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Effects of acute or multiple administrations of neuroleptics, on neuropeptide Y system in the rat nucleus accumbens
BEHAVIOURAL
EFFECTS
OF
SARMESIN
V.Georgiev, J.Matsoukas I , M.Opitz, D.Georgieva and I.Todorov. Lab. Exptl. Psychopharmacology, Inst. Physiology,Bulg.Acad. Sci.,l113 Sofia, Bulgaria; iDept. Chemistry,Univ. Patras, Patras 26500, Greece. Sarmesin (S) is an analogue, of [Sar I] angiotensin II. It is produced by methylating the Tyr hydroxyl group in [Sar ~] angiotensin II. s,is reversible and competitive angiotensin II (ATII) receptor antagonist (type II ATII receptor antagonist). The behavioural effects of S were studied using the following paradigms: pentylenetetrazol (PTZ)-induced seizures in mice; active avoidance in rats; passive avoidance in rats; exploratory activity in rats (ambulation,rearing; hole board); acute hypOxia in mice. It was found that S administered intracerebrovetricularly (i.c.v.) decreased the intensity of seizures and tended to increase the threshold of seizures. Post-trial i.c.v. injection of S improved retention in passive avoidance and tended to improve it in active avoidance paradigms. S increased exploratory activity. S did not influence acute hipoxia. Taken together the results specify Sarmesin as a behaviourally active peptide which deserves more thorough investigation.
BEHAVIOURAL EFFECTS OF T W O KININ A N A L O G U E S J M V 2 3 6 A N D
N E U R O P E P T I D E Y R E C E P T O R B I N D I N G SITES IN THE RAT HIPPOCAMPUS AFTER LIMBIC S E I Z U R E S I N D U C E D BY K A I N I C A C I D AND KINDLING M. Gobbi, T. Mennini, R. Mohemius, R. Samanin and A, Vezzani Istituto Mario Negri, Via Eritrea 62, Milano, Italy. N e u r o p e p t i d e Y (NPY) m o d u l a t e s g l u t a m a t e r g i c ncurotransmission and granule cells excitability acting on Y2 (presynaptic) and YI (postsynaptic) receptor subtypes. Using receptor autoradiography, we assessed the status of NPY receptor subtypes in the hippocampus of rats 30 days after limbic seizures induced by 10 mg/kg kainic acid (KA) or one week after completion of hippocampal kindling of the dentate gyms. In KAtreated rats, specific 125I-pYY binding (labeling Y1 and Y2 receptors) was significantly reduced in the strata radiatum, oriens and moleculare of the dorsal hippocampus. This decrease was largely due to a drop (by 52-76%) in the (Leu31)-(Pro34) NPY sensitive binding (labeling Y1 receptor subtypes). In the hilus of the dentate gyms PYY and (Leu31)-(Pro34) NPY sensitive and insensitive (labelling Y2 receptors) binding did not significantly change. In rats treated with KA+phenobarbital which had acute limbic seizures but were protected from late neurotoxicity, specific PYY binding was unchanged in the hippocampus proper while Y 1 and Y2 specific binding were respectively decreased by 50% and enhanced up to 80% of control values. In the hilus of the dentate gyms a 250% increase on average in Y2 receptor sites was found (p<0.01). In kindled rats, PYY and Y2 specific binding were decreased by 25% on average (p<0.05) in stratum oriens CA1, CA3 and in stratum radiatum CA1 while a 60% increase on average was selectively found in the hilus. The decrease in Y2 and Y1 receptors may be due to nerve cell loss or to receptor desensitization. The increase in Y2 receptor sites in the hilus may be an adaptive response to tissue hyperexcitability.
CHOLECYSTOJMV179
Ch. Hadliivanova t, V. V. Petkov 1, R. Kehayov' and J. Martinez 2 ' Institute of Physiology, Bulgarian Academy of Sciences, Acad. Georgi Bonchev st. bl. 23, 1113 Sofia, Bulgaria; 2 Laboratoire de Chimie et Pharmacologie de Molecules dlnteret Biologique EPCNRS 51, Montpetlier, France The behavioural effects o f two cholecystokinin analogues Boc-Tyr(SO, H)-Nle-Gly-Trp-N!e-Asp-Phe-NH 2 (JMV236), a potent CCK agonist, and Boc-Tyr(SO3H)-NleGly-DTrp-Nle-Asp-2-Phenylethylester (JMV179), a CCK antagonist were studied. JMV236 dose-dependently decreased the horizontal (significant effect at doses of 12.5 and 50 I.tg/kg and vertical (significant effect at a dose of 50 Ixg/kg) activity. JMV179 dose-dependently decreased only the vertical actvity (significant effect at a dose of 50 I.tg/kg). JMV236 administered immediately after training significantly facilitated short-term memory in passive avoidance situation but only tended to increase the mean latency upon retention testing on the 7th day. JMV179 tended to increase the latency of the passive avoidance response upon retention testing at the 24 hour but not on the 7th day after training. JMV236, a more stable and enzyme-resistant CCK agonist compared to endogenous CCK, and JMV179, a full CCK receptor antagonist, might prove useful for elucidating the role of CCK in learning and memory processes.
