The selective P2X purinoceptor agonist, β,γ-methylene-L-adenosine 5′-triphosphate,discriminates between smooth muscle and neuronal P2X purinoceptors

The effects of the putative selective P_2X purinoceptor agonist, ,-methylene-l-adenosine 5-triphosphate (me-l-ATP), were determined at rat neuronal and smooth muscle P_2X purinoceptors.Me-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 M. In contrast, the archetypal P_2X purinoceptor agonist, , methylene ATP (meATP;1–100 M), produced concentration-related depolarisation responses with a mean EC₅₀ value of 10.8 M. The depolarising effects of meATP were not attenuated by me-l-ATP (100 M). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 M), but not me-l.-ATP (1–300 M), evoked rapid ( < 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, me-d-ATP and meATP competed with high affinity for [³H]Lx meATP binding sites, with mean pIC₅₀ values of 7.7 and 8.3, respectively. However, me-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 M (mean pIC₅₀ value 4.1).In prostatic segments of the rat vas deferens, me-l-ATP (1–100 M) and meATP (0.3–100 M) each produced concentration-related contractile responses with mean EC₅₀ values of 17.1 and 3.6 M, respectively. Me-l-ATP (1–10 M) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [³H]meATP exhibited high affinity for me-l-ATP, meATP and me-d-ATP with mean PIC₅₀ values of 7.7, 8.4 and 7.3, respectively.These results indicate that me-l-ATP exhibits neither agonist nor antagonist properties at P_2X purinoceptors on rat vagal neurones and possesses only very low affinity for [³H]meATP binding sites in rat brain. In contrast, me-l-ATP is a potent, high affinity agonist at smooth muscle P_2X purinoceptors of the rat vas deferens. This selective agonist action of me-l-ATP suggests that P_2X purinoceptors in smooth muscle and neurones are different and represent distinct P_2X purinoceptor subtypes.     

Studies on some metabolic effects of dopa and dopamine in the rat

Summary In male rats some metabolic effects of l-dopa and dopamine were compared with those of noradrenaline, adrenaline and tyramine by measuring the changes of plasma free fatty acids (FFA), plasma glycerol and plasma glucose as well as those of blood lactate and blood pyruvate. After intravenous injection of dopamine lactate and pyruvate concentrations were elevated maximally already within 5 min and returned to control levels after 10–20 min, i.e. at a time, when the levels of FFA, glycerol and glucose were maximally elevated in plasma. l-dopa had about 1/8 to 1/6 the potency of dopamine in producing these metabolic effects. The effects of dopamine were similar to those obtained with 1/20 the dose of noradrenaline, while adrenaline produced a more pronounced hyperglycaemic response than dopamine did when given in lipolytically equieffective doses.Pretreatment of the animals with phentolamine completely prevented the hyperglycaemic response to dopamine or noradrenaline without clearcut effects on the lipolytic effect of these catecholamines. Also, pretreatment with dihydroergotamine antagonized the hyperglycaemic effect of adrenaline and prevented that of dopamine and noradrenaline, while the effect of catecholamines on plasma glycerol concentration was not affected. However, the elevation in plasma FFA level induced by catecholamines was clearly antagonized by dihydroergotamine. The -adrenolytic drug Kö 592 had no effect on the hyperglycaemic effect of dopamine or noradrenaline, but antagonized the lipolytic effect of these amines. Pargyline enhanced the elevation of FFA and glycerol induced by dopamine or noradrenaline but reduced their hyperglycaemic effect. Chemical sympathectomy induced by pretreatment with 6-hydroxydopamine prevented the hyperglycaemic and lipolytic effects of tyramine, antagonized those of dopamine and potentiated the lipolytic response to noradrenaline. The effect of syrosingopine on the metabolic responses to the catecholamines was similar to that of 6-hydroxydopamine.Since the metabolic effects of dopamine were clearly antagonized by various - and -receptor-blocking agents and by chemical sympathectomy, we conclude that dopamine exerts its metabolic effects through a stimulation of - and -adrenoceptors and that part of this effect is mediated by a tyramine-like action of dopamine.     

