5-HT (metisergid, PCPA) decrease the effect of cathinone on the differentiation and 5-HTP intensifies it to some extent. Decrease of the cathinone effect under the influence of methysergide and PCPA is in line with the finding by Stevens [12] that under activation of the 5HT system the ability to differentiate is reduced. It is worth noting that 5-HTP and PCPA affect the cathinone effect with respect to DSS as well as DPS and methysergide decreases the cathinone effect with respect to DPS only. Methysergide does not block all the effects of serotonin [ 131 and besides it is effective in not all the regions, where serotonin receptors were detected 1141 which according to the latest data differ in the raphe and in other regions of a brain [15,16].
35
Analogically we can explain the fact that (Y- and P-adrenoblockers do not hamper the effect of cathinone since it is known that the adrenoblockers act differently on effects of norepinephrine, whereas L-MPT alters the content of all the catecholamines. Thus the experiments carried out demonstrate that the cathinone effects with respect to the differentiation of the visual stimuli are connected with the serotonin- and dopaminergic systems whereby the activation of the 5-HT system intensifies the cathinone effect whereas the activation DAergic system leads to its decrease. REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
X. Schomo and E. Steinegger, United Nations Document (Geneva), MNAR (71 1978. World Health Organization, Advisory Group on Khat, Bull. Narcotics, 32 (1981) 83. J.L. Zelger and E.A. Carlini, Neuropharmacology, 20 (19811 839. N.K. Barkov and L.M. Andronova, IY Vsesojuzny simpozium po tselena-pravlennomu izyskaniju fiziologicheski aktivnyh veschestv, Riga, 1981. C. Valterio and P. Kalix, Arch. Int. Pharmacodyn. 255 (1982) 196. P. Kalix, Progr. Neuropsychopharmacol., 6 (1982) 43. A.I. Machula, N.K. Barkov and V.P. Fisenko, Farmakologiya i toksikologiya (1980) 16. A.J. Oke and R.N. Adams, Pharmacol. B&hem. Behav., 9 (1978) 429. N.C. de Lanerolle and J.R. Millam, J. Comp. Physiol. Psychol., 94 (1980) 346. T.J. Brozoski et al., Proc. 4th Int. Catecholamine Symp. Pacific Grove, California, Vol. 2. 1978. M. Baraldi, M. Sandrini and A. Benassi-Benelli, Riv. farmacol. eter., 8 (1978) 381. D.A. Stevens, Life Sci., 9 (1970) 1127. H.J. Haigler and G.K. Adhajanian, J. Neural. Trans., 35 (1974) 257. H.J. Haigler and G.K. Adhajanian, Fed. Proc., 36 (1977) 2159. C. Ennis, Br. J. Pharmacol., 74 (1981) 290. C. Ennis and B. Cox, Neuropharmacology, 21 (1982) 41.
Drug and Alcohol Dependence, 12 (1983) 3135 Elsevier Scientific Publishers Ireland Ltd.
MEDIATOR MECHANISMS BEHAVIOUR
E.A. BABAYAN,
N.K. BARKOV’
Serbsky All-Union (Received February
Research
OF CATHINONE
EFFECTS
ON ANIMAL
and A.I. MACHULA
Institute of General and Forensic
Psychiatry,
Moscow
(U.S.S.R.)
8th. 1983)
SUMMARY
The effect of cathinone on the visual differentiation of cats was investigated by the method of defense conditioned reflexes. It was found that cathinone decreases the differentiation of both the short-term and prolonged visual stimuli. These effects of cathinone increase when the serotoninergic system is activated and decrease under dopaminergic system activation.
Key words: Cathinone
-Visual
differentiation
- Animals
INTRODUCTION
Only a few reports deal with the biological effects of cathinone ((Yaminopropiophenone), an active compound of Khat (Cutha eduhs) 11,21. It was demonstrated that cathinone manifests effects similar to those of amphetamines in such tests as circular movement 131 and locomotor activity [4-61. There are some data showing that cathinone affects dopamine turnover [3]. Therefore its effects are produced at least partially, by interaction with monoaminergic systems. In this connection it seemed interesting to study the effect of chathinone on conditioned reflexes and the involvement of monoaminergic systems in the realization of these effects.
“To whom correspondence should be sent. Abbreviations: CR, conditioned reflex; DA, dopamine; DPS, differentiation of the prolonged stimulus of 3000 ms; DSS, differentiation of the short stimulus of 500 ms; 5-I-IT, serotonin; 5-HTP, 5-hydroxytryptophan; IR, interstimuli responses; LP, latent period; LPD, LP of conditioned reflexes for the differentiated stimuli; LPS, LP of conditioned reflexes for the single stimuli: L-MPT, L-methylparatyrosine; PCPA, parachlorphenylalanine. 03768716/83/$03.00 @ 1983 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland Ltd.
