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Paradoxical effect of neuroleptic drugs on prolactin secretion from cultured rat pituitary cells
PHARMACOLOGICAL CORRECTION OF EXPERIMENTAL PARKINSONIAN SYNDROME INDUCED BY DIFFERENT CHEMICAL AGENTS L N.Nerobkova, N.V.Markina, T.A.Voronina, L.M.Scharkova ~ute of Pharmacology RAMS, Ba tijskaja, 8, 125315, Moscow, Russia.
ARGININE-ASPARTATE AND HALOPERIDODINDUCED NEUROBEHAVIORAL EFFEC-WS IN THE RAT. F.ILPatacchioli, ILDi Grezia: and L.Angelucci Insutute of Pharmacology, 2nd Chair, Univeristy of Rome "La Sapienza" and t lMN-Sanatnx, Pozzflli (IS), Italy.
Parkinsonian syndrome (PS) was provoked by 1methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP, 313-40 mg/k9, i.p.) in C57BI/6 mice, 1-methyl-4-phenyl-pyridinium ion (~PP+, 5 mg/k9, intraniclral injection, bilateral) in rats and arecoline (25 mcj/kg, i.kJ and oxotremorine (100 mg/kg) in albino mice. Oligo'kinesia, rigidity, tremor, Straulhe syndrome and salivation were observed after the agents injection both in rats and mice. The definite dynamics of motor disturbance (ME)) development were revealed and it w a s accompanied by EEG-disorders in the sensorimotory cortex, nucleus caudatus, 91obus pallidus and substantia nigra. The observed antiparkinsonian effects of pharmacological drugs were the inhibition of basic MD and normalization of EEG. All drugs were administered while the pronounced PS was observed. It was found that levodopa (100-150 mg/k9, i.p.) and midantane (50 mg/kg, i.p.) decreased the rigidity andoligokinesia and corrected the EEG in rats witl5 MPP+-induced PS and in C57BI/6 mice with MPTP-induced PS. At the same time levodopa increased tremor, induced by MPP+, and reduced tremor nduced by oxotremorine. Cyclodolum (6 mg/kg) eliminated the tremor, reduced riqidity, but provokea Ionger-lastinq episodes of "freezing" during a high-amplitude "peak-wave" activity in EEG in the rats with MPP+ induced PS. Comparison of the effects of DA-mimetics and cholinergic drugs on different PS models suqgest tlhat pharmacotherapy of PS strongly depends on the character of clinical symptomes.
Clinical observations have shown that Arginine-Aspartate (AA) treatment improves some extrapyramidal symptoms in psychotic patients undergoing long-term "troaCnem ~nth neuroleptics, On the basis of these rather old, but very stimulating, observations we decided to investigate a potentially new pharmacological effect of AA. For this purpose, we used the experimental model provided by haloperidol-induced catalep~ and decrease of locomotor activity as a tool to study the effects of a chronic AA treatment on the strietal dopaminergic activity in the rat. Therefore, locomotor activity, ~atalepsy and striatal dopamine (DA), homovanillic acid (HVA) and dihydroxyphenylacetic acid {DOPAC) levels were measured in rats treated with haloperidol (0.5 mg/Xg i.p.) after 8-day admins*.rafion of AA in the drinking water (20 grfliter). Pretreatment with AA was able to partially counteract the haloperidol-induced changes tn dopamine metabolism as well to significantly reduce catalepsy. The above results suggest ~hat the action of A A on haloperidol-induced nellrobehavioral effects is mediated by interference with ~triatal dopaminergi¢ innervation.
PARADOXICAL EFFECT OF NEUROLEPTIC DRUGS ON PROLACTIN SECRETION FROM C ULTURED RAT PITUITARY CELLS Braghiroli L., Portzianelli A., Leone M.G., Palmery M., Mazzanti G. Institute of Pharmacology and Pharmacognosy, University of Rome "La Sapienza" - Italy.