Glucose both inhibits and stimulates insulin secretion from isolated pancreatic islets exposed to maximally effective concentrations of sulfonylureas

Summary Isolated pancreatic islets from mice were perifused with media containing maximally effective concentrations of glibenclamide (0.1–10 mol/l) or glipizide (1 mol/l). In these islets an increase of the glucose concentration from 10 mmol/l to 40 mmol/l or addition of d-glyc-eraldehyde (20 mmol/1) caused a temporary decrease in insulin release which was followed by a sustained enhancement of release. -Ketoisocaproate (3 or 20 mmol/1) did not inhibit insulin release; at high concentration it was an even stronger secretagogue than d-glucose or d-glyceraldehyde. It is concluded that high energy phosphates couple B-cell fuel metabolism and insulin release by acting both on the ATP-dependent K⁺ channel and on other targets not yet identified.Some of the results described here are part of the medical thesis of A. WallaschSend offprint requests to U. Panten at the above address     

The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties

Summary Four groups of narcotic analgesic drugs have been assessed for their opiate activities by using three binding assays and three pharmacological bioassays. In the binding assays, their inhibition constants (K _I, nM) were determined against the binding of the -ligand, [³H]-[d-Ala ² ,MePhe ⁴ , Gly-ol⁵]enkephalin, of the -ligand, [³H]-[d-Ala ² ,d-Leu ⁵]enkephalin and of the -ligand, [³H]-(±)-ethylketazocine after suppression of - and -binding by 100 nM of the unlabelled -ligand and 100 nM of the unlabelled -ligand. The pharmacological agonist or antagonist activities were assayed on the guinea-pig ileum, mouse vas deferens and rat vas deferens.The first group of compounds were pure agonists in all three pharmacological bioassays. The majority of the compounds showed preference to -binding but phenazocine and particularly etorphine had also high affinities to the - and -binding sites.The second group consisted of N-allyl and N-cyclopropylmethyl homologues of the morphine, 3-hydroxymorphinan and normetazocine series which had agonist and antagonist activities in the guinea-pig ileum and mouse vas deferens but were pure antagonists in the rat vas deferens. In the binding assays, -binding and -binding were prominent.The third group was made up by the ketazocine-like compounds which in the guinea-pig ileum and mouse vas deferens were pure agonists and in the rat vas deferens pure antagonists. The binding spectrum showed particularly high binding to the -binding site.The fourth group was the antagonists which were devoid of agonist activity with the exception of diprenorphine and Mr 2266 which had retained some agonism. The binding spectrum showed considerable variation, naloxone in low concentration being a selective -antagonist, Mr 2266 having high affinities to the - and -binding sites and diprenorphine having considerable affinities to the -, - and -binding sites.Since each of the four groups of compounds, whether pure agonists, agonist-antagonists, ketazocine-like drugs or pure antagonists, shows independent varittions in the affinities to the - and -binding sites, their different pharmacological behaviour cannot be solely due to difference in the binding spectra.     

Acute dyskinesias in monkeys elicited by halopemide,mezilamine and the “antidyskinetic” drugs,oxiperomide and tiapride

Oxiperomide and tiapride are dopamine receptor antagonists claimed to have antidyskinetic properties in animal models and in the clinic. Halopemide and mezilamine are other dopamine antagonists predicted to lack extrapyramidal side effects in man on the basis of animal studies. Acute dyskinesias, a neuroleptic-induced acute extrapyramidal syndrome, were elicited in squirrel monkeys by oxiperomide (1 mg/kg), tiapride (30 mg/kg), and halopemide (10 mg/kg). The dyskinesias were virtually indistinguishable from those caused by a standard behaviorally equivalent dose of haloperidol (1.25 mg/kg PO) in the same individual monkeys. Mezilamine (0.3 mg/kg) also induced dyskinesias, which appeared to be less pronounced than those following haloperidol. The antidyskinetic properties of oxiperomide and tiapride evidently do not confer protection against dyskinetic movements induced by dopamine antagonism.     

Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with -lapachone (-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between -lap and four cyclodextrins (-, -, -, and HP-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and ¹H-NMR spectroscopy. Biologic activity and bioavailability of -lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that -lap solubility increased in a linear fashion as a function of -, -, or HP-CD concentrations but not -CD. Maximum solubility of -lap was achieved at 16.0 mg/ml or 66.0 mM with HP-CD. Fluorescence and ¹H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between -CD and HP-CD with -lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of -lap in -CD or HP-CD inclusion complexes (TD₅₀ = 2.1 M). Animal studies in mice showed that the LD₅₀ value of -lap in an HP-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of -lap with HP-CD offers a major improvement in drug solubility and bioavailability.     

Central and peripheral effects of 5-hydroxytryptophan on motor activity in mice

Spontaneous motor activity was studied in mice given dl-5-hydroxytryptophan (5-HTP) i.p. in doses ranging from 6.25 to 800 mg/kg with and without previous administration of l--hydrazino--methyl--(3,4-dihydroxyphenyl)-propionic acid (MK-486), an inhibitor of peripheral amino acid decarboxylase. Some mice were also given repeated injections of dl--methyl-metatyrosine (-MMT) prior to MK-486 and 5-HTP. The brain levels of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) were also determined in these animals.5-HTP in doses between 100 and 800 mg/kg caused a decrease in motor activity when given alone, whereas after pretreatment with MK-486 it increased motor activity. Lower doses of 5-HTP, alone or in combination with MK-486, had no significant effect on motor activity. Pretreatment with -MMT caused a marked depletion of NA and DA without counteracting the increase in motor activity induced by MK-486 and 5-HTP.It is concluded that the central effects of large doses of 5-HTP are excitatory whilst the effects outside the blood-brain barrier have an inhibitory influence on the motor activity in mice. The mechanisms for the central excitatory effects are discussed.     

GABA agonists in cebus monkeys with neuroleptic-induced persistent dyskinesias

Tetrahydroisoxazolopyridinol (THIP), a GABA receptor agonist, -acetylenic-GABA(GAG) and -vinyl-GABA(GVG), two GABA transaminase inhibitors were given in single parenteral doses to three Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol. High doses of THIP temporarily abolished dyskinesias but also caused bradykinesia, ataxia, dystonia and myoclonic jerks. GAG and GVG reduced dyskinesias to a lesser extent and with fewer side effects. Whether the observed antidyskinetic effect is secondary to the concomitant general toxic effects or if these drugs have a specific antidyskinetic action remains an open question.     

N-methyl-d-aspartate (NMDA) receptor-mediated stimulation of noradrenaline release,but not release of other neurotransmitters,in the rat brain cortex: receptor location,characterization and desensitization

