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Effects of subacute repeated injections of phencyclidine and MK-801 on substance P content in the rat brain
352
Regulator) Peptldes. 46 (1993) 352-353 © 1993 Elsevier Science Pubhshers B V All rights reserved 0167-0115/93,'$06 00
REGPEP 01458
Effects of subacute repeated injections of phencyclidine and MK-801 on substance P content in the rat brain H. Mitsushio, Y. Shirayama, T. N l s h i k a w a and K. T a k a h a s h l Dtvtston of Mental Disorder Research, National Center of Neurosclence, Tokyo (Japan)
Key words" Substance P; Schizophrenia; Phencyclldlne; Methamphetamine, MK-801; Prefrontal cortex; Rat brain
Introduction
Several species of evidence suggest that substance P (SP) is revolved m the pathogenesls of schizophrenia (1) It is well known that hyper-dopaminergic state exist in the brain of schizophrenics It is also well estabhshed that SP has an excitatory effect on the activity of dopamine neuron [1] Moreover, the m~croinjection of antl-SP antibody into the ventral tegmental area (VTA) prevents the stress-induced increase in dopamlne turnover in the frontal cortex [2]. (2)We have reported the elevation of SP concentration at various brain regions including the prefrontal cortex in the post-mortem brains from chromc schizophrenics [3]. There were highly significant positive correlations between SP and actwlty of tyrosine hydroxylase, which is the rate llmmng enzyme ofdopamine synthesis (3) Methamphetamine, which
causes an psychotic state stmilar to the acute schizophrenia with posltwe symptoms (delusions or hallucinations) after abuse, decrease SP concentration in the nlgro-striatal system after a single injection [4], and increase SP concentration m the same brain areas after large dose repeated injections [5]. Phencyclidine (PCP), which is a non-competitive N M D A receptor antagomst, also causes a psychosis with both positive and negatwe symptoms (auUsm, emoUonal withdraw or abuha) which is more similar to schizophrenia [6] than methamphetamme In this experiment, we investigated whether PCP affected SP levels m the brain after single or repeated admmlstration To compare with PCP, effects of MK-801, which is a non-competitive N M D A receptor antagonist but not has the psychosis inducing effect, is also investigated.
Methods Correspondence to H Mltsushlo, Divaslon of Mental Disorder Research, National Center of Neurosc]ence, NCNP, 4-1-1 Ogawahlgashlmachl, Kodalra, Tokyo 187, Japan
Smgle admintstratton Male Wlstar r a t s w e i g h i n g 180-200 g were used. PCP was given at doses 2.0, 5.0, 10 mg/kg 1.p. and decapitated 60 mm after the
353 TABLE I Increase in SP content m the prefrontal cortex 24 h after PCP repeated administration Area
Control
PCP (10mg/kg)
MK-801 (1.0mg/kg)
Prefrontal cortex Llmblc forebram Stnatum Substantla mgra Ventral tegmental area
135 _+6 736 + 45 603+31 3922_+ 197 1801+ 169
158 + 28* 688 + 60 599+29 3727+ 304 1582+ 188
144 + 15 639 + 30 579+23 3318 + 227 1528+ 92
Values are mean + S E.M * P < 0 05
injection MK-801 was given at doses 0.1, 0.5, 1.0 mg/kg i.p. and decapitated 30 rain after the rejection. Repeated admintstratzon. PCP (10mg/kg) or MK-801 (1 mg/kg) were gaven i.p. six times every 4 - 6 h and decapitated 24 h after the last injection. Saline was administered as controls. Brains were quickly removed and striatum, substantia nigra, frontal cortex, ventral tegmental area (VTA) and limblc area were dissected out immediately and stored at - 8 0 ° C until assay. The supernatant of the homogenate was lyophilized and apphed to the EIA of substance P using specific antiserum against substance P as described elsewhere [7,8].
ConcLusions A single administration of PCP dose-dependently reduced the SP levels in the prefrontal cortex, limbic forebrain, stnatum, substantia nigra but not in the VTA. A single administration of MK-801 dosedependently reduced SP levels in the prefrontal cortex and limbic forebrain but not in the striatum, sub-
stantta nigra or VTA. Repeated administration of PCP, not MK-801, increased SP level only in the prefrontal cortex (Table I) The finding that the repeated admimstratlon of PCP but not MK-801 increased SP content only m the prefrontal cortex suggests that prefrontal, not striatonigral, SP neuron might be lmphcated in the effect of PCP in reducing schizophrenia-like psychotic state.