32 METHODS
Cats were trained by means of the defense conditioned reflex to distinguish between two differently orientated lines presented for 500 and 3000 ms. The training was considered to be completed when the differentiation of the visual stimuli at 3000 ms was accomplished correctly in the overwhelming majority of cases (approximating 100%). The correctness of the differentiation at 500 ms was at lower level (60-70%) irrespective of the length of training. Details of the methods used had been described by us previously [7]. The following parameters of the conditioned reflex (CR) were studied: differentiation of the short stimulus of 500 ms (DSS) and the prolonged stimulus of 3000 ms (DPS), latent period (LP) of the conditioned reflexes for the differentiated (LPD) and single stimuli (LPS), number of the inter-stimuli responses (IR). To analyze the effect of cathinone the following substances relative to three transmitted systems were used: (1) Serotoninergic. 1 mg/kg of methysergide (blocker of serotonin (5-I-IT)) receptors 45 min before cathinone administration; 20 mglkg of 5-hydroxytryptophan (5-HTP) - precusor of 5-HT - 1 h before cathinone administration; 200 mgfkg of parachlorphenylalanine (PCPA) -decreasing the synthesis of serotonin at the stage of the tryptophan hydroxylation -48 h before cathinone administration. (2) Dopaminergic. 20 mg/kg of L-DOPA - precusor of dopamine (DA) cathinone administration; 0.3 mg/kg of apomorphine -agonist of the DA receptors - 60 and 45 min respectively before cathinone administration. (3) Adrenergic. 2 mg/kg of phentolamine hydrochloride - cyadrenoblocker - and 3 mg/kg of propranolol - /?-adrenoblocker - 45 min before cathinone administration; 100 mg/kg of L-methylparatyrosine (LMPT) -blocker of the synthesis of catecholamines - 8 h before cathinone administration. All substances were administered intraperitoneally in the doses which did not alter the parameters of the conditioned reflexes. The cathinone dose was 1 mg/kg. The results of the experiments were processed statistically. RESULTS
In preliminary experiments it was demonstrated that the administration of cathinone 1 mg/kg led to the deterioration of the differentiation of the short and prolonged stimuli; did not alter the latent period of the conditioned reflex in response to differentiated stimuli; accelerated the conditioned reflex in response to a single stimulus, increased the number of interstimulus responses (Table I). In the experiments with the substances altering the activity of the mediator systems the following results were obtained. Methysergide removed the oppressive effect of cathinone on DPS, did not alter the effect of the latter on DSS and LPS and intensified its oppressive effect on IR.
I
DSS (%I DPS (%ng) LPD (S) LPS (S) IR WI
M t S.D.
*Difference substance:
53 f 3.34
82 t 4.26
9.6 IT0.065
7.3 t 0.045
2.1 f 0.095
95 it 2.25
9.5 -t 0.07
7.5 t 0.035
1.4 2 0.07
M -t S.D.
1 mgkg
Cathinone
72 t 3.8
Pi-e-Drug
P < 0.05.
*2.2 t 0.071
7.2 -t 0.055
9.7 c 0.033
“95 i 2.25
53 i 4.9
M 2 S.D.
1 mgkg M rt S.D. *66 2 2.13 *95 t 2.24 9.5 + 0.055 7.3 t 0.045 2.0 2 0.064
*42 2 3.076 “68 2 3.07 9.6 -t 0.041 7.3 + 0.063 2.1 t 0.07
20 mg/kg
Cathinone L-DOPA
M 2 SD.
+
+
*65 t 2.24 *97*2.11 9.5 i 0.095 7.2 2 0.08 2.1 r 0.095
‘72 2 3.076 *95 i- 2.24 9.6 + 0.054 “7.0 ? 0.063 “2.5 + 0.095
Cathinone + apomorphine 0.3 mg/kg M ITSD.
+
M lr S.D.
200 mglkg
Cathinone PCPA
M k S.D. *53 + 3.4 81+ 4.02 9.6 -t 0.065 7.2 2 0.055 2.1 1-0.16
‘43 + 2.11 “70 t 2.56 9.6 i 0.083 7.2 z 0.065 2.2 2 0.07
2 mgkg
Cathinone + phentolamine HCl
M 5 S.D.
+
2.2 t 0.65
7.2 -t 0.065
9.6 2 0.045
83 -+3.33
54 t 4.9
M t SD.
