L. Maitre

Blockade of presynaptic ?-receptors and of amine uptake in the rat brain by the antidepressant mianserine

SummaryMianserine (Org GB 94, Tolvon®) is 1, 2, 3, 4, 10, 14b-hexahydro-2-methyl-dibenzo [c, f] pyrazino [1, 3-a] azepine hydrochloride, a new antidepressant drug. Its effect on noradrenaline release and its capacity to inhibit amine uptake were investigated. Mianserine increased the release of 3H-noradrenaline from field-stimulated cortical slices previously labelled with the tritiated transmitter. The assumption that this effect is due primarily to the blockade of the presynaptic noradrenergic α-receptors is supported by the fact that mianserine failed to augment 3H-noradrenaline release further after blockade of the presynaptic α-receptors by phentolamine. In the reciprocal experiment, phentolamine failed to augment 3H-noradrenaline release after exposure of the slices to mianserine. The hypothesis is further reinforced by the fact that mianserine antagonized the reduction of 3H-noradrenaline release by clonidine in the same manner as the α-blocking drugs phentolamine and phenoxybenzamine. Mianserine inhibited noradrenaline uptake in vitro and in vivo (in the rat heart and midbrain-diencephalon synaptosomes from pretreated rats.) Only a marginal inhibition of serotonin uptake was observed.It therefore appears that mianserine increases the concentration of noradrenaline in the synaptic cleft by blocking the presynaptic α-receptors and inhibiting uptake. Whether or not this increase has functional consequences at postsynaptic noradrenergic receptor sites is unknown. It is possible, however, that postsynaptic receptor blockade counteracts the increase in available noradrenaline.

Preferential deamination of dopamine by an A type monoamine oxidase in rat brain.

SummaryThe effect of graded closes of clorgyline, a preferential inhibitor of MAO A, and of deprenil, a preferential inhibitor of MAO B, on the activities of serotonin-deaminating MAO (MAO A) of dopamine-deaminating MAO, and of phenethylamine-deaminating MAO, (MAO B), in rat corpus striatum were compared with the effects of the drugs on striatal levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC).The dose-response curves for the two last-mentioned dopamine metabolites closely follow those for MAO A and dopamine-deaminating activity, whether clorgyline or deprenil was used as MAO inhibitor.In addition, the effect of these drugs on dopamine levels and on the accumulation of 3H-dopamine + 3H-methoxytyramine formed from 3H-DOPA in rat whole brain was analysed. In contrast to the marked increases caused by clorgyline, the effects of deprenil were negligible. In reserpinized rats, clorgyline potentiated the effect of l-DOPA on motor activity; deprenil did not.These results suggest that the deamination of dopamine in vivo is almost entirely effected by MAO A.

Oxaprotiline, a noradrenaline uptake inhibitor with an active and an inactive enantiomer

Abstract The new antidepressant drug, oxaprotiline, and its two enantiomers were investigated with respect to their effects on noradrenaline (NA) and serotonin (5-HT) uptake in vitro and in vivo after acute and repeated treatment. Moreover, the alpha-adrenolytic effects in vitro were also studied. Oxaprotiline proved to be a highly potent and selective inhibitor of NA uptake in rat synaptosomal preparations in vitro and in the rat heart and brain in vivo The NA uptake-inhibiting properties were found to be confined entirely to the (+)- or S-enantiomer: (−)- or R-oxaprotiline, the absolute configuration of which corresponds to that of the naturally occurring (−)-NA, was about 1000 times less potent than the (+)-form in vitro , and was inactive in vivo at doses exceeding the ED 50 of the latter 100-fold. The selectivity of oxaprotiline with respect to NA uptake inhibition was retained after 10 daily administrations. No sign of cumulation or attenuation of the effect was evident. No uptake-inhibiting effect of (−)-oxaprotiline appeared after 10 daily administrations of high doses, indicating that no racemization occurred in the organism. The α 1 -adrenoceptor antagonistic effect of oxaprotiline, as determined by the ability to displace [ 3 H]prazosin, was in the range of that of imipramine, the (−)-enantiomer being somewhat more potent than the (+)-form. In contrast to imipramine, oxaprotiline was devoid of α 2 -adrenoceptor antagonistic effects, as judged by the ability to affect the impulse-related release of [ 3 H]NA from rat cortical slices. Since oxaprotiline proved to be an effective antidepressant, clinical testing of its two enantiomers might be helpful with respect to the validation of the catecholamine hypothesis of depression. Moreover, in animal studies, they might help to determine which effects of antidepressants are related to NA uptake inhibition and which are not.

The Use of Inhibitors of GABA‐Transaminase for the Determination of GABA Turnover in Mouse Brain Regions: An Evaluation of Aminooxyacetic Acid and Gabaculine

Abstract: The accumulation of γ‐aminobutyric acid (GABA) after inhibition of GABA‐T (4‐aminobutyrate: 2‐oxoglutamate aminotransferase, EC 2.6.1.19) by various doses of aminooxyacetic acid (AOAA) and gabaculine was studied in four different regions of the mouse brain. The dose‐response curve for GABA accumulation after treatment with AOAA was linear up to 10 mg/kg i.p., and then leveled off. The increase in GABA accumulation after gabaculine treatment was linear up to 100 mg/kg i.p. No further increase was observed with doses up to 300 mg/kg i.p. The selectivity of both GABA‐T inhibitors was assessed by measuring their effects on the content of free amino acids in mouse brain. Apart from the substantial increase in the GABA concentration, there were significant decreases in the content of glutamic acid, aspartic acid, alanine and glutamine, and an increase in ornithine content after administration of gabaculine. The same changes in amino acid content were observed after treatment with AOAA, but the level of lysine was also increased and the change in alanine level was biphasic. All these changes, however, were very small compared with the large increase in GABA level. A method for estimating the rate of the GABA turnover in vivo by measuring the initial rate of GABA accumulation after administration of AOAA or gabaculine is proposed, and the validity of the two techniques is discussed. The effect of diazepam on GABA levels and on the gabaculine‐induced accumulation of GABA was studied. The results obtained with diazepam show that this method can provide valuable insight into the effects of drugs on GABAergic mechanisms in vivo.