Summary Rat brain cortex slices and synaptosomes (in a few experiments also hippocampal synaptosomes) preincubated with ³H-noradrenaline, ³H-5-hydroxytryptamine, ³H-choline, ³H-glutamate or ³H--aminobutyric acid were used to investigate the ³H-transmitter release in response to exposure to N-methyl-d-aspartate (NMDA) and other excitatory amino acids. The slices and synaptosomes were superfused with Mg²⁺-free, otherwise physiologically composed salt solution.In cortical slices preincubated with ³H-noradrenaline, NMDA concentration-dependently stimulated ³H overflow, whereas no such effect occurred in slices preincubated with ³H-5-hydroxytryptamine, ³H-choline, ³H-utamate or ³H--aminobutyric acid. In cortical slices preincubated with ³H-noradrenaline, the NMDA-evoked ³H overflow was abolished by tetrodotoxin, presence of Mg²⁺ 1.2 mmol/l or absence of Ca²⁺. 2-Amino-5-phosphonovaleric acid produced a parallel shift to the right of the NMDA concentration-response curve, whereas (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine hydrogen maleate (MK-801) not only shifted the concentration-response curve to the right but also reduced the maximum effect of NMDA. Other excitatory amino acid receptor agonists also stimulated ³H overflow, yielding the following rank order of potency: NMDA > l-glutamate > l-aspartate. Kainate and, in particular, quisqualate exhibited only low potencies and/or intrinsic activities. Prolonged (25 min) exposure of ³HNA-preincubated cortical slices to a high NMDA concentration produced a short-lasting peak of ³H overflow, followed by a second phase lasting as long as the compound was present; in this phase, ³H overflow was clearly less pronounced and gradually decreased with time. The stimulatory effect of a high NMDA concentration was concentration-dependently reduced by 20 min of pre-superfusion with NMDA or l-glutamate at concentrations which by themselves produced either no or, at the most, moderate increase in ³H efflux in the two 5-min periods before application of the NMDA stimulus; in contrast, the veratridine-evoked ³H overflow was increased by pre-exposure to these NMDA concentrations. Neither in 3H-noradrenaline-preincubated synaptosomes prepared from the cortex or hippocampus nor in cortical synaptosomes preincubated with ³H-5-hy-droxytryptamine did NMDA evoke ³H overflow. The veratridine-evoked ³H overflow from ³H-noradrenaline-preincubated cortical synaptosomes was not affected by simultaneous administration of NMDA.It is concluded that NMDA selectively stimulates noradrenaline release in the rat brain cortex via NMDA receptors which appear not to be located on the noradrenergic nerve terminals. The NMDA receptor is rapidly desensitized in response to continuous application of NMDA (tachyphylaxis) or l-glutamate (cross-tachyphylaxis). Send offprint requests to M. Göthert at the above address     

Studies on the chemical constituents from the roots of <Emphasis Type="Italic">Platycodon grandiflorum</Emphasis>

Three known monodesmosidic saponins: 3-O--d-glucopyranosyl-2,3,16,23,24-pentahydroxyolean-12-ene-28-oic acid, 3-O--d-glucopyranosyl polygalacic acid, and 3-O--d-glucopyranosyl-(13)--d-glucopyranosyl polygalacic acid; and two known nonsaponin compounds: a mixed compound of n-tetracosanoic acid (lignoceric acid), n-hexacosanoic acid (cerotic acid), and n-octacosanoic acid, and -monopalmitin; were isolated for the first time from the root of Platycodon grandiflorum A. DC. together with another seven known compounds: platycoside G₁ (3-O--d-glucopyranosyl-(16)--d-glucopyranosyl-(16)--d-glucopyranosyl-2,3,16,23,24-pentahydroxyolean-12-ene-28-oic acid 28-O--d-xylopyranosyl-(14)--l-rhamnopyranosyl-(12)--l-arabinopyranoside), deapio-platycodin D, Polygalacin D, deapio-platycodin D₃, platycoside A, -spinasterol, and -spinasteryl-3-O--d-glucopyranoside. Alkaline hydrolysis of platycoside G₁ afforded a new monodesmosidic prosaponin: 3-O--d-glucopyranosyl-(16)--d-glucopyranosyl-(16)--d-glucopyranosyl-2,3,16,23,24-pentahydroxyolean-12-ene-28-oic acid. Their chemical structures were elucidated on the basis of their spectral data and chemical evidence.     

l-Dopa effects on motor and “central programming” deficits in Parkinsonism

A study was made to test the effects of treatment by l-Dopa on both motor and central programming deficits in Parkinsonism.Nine patients with Parkinsonism were tested on psychomotor tasks, involving both unimanual and bimanual performance, before and after treatment. Control data was obtained from 28 age-matched subjects. These were only tested on one occasion.As expected, there was a very significant improvement in motor performance of the Parkinsonism group after treatment by l-Dopa. The evidence of improvement in the central programming deficit was less conclusive, but seemed substantial enough to warrant further investigation.     