References 1 Mlchelot, R_, Levxel, V., G~orguteff-Chesselet, M F , Ch~ramy, A and Glowmska, J , Effects of the unilateral nlgral modulation of substance P transmission on the actwlty of the two nlgrostnatal dopammerglc pathways, Life ScL, 24 (1979) 715-724 2 Bannon, M J_, Elhott, P J , Alpert, J E , Goedert, M_, Iversen, S D. and Iversen, L_L, Role of endogenous substance P in stress-reduced actavat~on of mesocorucal dopamine neurones, Nature, 306 (1983) 791-792. 3 Toru, M , Watanabe, S , Shlbuya, H , Nlshikawa, T , Noda, K., Mltsushlo, H , Ichlkawa, H , Kurumajl, A, Takashlma, M , Mataga, N and Ogawa, A., Neurotransrmtters, receptors and neuropeptades m post-mortem brmns of chromc schizophrenic patients, Acta Psych Scand, 78 (1988) 121-137 4 L1, S.J, Swam, S P , McGmty, J . F , Huang, Y_S. and Hong, J S, Dopammergac regulation of tachykanm metabohsm m the stnatonigral pathway, J Pharmacol Exp Ther., 243 (1987) 792-798 5 Ratter, J K , Schrmdt, C J , Glbb, J W. and Hanson, G R., Increases of substance P-ltke lmmunoreactwlty w~thm stnatalmgral structures after subacute methamphetamme treatment J Pharmacol Exp Ther, 229 (1984) 487-492 6 Snyder, S H , Phencychdme, Nature, 285 (1980) 385-386 7 Mltsushlo, H , Takashtma, M , Mataga, N and Toru, M , Effects of chromc treatment w~th tnhexyphemdyl and earbamazepme alone or m combination with halopendol on substance P content m rat brain a possible imphcatlon of substance P in affectwe &sorders, J. Pharm Exp Ther, 245 (1988) 982989_ 8 Mitsusluo, H_, Takashuna, M and Takahashl, K , Effects of 40-day treatment with carbamazepine, sodmm valproate and clonazepam on GABA content in rat substantla nlgra, Mol Neuropharm, 2 (1992) 185-188
Regulator) Peptldes. 46 (1993) 352-353 © 1993 Elsevier Science Pubhshers B V All rights reserved 0167-0115/93,'$06 00
REGPEP 01458
Effects of subacute repeated injections of phencyclidine and MK-801 on substance P content in the rat brain H. Mitsushio, Y. Shirayama, T. N l s h i k a w a and K. T a k a h a s h l Dtvtston of Mental Disorder Research, National Center of Neurosclence, Tokyo (Japan)
Key words" Substance P; Schizophrenia; Phencyclldlne; Methamphetamine, MK-801; Prefrontal cortex; Rat brain
Introduction
Several species of evidence suggest that substance P (SP) is revolved m the pathogenesls of schizophrenia (1) It is well known that hyper-dopaminergic state exist in the brain of schizophrenics It is also well estabhshed that SP has an excitatory effect on the activity of dopamine neuron [1] Moreover, the m~croinjection of antl-SP antibody into the ventral tegmental area (VTA) prevents the stress-induced increase in dopamlne turnover in the frontal cortex [2]. (2)We have reported the elevation of SP concentration at various brain regions including the prefrontal cortex in the post-mortem brains from chromc schizophrenics [3]. There were highly significant positive correlations between SP and actwlty of tyrosine hydroxylase, which is the rate llmmng enzyme ofdopamine synthesis (3) Methamphetamine, which
causes an psychotic state stmilar to the acute schizophrenia with posltwe symptoms (delusions or hallucinations) after abuse, decrease SP concentration in the nlgro-striatal system after a single injection [4], and increase SP concentration m the same brain areas after large dose repeated injections [5]. Phencyclidine (PCP), which is a non-competitive N M D A receptor antagomst, also causes a psychosis with both positive and negatwe symptoms (auUsm, emoUonal withdraw or abuha) which is more similar to schizophrenia [6] than methamphetamme In this experiment, we investigated whether PCP affected SP levels m the brain after single or repeated admmlstration To compare with PCP, effects of MK-801, which is a non-competitive N M D A receptor antagonist but not has the psychosis inducing effect, is also investigated.