-- 280 --
EFFECTS OF ACUTE OR MULTIPLE ADMINISTRATIONS OF NEUROLEPTICS, ON NEUROPEPTIDE Y SYSTEM IN THE RAT NUCLEUS ACCUMBENS
E.Obuchowicz Z.S.Herman,W.Lasofi* Department of Clinical Pharmacology,Silesian University School of Medioine,Medykow 18,40-752 Katowioe,Poland, * Department of Endocrinology,Institute of Pharmacology, Polish Academy of Sciences,SmQtna 12,31-343 Cracow,Poland. In the present study we have investigated the effect of acute,14 or 28-day ip.treatment with Chlorpromazine (CPZ)(2 or 10mg/kg); Halopeddol (HAL)(0.5 or 2mg/kg);Sulpiride (SULP)(50 or 100mg/kg);Clozapine (CLOZ)(10 or 25mg/kg) on NPY concentration (NPYLI), which was measured by radioimmunoassay. There was only a tendency for reduced NPYLI as a result of the single injection of CPZ or HAL. 14 or 28-day treatment with four applied neuroleptics induced significant decrease of NPYLI. The magnitude of this effect was dose and time dependent and was the highest after HAL administration. Single injection of the D2 agonist Quinpirole(3mg/kg ip.) had no effect by itself but reversed change induced by CPZ and attenuated effect of HAL. Futhermore, we claimed that 14-day treatment with the D~ antagonist SCH23390 (lmg/kg ip.) decreased NPYLI in comparison with control. This effect was remarkably enhanced by coadministration SCH233390 with SULP. The level NPYmRNA quantified by hybridization in situ was significantly decreased after single injection of HAL or CLOZ and subchronic treatment with CLOZ. In summary we suggest that NPY may be involved in the mechanism of action of neuroleptics. It seems that D2 receptors are important in maintaining NPY level in nucleus accumbens and mainly responsible for decrease observed after treatment with neuroleptics. Our results indicate that probable change in NPY content is a consequence of diminished synthesis.
EFFECTS
OF
SARMESIN
V.Georgiev, J.Matsoukas I , M.Opitz, D.Georgieva and I.Todorov. Lab. Exptl. Psychopharmacology, Inst. Physiology,Bulg.Acad. Sci.,l113 Sofia, Bulgaria; iDept. Chemistry,Univ. Patras, Patras 26500, Greece. Sarmesin (S) is an analogue, of [Sar I] angiotensin II. It is produced by methylating the Tyr hydroxyl group in [Sar ~] angiotensin II. s,is reversible and competitive angiotensin II (ATII) receptor antagonist (type II ATII receptor antagonist). The behavioural effects of S were studied using the following paradigms: pentylenetetrazol (PTZ)-induced seizures in mice; active avoidance in rats; passive avoidance in rats; exploratory activity in rats (ambulation,rearing; hole board); acute hypOxia in mice. It was found that S administered intracerebrovetricularly (i.c.v.) decreased the intensity of seizures and tended to increase the threshold of seizures. Post-trial i.c.v. injection of S improved retention in passive avoidance and tended to improve it in active avoidance paradigms. S increased exploratory activity. S did not influence acute hipoxia. Taken together the results specify Sarmesin as a behaviourally active peptide which deserves more thorough investigation.