CHROMATOGRAPHIC MODELING OF INTERACTIONS BETWEEN MELANIN AND NEUROLEPTICS A. Radwafiska~,T. Fr~ckowiak1,H. lbrahim2,A.-F. Aubry2 and R. Kaliszan ~ 1Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gda.tsk, Gen. J. Hallera 107, 80-416 Gdaflsk, Poland and 2Royal Victoria Hospital, 687 Pine Avenue W., Montrtal, H3A 1AI, Quebec, Canada
Several antipsyehotic drugs, including chlorpromazine and haloperidol, increase, at low concentrations, prolactin release in cultured rat pituitary cells, acting as competitive antagonists to dopamine (1). Higher concentrations of the drugs are less effective to reverse the dopamine-mediated inibition of prolactin release, furthemore they reduce prolactin secretion also in absence of dopamine. Mechanism of this paradoxical effect is uncertain; it has not been established whether or not it reflects a non specific toxic action on cultured cells. Clozapine antagonizes the dopamine-mediated inhibition of prolactin release in cultured rat pituitary cells (2) in a dose-dependent manner up to 0.1 riM; however at higher concentration the effect is reversed. In this study we investigated the effect of clozapine and fluphenazine at high doses on basal prolactin secretion from cultured rat pituitary ceils, Our resuks show that both drugs, at concentrations higher than lOgM inhibit the prolactin secretion. This effect isn't related to a citotoxic action of the drugs on pituitary cells, because the vitality of the cells is unmodified atier drug incubation. References 1) L. Braghiroli, A. Ponzianelli, M. Fiani, G. de Feo and G. Mazzanti: in this Congress. 2) G.M. Besser, G. Detitala, A. Grossman and W.A. Stubbs (1980). Br.J.Pharmacol., 71,569,573.
Binding of a series of phenothiazineneuroleptics to synthetic melanin was determined by-an ultrafiltration method. In a separate experiment the differences in drug-melanin interactions were determined for a larger series of phenothiazines by means of nigh-performance liquid chromatography (HPLC). The HPLC column was packed with a stationary phase prepared by chemical immobilization of melanin on silica particles: The melaninbinding parameters determined by the standard slow-equilibrium method and by the HPLC method correlated well. This demonstrates the usefulness of HPLC on a melanin-based stationary phase as a convenient, fast, inexpensive and accurate method providing comparable data which reflect quantitatively the differences in binding to melanin within large series of xenobiotics. With sufficiently large set of neuroleptics for which the melanin-binding-related parameters have been determined in the same conditions an analysis of quantitative structure-activity relationships (QSAR) could have been performed. The &'ugs were characterized structurally by means of computational chemistry (MOPAC procedure within InsightlI,Biosym Technologies, San Diego, CA, USA). It was found that retention of neuroleptics by the melanin column could be described by a two-parameterregressionequationcomprising the terms: water accessible sta-face of a drug molecule and energy of the lowest unoccupied molecular orbital (LUMO). The QSAR equation obtained allows for predicting of melanin binding and thus of potential Parkinsonian-like side effects of the existing drugs and drug candidates.
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ARGININE-ASPARTATE AND HALOPERIDODINDUCED NEUROBEHAVIORAL EFFEC-WS IN THE RAT. F.ILPatacchioli, ILDi Grezia: and L.Angelucci Insutute of Pharmacology, 2nd Chair, Univeristy of Rome "La Sapienza" and t lMN-Sanatnx, Pozzflli (IS), Italy.
Parkinsonian syndrome (PS) was provoked by 1methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP, 313-40 mg/k9, i.p.) in C57BI/6 mice, 1-methyl-4-phenyl-pyridinium ion (~PP+, 5 mg/k9, intraniclral injection, bilateral) in rats and arecoline (25 mcj/kg, i.kJ and oxotremorine (100 mg/kg) in albino mice. Oligo'kinesia, rigidity, tremor, Straulhe syndrome and salivation were observed after the agents injection both in rats and mice. The definite dynamics of motor disturbance (ME)) development were revealed and it w a s accompanied by EEG-disorders in the sensorimotory cortex, nucleus caudatus, 91obus pallidus and substantia nigra. The observed antiparkinsonian effects of pharmacological drugs were the inhibition of basic MD and normalization of EEG. All drugs were administered while the pronounced PS was observed. It was found that levodopa (100-150 mg/k9, i.p.) and midantane (50 mg/kg, i.p.) decreased the rigidity andoligokinesia and corrected the EEG in rats witl5 MPP+-induced PS and in C57BI/6 mice with MPTP-induced PS. At the same time levodopa increased tremor, induced by MPP+, and reduced tremor nduced by oxotremorine. Cyclodolum (6 mg/kg) eliminated the tremor, reduced riqidity, but provokea Ionger-lastinq episodes of "freezing" during a high-amplitude "peak-wave" activity in EEG in the rats with MPP+ induced PS. Comparison of the effects of DA-mimetics and cholinergic drugs on different PS models suqgest tlhat pharmacotherapy of PS strongly depends on the character of clinical symptomes.