SK&F 104078, a post-functionally selective α2-adrenoceptor antagonist in the human saphenous vein in vitro

Summary The present study investigated the effects of SK&F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxy]-3methyl-1H,2,3,4,-tetrahydro-3-benzazapine) at pre- and post functional ₂-adrenoceptors in the human isolated saphenous vein. Noradrenaline (0.001–100 mol/l) produced concentration-dependent contractions of the human saphenous vein which were competitively antagonised by the ₁-adrenoceptor antagonist prazosin (0.01–1.0 mol/l) and the ₂-adrenoceptor antagonist, rauwolscine (0.01–1.0 mol/l), indicating the presence of both post functional ₁- and ₂-adrenoceptors in this preparation. The selective ₂-adrenoceptor agonist, UK-14,304 (0.01–100 mol/l) also produced concentration-dependent contractions of the human saphenous vein which were antagonised by both rauwolscine (0.1 mol/l) and prazosin (0.1 mol/l). In the presence of angiotensin II (0.05 mol/l), which itself produced a transient contraction, rauwolscine (0.1 mol/l) produced a rightward shift of the UK-14,304 concentration-response curve while prazosin (0.1 mol/l) had no effect. SK&F 104078 (10.0 mol/l) under these conditions also produced a rightward shift of the concentration-response curve to UK-14,304, but was at least 100-fold less potent than rauwolscine. At pre functional ₂-adrenoceptors, exogenous noradrenaline (0.01 and 0.1 gmol/l) induced a concentration-dependent inhibition of stimulation-evoked [7-³H]-noradrenaline release from the human saphenous vein in vitro, which was antagonised by rauwolscine (0:1 mol/l) and tolazoline (10.0 mol/l) but not by SK&F 104078 (10.0 gmol/l).Rauwolscine (0.1 mol/l) produced a small increase in stimulation-evoked [7-³H]-noradrenaline release while both tolazoline and SK&F 104078 failed to produce any enhancement in release in the absence of exogenous agonist atconcentrationsupto10 gmol/l.Insummary, noradrenaline and UK-14,304 contracted the human isolated saphenous vein by an action at both postfunctional ₁- and ₂-adrenoceptors. These data demonstrate that SK&F 104078 discriminates between post- and pre-junctional ₂-adrenoceptors in the human isolated saphenous vein. Send offprint requests to M. V. Sennitt at the above address     

Neurotoxicity and pharmacology of Lathyrus sativus extracts of high- and low-toxicity strains

Neurolathyrism is characterized by spastic paraparesis of the legs. It is caused by overconsumption of grass pea (Lathyrus sativus L.; Leguminosae). We studied toxicity of extracts of L. sativus seeds from two different areas—Bangladesh and Canada—toward rat primary neuron/glia culture. Both extracts showed acute neurotoxicity within 24 h when the 75% ethanol extracts were added to the neuron/glia culture. Fractionation of the extracts showed that the water-soluble fraction accounted for ca. 75–84% of total toxicity in which 3-N-oxalyl-l-2,3-diaminopropanoic acid (l--ODAP) was present at the highest concentration. Toxicity of the water-soluble fraction obtained from Bangladeshi seeds was significantly higher than that obtained from Canada. Effects of these fractions were reversed almost completely by 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX), an antagonist of AMPA-receptor. They were partially reversed by group I metabotropic glutamate receptor antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid, or (S)--methyl-4-carboxyphenyl-glycine [(S)-MCPG]. Nitric oxide synthase inhibitor N^G-nitro-l-arginine methyl ester (l-NAME) strongly decreased the extracts toxicity. These data show that the neurotoxicity of grass pea seeds is attributable to l--ODAP, the toxicity of which is mediated by collective effects of l--ODAP on the AMPA-type receptor, metabotropic glutamate receptors, and NO production.     