METHYLHISTAMINE: EVIDENCE FOR SELECTIVE DEAMINATION BY MAO B IN THE RAT BRAIN IN VIVO

Abstract— A new method has been developed for the separation of histamine and its metabolites after intracisternal injection of [3H]histamine into the rat brain, involving solvent extraction and subsequent thin‐layer chromatography.

Blockade of noradrenaline uptake by 34276-Ba, a new antidepressant drug

Abstract 34276-Ba is 1-(3-methylaminopropyl)-dibenzo[b, e]bicyclo-[2.2.2.] octadiene hydrochloride, an antidepressant drug from a new class of chemical compounds. Its effects on noradrenaline uptake have been studied and compared with those of imipramine or desmethylimipramine. 34276-Ba was found to be a powerful inhibitor of noradrenaline uptake through the nerve cell membrane in several sympathetically innervated organs of the rat, cat and chick in vivo . The inhibitory effect was very pronounced in the brain as well as in peripheral tissues. The new antidepressant drug also inhibited the guanethidine-induced depletion of the endogenous noradrenaline stores and the uptake of [ 3 H]metaraminol in the rat heart. Although 34276-Ba caused a concentration dependent inhibition of noradrenaline uptake into isolated bovine splenic nerve granules, it did not alter markedly the endogenous concentration of catecholamines in heart and brain even after repeated daily treatment.

Effects of baclofen on dopamine metabolism and interaction with neuroleptic effects

Baclofen increased striatal levels of dopamine (DA), homovanillic (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) dose-dependently above 10 mg/kg i.p. The effect on the DA metabolites was shown to be caused only by the (-)-isomer. The HVA increase after 20 mg/kg i.p. was not antagonized by either scopolamine or picrotoxin. Repeated treatment produced a smaller increase in HVA than a single administration. Baclofen reduced both the disappearance of DA after alpha-methyl-p-tyrosine and the acceleration of the DA disappearance caused by neuroleptics in corpus striatum and in the mesolimbic area. The neuroleptic-induced increases in HVA and DOPAC and in DOPA accumulation after central decarboxylase inhibition were also reduced. Picrotoxin could not antagonize these effects of baclofen which therefore cannot be regarded as being garbergic. Baclofen effects on DA metabolism are similar to those reported for gamma-hydroxybutyric acid and are probably a consequence of inhibition of firing of DA neurons.

Clozapine: Reduction of the initial dopamine turnover increase by repeated treatment

The levels of homovarillic acid and 3,4-dihydroxyphenylacetic acid in rat c. striatum after acute and 10 day administration of clozapine (30 and 100 mg/kg p.o.), thioridazine (100 mg/kg p.o.), haloperidol (1 mg/kg p.o.), and chlorpromazine (30 mg/kg p.o.), were estimated. With clozapine and haloperidol, the mesolimbic area was also investigated. With all these neuroleptics, the levels of both dopamine metabolites were reduced after a 10 day treatment as compared to acute administration, sometimes almost to control values. With clozapine, however, such a reduction occurred only with the higher dose of 100 mg/kg p.o., acting for a period longer than 24 h. This tolerance phenomenon was also observed with clozapine and haloperidol in the mesolimbic area. We conclude that clozapine is not qualitatively different from classical neuroleptics with respect to development of biochemical tolerance.

Selective inhibition of noradrenaline and serotonin uptake by C 49802-B-Ba and CGP 6085 A.

The effects of two new compounds, 1-(1-methylamino-2-hydroxy-3-propyl)-dibenzo[b,e]bicyclo[2,2,2]octadiene-HCl (C 49802-B-Ba) and 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A), on noradrenaline (NA) and serotonin (5-HT) uptake were investigated in different test systems, CGP 6085 A is a very potent and selective inhibitor of 5-HT uptake in rat brain (ED50 1-4 mg/kg p.o., depending on test system). Doses up to 1000 mg/kg p.o. did not inhibit NA uptake. C 49802-B-Ba is a potent and selective inhibitor of NA uptake in rat brain (ED50 5-10 mg/kg p.o. depending on test system) and heart (ED50 1.5 mg/kg p.o.). At 300 mg/kg p.o., this compound caused no inhibition of 5-HT uptake.

An automated fluorometric method for the estimation of dopamine in brain tissue extracts

Abstract A method for the automated estimation of dopamine in the concentration range of 10–2000 ng/ml is presented which can process 30 samples/hour with an average error of 0.87%. Interference by dopa is high. Interferences by noradrenaline and adrenaline are 0.6 and 0.5%, respectively, and can normally be neglected. Dopamine contents of striata of controls and of α-methyltyrosine-treated rats were estimated with this system.