Clinical observations have shown that Arginine-Aspartate (AA) treatment improves some extrapyramidal symptoms in psychotic patients undergoing long-term "troaCnem ~nth neuroleptics, On the basis of these rather old, but very stimulating, observations we decided to investigate a potentially new pharmacological effect of AA. For this purpose, we used the experimental model provided by haloperidol-induced catalep~ and decrease of locomotor activity as a tool to study the effects of a chronic AA treatment on the strietal dopaminergic activity in the rat. Therefore, locomotor activity, ~atalepsy and striatal dopamine (DA), homovanillic acid (HVA) and dihydroxyphenylacetic acid {DOPAC) levels were measured in rats treated with haloperidol (0.5 mg/Xg i.p.) after 8-day admins*.rafion of AA in the drinking water (20 grfliter). Pretreatment with AA was able to partially counteract the haloperidol-induced changes tn dopamine metabolism as well to significantly reduce catalepsy. The above results suggest ~hat the action of A A on haloperidol-induced nellrobehavioral effects is mediated by interference with ~triatal dopaminergi¢ innervation.
PARADOXICAL EFFECT OF NEUROLEPTIC DRUGS ON PROLACTIN SECRETION FROM C ULTURED RAT PITUITARY CELLS Braghiroli L., Portzianelli A., Leone M.G., Palmery M., Mazzanti G. Institute of Pharmacology and Pharmacognosy, University of Rome "La Sapienza" - Italy.
CHROMATOGRAPHIC MODELING OF INTERACTIONS BETWEEN MELANIN AND NEUROLEPTICS A. Radwafiska~,T. Fr~ckowiak1,H. lbrahim2,A.-F. Aubry2 and R. Kaliszan ~ 1Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gda.tsk, Gen. J. Hallera 107, 80-416 Gdaflsk, Poland and 2Royal Victoria Hospital, 687 Pine Avenue W., Montrtal, H3A 1AI, Quebec, Canada
Several antipsyehotic drugs, including chlorpromazine and haloperidol, increase, at low concentrations, prolactin release in cultured rat pituitary cells, acting as competitive antagonists to dopamine (1). Higher concentrations of the drugs are less effective to reverse the dopamine-mediated inibition of prolactin release, furthemore they reduce prolactin secretion also in absence of dopamine. Mechanism of this paradoxical effect is uncertain; it has not been established whether or not it reflects a non specific toxic action on cultured cells. Clozapine antagonizes the dopamine-mediated inhibition of prolactin release in cultured rat pituitary cells (2) in a dose-dependent manner up to 0.1 riM; however at higher concentration the effect is reversed. In this study we investigated the effect of clozapine and fluphenazine at high doses on basal prolactin secretion from cultured rat pituitary ceils, Our resuks show that both drugs, at concentrations higher than lOgM inhibit the prolactin secretion. This effect isn't related to a citotoxic action of the drugs on pituitary cells, because the vitality of the cells is unmodified atier drug incubation. References 1) L. Braghiroli, A. Ponzianelli, M. Fiani, G. de Feo and G. Mazzanti: in this Congress. 2) G.M. Besser, G. Detitala, A. Grossman and W.A. Stubbs (1980). Br.J.Pharmacol., 71,569,573.
Binding of a series of phenothiazineneuroleptics to synthetic melanin was determined by-an ultrafiltration method. In a separate experiment the differences in drug-melanin interactions were determined for a larger series of phenothiazines by means of nigh-performance liquid chromatography (HPLC). The HPLC column was packed with a stationary phase prepared by chemical immobilization of melanin on silica particles: The melaninbinding parameters determined by the standard slow-equilibrium method and by the HPLC method correlated well. This demonstrates the usefulness of HPLC on a melanin-based stationary phase as a convenient, fast, inexpensive and accurate method providing comparable data which reflect quantitatively the differences in binding to melanin within large series of xenobiotics. With sufficiently large set of neuroleptics for which the melanin-binding-related parameters have been determined in the same conditions an analysis of quantitative structure-activity relationships (QSAR) could have been performed. The &'ugs were characterized structurally by means of computational chemistry (MOPAC procedure within InsightlI,Biosym Technologies, San Diego, CA, USA). It was found that retention of neuroleptics by the melanin column could be described by a two-parameterregressionequationcomprising the terms: water accessible sta-face of a drug molecule and energy of the lowest unoccupied molecular orbital (LUMO). The QSAR equation obtained allows for predicting of melanin binding and thus of potential Parkinsonian-like side effects of the existing drugs and drug candidates.
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