Selective potentiations in opioid analgesia following scopolamine pretreatment

The effects of the muscarinic receptor antagonist scopolamine upon analgesia induced by d-ala-d-leu-enkephalin (DADL), beta-endorphin (BEND) and morphine were examined. While scopolamine (10 mg/kg, IP) significantly potentiated the analgesic responses following DADL (40 g, ICV) and morphine (5 mg/kg, SC) on the jump test, it failed to alter significantly BEND (1 g, ICV) analgesia.     

(±)[125Iodo]cyanopindolol,a new ligand for β-adrenoceptors: Identification and quantitation of subclasses of β-adrenoceptors in guinea pig

Summary (±)[¹²⁵Iodo]cyanopindolol (ICYP) is a radioligand which binds with an extraordinarily high affinity and specificity to -adrenoceptors. In contrast to (±)[¹²⁵Iodo]-hydroxybenzylpindolol (IHYP), the new ligand has neither affinity to - nor to 5-HT-receptors. The dissociation constants of ICYP for -adrenoceptors in various tissues range from 27 to 40 pM, thereby exceeding the affinity of IHYP by a factor of 3.ICYP does not discriminate between ₁– and ₂–. Therefore, the densities of the two receptor subtypes can be determined from competition curves of ICYP by drugs previously found to show in vitro selectivity for ₁–adrenoceptors.The guinea pig left ventricle contains only ₁– adrenoceptors, whereas in the lung tissue, the ratio of ₁– to ₂–adrenoceptors is 1 to 4. The calculated affinities of five ₁– selective antagonists for ₁–adrenoceptors were nearly identical in the ventricle and the lung.Kinetic studies of ICYP binding to guinea pig lung membranes indicated that the dissociation reaction consists of two components, a fast process (t _1/2=9 min) and a slower process (t _1/2=8.8 h). A mathematical treatment revealed two possibilities of interpretation: 1. Two forms of the receptor exist which are interconvertible. 2. The (+)- and (–)-enantiomers of ICYP dissociate with different rate constants.The low dissociation constant of ICYP in combination with its high specific radioactivity (2175 Ci mmole^–1) allows binding studies to be carried out with small protein and ligand concentrations, e.g. 3 g protein per assay in guinea pig lung membranes.Abbreviations CYP (±)cyanopindolol, [(±)4-(3-tert-butylamino-2-hydroxypropoxy)-1H-indole-2-carbonitrile] - ICYP (±)-3-[¹²⁵iodo]-cyanopindolol - HYP (±)hydroxybenzylpindolol; IHYP, (±)[¹²⁵iodo]-hydroxybenzylpindolol - ³H-DHA (–)-[³H]dihydroalprenolol Part of this work has been presented in Mainz, March 1980, at the Spring Session of the German Pharmacological Society, and in Brussels, June 1980, at the 4th International Conference on Cyclic Nucleotides     

Isolation and identification of histamine-release inhibitors from Pistacia weinmannifolia J. Pisson ex. Franch

Seven histamine-release inhibitors were isolated from Pistacia weinmannifolia J. Pisson ex. Franch. They were identified as gallic acid, 3-O-galloylquinic acid, methyl gallate, ethyl gallate, penta-O-galloyl--d -glucopyranoside, myricetin 3-O--l-rhamnopyranoside, and myricetin- 3-O-(3-O-galloyl)--l-rhamnopyranoside. These compounds suppressed the compound 48/80-induced histamine release from rat peritoneal mast cells.     

Tryptophan antidepressant ‘physiological sedative’: Fact or fancy?

Some recent publications relating to the allegedly antidepressive and sedative effects of L-tryptophan the precursor of 5-HT have been reviewed.The evidence to date suggests that the amino acid is as effective as standard tricyclic drugs in alleviating the symptoms of depression, especially those cases presenting with mainly psychomotor retardation, and is synergistic with MAOIs. L-Tryptophan would also appear to be a physiological sedative. This action, however, appears to be related to the time of administration and at present has only been demonstrated at night, when endogenous levels of 5-HT are at their peak.In terms of practical therapeutics L-tryptophan would appear to have greater potential as an antidepressant than as a sedative.     