Methods Correspondence to H Mltsushlo, Divaslon of Mental Disorder Research, National Center of Neurosc]ence, NCNP, 4-1-1 Ogawahlgashlmachl, Kodalra, Tokyo 187, Japan
Smgle admintstratton Male Wlstar r a t s w e i g h i n g 180-200 g were used. PCP was given at doses 2.0, 5.0, 10 mg/kg 1.p. and decapitated 60 mm after the
353 TABLE I Increase in SP content m the prefrontal cortex 24 h after PCP repeated administration Area
Control
PCP (10mg/kg)
MK-801 (1.0mg/kg)
Prefrontal cortex Llmblc forebram Stnatum Substantla mgra Ventral tegmental area
135 _+6 736 + 45 603+31 3922_+ 197 1801+ 169
158 + 28* 688 + 60 599+29 3727+ 304 1582+ 188
144 + 15 639 + 30 579+23 3318 + 227 1528+ 92
Values are mean + S E.M * P < 0 05
injection MK-801 was given at doses 0.1, 0.5, 1.0 mg/kg i.p. and decapitated 30 rain after the rejection. Repeated admintstratzon. PCP (10mg/kg) or MK-801 (1 mg/kg) were gaven i.p. six times every 4 - 6 h and decapitated 24 h after the last injection. Saline was administered as controls. Brains were quickly removed and striatum, substantia nigra, frontal cortex, ventral tegmental area (VTA) and limblc area were dissected out immediately and stored at - 8 0 ° C until assay. The supernatant of the homogenate was lyophilized and apphed to the EIA of substance P using specific antiserum against substance P as described elsewhere [7,8].
ConcLusions A single administration of PCP dose-dependently reduced the SP levels in the prefrontal cortex, limbic forebrain, stnatum, substantia nigra but not in the VTA. A single administration of MK-801 dosedependently reduced SP levels in the prefrontal cortex and limbic forebrain but not in the striatum, sub-
stantta nigra or VTA. Repeated administration of PCP, not MK-801, increased SP level only in the prefrontal cortex (Table I) The finding that the repeated admimstratlon of PCP but not MK-801 increased SP content only m the prefrontal cortex suggests that prefrontal, not striatonigral, SP neuron might be lmphcated in the effect of PCP in reducing schizophrenia-like psychotic state.
References 1 Mlchelot, R_, Levxel, V., G~orguteff-Chesselet, M F , Ch~ramy, A and Glowmska, J , Effects of the unilateral nlgral modulation of substance P transmission on the actwlty of the two nlgrostnatal dopammerglc pathways, Life ScL, 24 (1979) 715-724 2 Bannon, M J_, Elhott, P J , Alpert, J E , Goedert, M_, Iversen, S D. and Iversen, L_L, Role of endogenous substance P in stress-reduced actavat~on of mesocorucal dopamine neurones, Nature, 306 (1983) 791-792. 3 Toru, M , Watanabe, S , Shlbuya, H , Nlshikawa, T , Noda, K., Mltsushlo, H , Ichlkawa, H , Kurumajl, A, Takashlma, M , Mataga, N and Ogawa, A., Neurotransrmtters, receptors and neuropeptades m post-mortem brmns of chromc schizophrenic patients, Acta Psych Scand, 78 (1988) 121-137 4 L1, S.J, Swam, S P , McGmty, J . F , Huang, Y_S. and Hong, J S, Dopammergac regulation of tachykanm metabohsm m the stnatonigral pathway, J Pharmacol Exp Ther., 243 (1987) 792-798 5 Ratter, J K , Schrmdt, C J , Glbb, J W. and Hanson, G R., Increases of substance P-ltke lmmunoreactwlty w~thm stnatalmgral structures after subacute methamphetamme treatment J Pharmacol Exp Ther, 229 (1984) 487-492 6 Snyder, S H , Phencychdme, Nature, 285 (1980) 385-386 7 Mltsushlo, H , Takashtma, M , Mataga, N and Toru, M , Effects of chromc treatment w~th tnhexyphemdyl and earbamazepme alone or m combination with halopendol on substance P content m rat brain a possible imphcatlon of substance P in affectwe &sorders, J. Pharm Exp Ther, 245 (1988) 982989_ 8 Mitsusluo, H_, Takashuna, M and Takahashl, K , Effects of 40-day treatment with carbamazepine, sodmm valproate and clonazepam on GABA content in rat substantla nlgra, Mol Neuropharm, 2 (1992) 185-188