3 mg/kg
Cathinone propranolol
BY SUBSTANCES
plus interacting
REFLEX
Cathinone L-MPT lOOmg/kg
and cathinone
OF THE CONDITIONED
reflex after cathinone
PARAMETERS
of the conditioned
Cathinone 5-HTP 20 mgkg
of a given parameter
Cathinone + methysergide
between the mean quantity
ALTERATION OF THE CATHINONE EFFECT ON THE DIFFERENT INFLUENCING THE ACTIVITY OF THE MEDIATOR SYSTEMS
TABLE
34
5-HTP intensified the oppressive effect of cathinone on DSS and DPS, but did not alter its effect on IR and LPS. PCPA removed the oppressive effect of cathinone on DSS and DPS and intensified it on LPS and IR. L-DOPA decreased the effect of cathinone on DPS and DSS, and did not alter its effect on LPS and IR. Apomorphine produced the same effect. Propranolol and phentolamine hydrochloride (blockers of 6- and aadrenoreceptors) did not alter the cathinone effect. L-MPT intensified the effect of cathinone on DSS and DPS. Thus the experiments demonstrated a number of facts indicative of the heterogeneous interaction of cathinone with the monoaminergic systems. It was found that the oppressive effect of cathinone on the differentiation of the visual stimuli was modified by simultaneous interaction with the serotonin - as well as dopaminergic system. Activation of the serotoninergic system intensifies the effect of cathinone and activation of the dopaminergic system decreases it. The blockade of the serotonin receptors affected the cathinone effect only with respect to the prolonged stimuli whereas alteration of the serotonin level changed the cathinone effect on the differentiation of the prolonged as well as of short-term stimuli. A still greater difference was observed in the cases of alteration of the catecholamine level and blockade of the adrenoreceptors. DISCUSSION
The experiments demonstrated that cathinone deteriorates the diff erentiation of the visual stimuli. Zelger and Carlini [3] have shown that after cathinone administration the release of dopamine is increased and its reuptake inhibited, resulting in the activation of the dopaminergic system. It is also known [8-101 that the activation of this system leads to the improvement of the visual differentiation. In contrast to Zelger and Carlini we administered cathinone in a small dose. Taking into account its similarity to amphetamine it is not unlikely that in this dose it, like amphetamine [ll] reduces the activity of the dopaminergic system. It is therefore, quite natural that the agonists of DA, L-DOPA and apomorphine decrease the effect of cathinone. It was found that the substances inhibiting the activity of 5-HT (metisergid, PCPA) decrease the effect of cathinone on the differentiation and 5-HTP intensifies it to some extent. Decrease of the cathinone effect under the influence of methysergide and PCPA is in line with the finding by Stevens [12] that under activation of the 5HT system the ability to differentiate is reduced. It is worth noting that 5-HTP and PCPA affect the cathinone effect with respect to DSS as well as DPS and methysergide decreases the cathinone effect with respect to DPS only. Methysergide does not block all the effects of serotonin [ 131 and besides it is effective in not all the regions, where serotonin receptors were detected 1141 which according to the latest data differ in the raphe and in other regions of a brain [15,16].
35
Analogically we can explain the fact that (Y- and P-adrenoblockers do not hamper the effect of cathinone since it is known that the adrenoblockers act differently on effects of norepinephrine, whereas L-MPT alters the content of all the catecholamines. Thus the experiments carried out demonstrate that the cathinone effects with respect to the differentiation of the visual stimuli are connected with the serotonin- and dopaminergic systems whereby the activation of the 5-HT system intensifies the cathinone effect whereas the activation DAergic system leads to its decrease. REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
X. Schomo and E. Steinegger, United Nations Document (Geneva), MNAR (71 1978. World Health Organization, Advisory Group on Khat, Bull. Narcotics, 32 (1981) 83. J.L. Zelger and E.A. Carlini, Neuropharmacology, 20 (19811 839. N.K. Barkov and L.M. Andronova, IY Vsesojuzny simpozium po tselena-pravlennomu izyskaniju fiziologicheski aktivnyh veschestv, Riga, 1981. C. Valterio and P. Kalix, Arch. Int. Pharmacodyn. 255 (1982) 196. P. Kalix, Progr. Neuropsychopharmacol., 6 (1982) 43. A.I. Machula, N.K. Barkov and V.P. Fisenko, Farmakologiya i toksikologiya (1980) 16. A.J. Oke and R.N. Adams, Pharmacol. B&hem. Behav., 9 (1978) 429. N.C. de Lanerolle and J.R. Millam, J. Comp. Physiol. Psychol., 94 (1980) 346. T.J. Brozoski et al., Proc. 4th Int. Catecholamine Symp. Pacific Grove, California, Vol. 2. 1978. M. Baraldi, M. Sandrini and A. Benassi-Benelli, Riv. farmacol. eter., 8 (1978) 381. D.A. Stevens, Life Sci., 9 (1970) 1127. H.J. Haigler and G.K. Adhajanian, J. Neural. Trans., 35 (1974) 257. H.J. Haigler and G.K. Adhajanian, Fed. Proc., 36 (1977) 2159. C. Ennis, Br. J. Pharmacol., 74 (1981) 290. C. Ennis and B. Cox, Neuropharmacology, 21 (1982) 41.