BEHAVIOURAL EFFECTS OF T W O KININ A N A L O G U E S J M V 2 3 6 A N D
N E U R O P E P T I D E Y R E C E P T O R B I N D I N G SITES IN THE RAT HIPPOCAMPUS AFTER LIMBIC S E I Z U R E S I N D U C E D BY K A I N I C A C I D AND KINDLING M. Gobbi, T. Mennini, R. Mohemius, R. Samanin and A, Vezzani Istituto Mario Negri, Via Eritrea 62, Milano, Italy. N e u r o p e p t i d e Y (NPY) m o d u l a t e s g l u t a m a t e r g i c ncurotransmission and granule cells excitability acting on Y2 (presynaptic) and YI (postsynaptic) receptor subtypes. Using receptor autoradiography, we assessed the status of NPY receptor subtypes in the hippocampus of rats 30 days after limbic seizures induced by 10 mg/kg kainic acid (KA) or one week after completion of hippocampal kindling of the dentate gyms. In KAtreated rats, specific 125I-pYY binding (labeling Y1 and Y2 receptors) was significantly reduced in the strata radiatum, oriens and moleculare of the dorsal hippocampus. This decrease was largely due to a drop (by 52-76%) in the (Leu31)-(Pro34) NPY sensitive binding (labeling Y1 receptor subtypes). In the hilus of the dentate gyms PYY and (Leu31)-(Pro34) NPY sensitive and insensitive (labelling Y2 receptors) binding did not significantly change. In rats treated with KA+phenobarbital which had acute limbic seizures but were protected from late neurotoxicity, specific PYY binding was unchanged in the hippocampus proper while Y 1 and Y2 specific binding were respectively decreased by 50% and enhanced up to 80% of control values. In the hilus of the dentate gyms a 250% increase on average in Y2 receptor sites was found (p<0.01). In kindled rats, PYY and Y2 specific binding were decreased by 25% on average (p<0.05) in stratum oriens CA1, CA3 and in stratum radiatum CA1 while a 60% increase on average was selectively found in the hilus. The decrease in Y2 and Y1 receptors may be due to nerve cell loss or to receptor desensitization. The increase in Y2 receptor sites in the hilus may be an adaptive response to tissue hyperexcitability.
CHOLECYSTOJMV179
Ch. Hadliivanova t, V. V. Petkov 1, R. Kehayov' and J. Martinez 2 ' Institute of Physiology, Bulgarian Academy of Sciences, Acad. Georgi Bonchev st. bl. 23, 1113 Sofia, Bulgaria; 2 Laboratoire de Chimie et Pharmacologie de Molecules dlnteret Biologique EPCNRS 51, Montpetlier, France The behavioural effects o f two cholecystokinin analogues Boc-Tyr(SO, H)-Nle-Gly-Trp-N!e-Asp-Phe-NH 2 (JMV236), a potent CCK agonist, and Boc-Tyr(SO3H)-NleGly-DTrp-Nle-Asp-2-Phenylethylester (JMV179), a CCK antagonist were studied. JMV236 dose-dependently decreased the horizontal (significant effect at doses of 12.5 and 50 I.tg/kg and vertical (significant effect at a dose of 50 Ixg/kg) activity. JMV179 dose-dependently decreased only the vertical actvity (significant effect at a dose of 50 I.tg/kg). JMV236 administered immediately after training significantly facilitated short-term memory in passive avoidance situation but only tended to increase the mean latency upon retention testing on the 7th day. JMV179 tended to increase the latency of the passive avoidance response upon retention testing at the 24 hour but not on the 7th day after training. JMV236, a more stable and enzyme-resistant CCK agonist compared to endogenous CCK, and JMV179, a full CCK receptor antagonist, might prove useful for elucidating the role of CCK in learning and memory processes.
-- 280 --
EFFECTS OF ACUTE OR MULTIPLE ADMINISTRATIONS OF NEUROLEPTICS, ON NEUROPEPTIDE Y SYSTEM IN THE RAT NUCLEUS ACCUMBENS
E.Obuchowicz Z.S.Herman,W.Lasofi* Department of Clinical Pharmacology,Silesian University School of Medioine,Medykow 18,40-752 Katowioe,Poland, * Department of Endocrinology,Institute of Pharmacology, Polish Academy of Sciences,SmQtna 12,31-343 Cracow,Poland. In the present study we have investigated the effect of acute,14 or 28-day ip.treatment with Chlorpromazine (CPZ)(2 or 10mg/kg); Halopeddol (HAL)(0.5 or 2mg/kg);Sulpiride (SULP)(50 or 100mg/kg);Clozapine (CLOZ)(10 or 25mg/kg) on NPY concentration (NPYLI), which was measured by radioimmunoassay. There was only a tendency for reduced NPYLI as a result of the single injection of CPZ or HAL. 14 or 28-day treatment with four applied neuroleptics induced significant decrease of NPYLI. The magnitude of this effect was dose and time dependent and was the highest after HAL administration. Single injection of the D2 agonist Quinpirole(3mg/kg ip.) had no effect by itself but reversed change induced by CPZ and attenuated effect of HAL. Futhermore, we claimed that 14-day treatment with the D~ antagonist SCH23390 (lmg/kg ip.) decreased NPYLI in comparison with control. This effect was remarkably enhanced by coadministration SCH233390 with SULP. The level NPYmRNA quantified by hybridization in situ was significantly decreased after single injection of HAL or CLOZ and subchronic treatment with CLOZ. In summary we suggest that NPY may be involved in the mechanism of action of neuroleptics. It seems that D2 receptors are important in maintaining NPY level in nucleus accumbens and mainly responsible for decrease observed after treatment with neuroleptics. Our results indicate that probable change in NPY content is a consequence of diminished synthesis.