Biotransformation of locally applied l-dopa in the corpus striatum of the hemi-Parkinsonian rat studied with microdialysis

Microdialysis was used to study the biotransformation of l-dopa in intact and denervated striata of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. Microdialysis probes were placed in the intact and in the denervated striatum. Observations were then made on freely moving rats. Extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid; HVA) were monitored before, during and after the local administration of l-dopa via the microdialysis probe for 20 min.A dose-dependent increase in extracellular dopamine levels was seen in intact striatum after application of l-dopa in concentrations ranging between 100 nmol/l and 10 mol/l. In the denervated striatum, the severity of the lesion influenced dopamine formation, so that no dose-effect relation could be established.The effects of the continuous intra striatal infusion of nomifensine, tetrodotoxin or benserazide on the l-dopa-induced dopamine outflow revealed that in the intact striatum this dopamine release is mainly voltage dependent. It was concluded that in the denervated striatum other cells of non-neuronal origin and containing aromatic l-amino acid decarboxylase make a major contribution to the increase in extracellular dopamine levels. Furthermore, l-dopa itself shows no dopamine-releasing properties, at least under the present experimental conditions. Correspondence to: S. Sarre at the above address     

Effects of low and high doses of l-Dopa on the tetrabenazine or α-methyltyrosine-induced suppression of behaviour in a successive discrimination task

The effect of the administration of l-Dopa, 10 or 100 mg/kg i.p., on the -methyltyrosine methylester HCl (-MT; 250+50 mg/kg i. p.) or tetrabenazine (TBZ; 2 mg/kg i.p.)-induced suppression of a successive discrimination-conditioned avoidance task has been studied. It was found that administration of the high l-Dopa dose resulted in a reversal of the -MT- or TBZ-induced suppression of the avoidance behaviour, although the discrimination was lost. Restoration of the avoidance behaviour and the correct discrimination was obtained with the low l-Dopa dose after -MT but not after TBZ. The difference in the behavioural response to l-Dopa after -MT as compared to the response obtained after TBZ is discussed in terms of the availability of the catecholamines formed from l-Dopa for release by the nerve impulses. Biochemical determinations of brain noradrenaline and dopamine were made in parallel. Further, a simple and reliable method for the aquisition of a successive discrimination in the rat is described.     

Relationship between tardive dyskinesia,l-Dopa-induced hyperkinesia and parkinsonism

In a study of 16 psychotic patients with neuroleptic-induced tardive dyskinesia and 16 patients with Parkinson's disease and l-Dopa-induced hyperkinesia kinesia it was found that (1) tardive dyskinesia, compared to l-Dopa hyperkinesia, was localized almost exclusively to the oral region (P<0.01), whereas the l-Dopa hyperkinesia was more pronounced in the neck (P<0.05) and the extremities (P<0.05); (2) l-Dopa hyperkinesia showed an increasing tendency to oral preponderance with age, irrespective of the severity of parkinsonism and extra-oral hyperkinesia, while tardive dyskinesia only itensified with age, without any change in distribution; and (3) extraoral l-Dopa hyperkinesia was related to the localization and severity of pretreatment parkinsonism, and more to bradykinesia than to rigidity and tremor. It is concluded that the irreversible neurotoxic effect of neuroleptic drugs may be associated with agerelated changes in the oral somatotopic region of the basal ganglia (to be given consideration in any future search for the pathogenetic process underlying irreversible tardive dyskinesia), and that the pathophysiology of involuntary hyperkinesia in neuroleptic-treated psychiatric patients and in l-Dopatreated Parkinson patients may consist of a primary dopamine deficiency (pharmacological or structural), and a secondary relative hyperactivity in the dopaminergic system (dopaminergic hypersensitivity) possibly corresponding to hypoactivity in the cholinergic system.