Inhibition Of Neuronal Uptake Research Articles

The rate constants for the efflux of deaminated metabolites of 3H-dopamine from the perfused rat heart.

Hearts of rats pretreated with reserpine and FLA 63 were perfused for 30 min with 1 mumol/l 3H-dopamine and in the presence of an inhibitor of either neuronal (30 mumol/l cocaine) or extraneuronal uptake (87 mumol/l corticosterone). From the rate at which the deaminated metabolites appeared in the venous perfusate and from the tissue content of the metabolites at the end of the perfusion rate constants for efflux (k-values) were determined. The k-values for the deaminated metabolites of dopamine did not differ when the deamination of dopamine was restricted to either extraneuronal or neuronal sites. However, marked differences existed between the rate constant for efflux of the deaminated acid DOPAC (dihydroxyphenyl-acetic acid) and the glycol DOPET (dihydroxyphenyl-ethanol). The relationship between the apparent lipophilicity and the rate constant for efflux of DOPAC fitted very well with that reported for other metabolites of catecholamines.

Effect of a specific 5HT uptake inhibitor (citalopram) on drug accumulation by rat lung slices.

Rat lung slices were used to examine the effects of citalopram, a compound reported to be a specific inhibitor of neuronal uptake of 5-hydroxytryptamine (5HT), on the pulmonary accumulation of 5HT, noradrenaline (NA), imipramine (IP) and paraquat (PQ). 5 X 10(-9) mol/l citalopram inhibited 5HT uptake by 30-40% but NA uptake was not affected at any of the concentrations of citalopram studied. At the highest concentrations of citalopram (10(-5) to 10(-4) mol/l) the accumulation of IP and PQ was reduced by25-30%. It is concluded that at low concentrations, citalopram is a specific and potent inhibitor of 5HT uptake by rat lung slices.

Interactions between conformationally restricted GABA analogues and the astroglial GABA carrier

The substrate specificity of GABA uptake into astrocytes in primary cultures has been investigated using GABA analogues of restricted conformation and the results compared with similar studies of neuronal GABA transport. Both transport systems are stereospecific with regard to the symmetrical H-atoms on C-4 in the GABA molecule. Moreover, the two carriers exhibit distinctly different substrate specificities. The following GABA analogues were found to be selective inhibitors of glial GABA uptake: (3RS, 4SR)-4-Hydroxynipecotic acid, (RS)-β-proline, 5,6,7,8-tetrahydro-4 H-isoxazolo[4,5 - c]azepin-3-ol and perhydroazepine-3-carboxylic acid of which the latter 3 were found to be competitive inhibitors. The following compounds were selective inhibitors of neuronal uptake: (RS)-3-Hydroxy-5-aminovaleric acid and (3RS,4SR,5SR)-4-hydroxy-5-methylnipecotic acid. It is suggested that the selective glial inhibitor 5,6,7,8-tetrahydro-4 H-isoxazolo-[4,5- c]azepin-3-ol may be useful for in vivo studies of the effect of selective blockade of glial GABA uptake on the GABA content in nerve endings.

Biochemical characterization of [3H]norepinephrine uptake in dissociated brain cell cultures from chick embryos.

The uptake of [3H]norepinephrine ([3H]NE) was studied in dissociated brain cell cultures prepared from 8-day-old chick embryos using the whole brain (minus optic lobes). Uptake [3H]NE, 5 x 10(-9) m, 10 min incubation, in freshly dissociated noncultured embryonic chick brain cells, was detected in 6-day-old embryos; it was temperature and drug (cocaine, metanephrine) sensitive and increased with brain development. In cultured cells, which were assayed at various days in culture, the increase in [3H]NE accumulation per culture was less than that seen in freshly dissociated noncultured embryonic cells. When [H]NE uptake was expressed per mg protein, a decrease with days in culture was observed. reflecting perhaps a dilution of growth or proliferation of cells not accumulating NE. Metanephrine, 5 X 10(-6) M, an inhibitor of extraneuronal uptake, inhibited [3H]NE in 5-day-old cultures whereas desmethylimipramine, an inhibitor of neuronal uptake, inhibited [3H]NE uptake in 15- and 20-day-old cultures. Cocaine, another neuronal inhibitor, inhibited [3N]NE at 10 and 15 days only. We interpret these findings to suggest that during early growth in culture most neuroblasts accumulate NE nonspecifically and, as neuronal maturation proceeds, NE accumulation becomes specific.

Effects of uptake inhibitors on responses of sheep coronary arteries to catecholamines and sympathetic nerve stimulation.

1. Transmural stimulation of intrinsic sympathetic nerves and exogenous catecholamines produce beta 1-adrenoceptor mediated relaxant responses in strips of contracted sheep coronary artery. 2. The neuronal uptake inhibitors, metaraminol, cocaine and desipramine and the extraneuronal uptake inhibitor, cortisol, failed to potentiate responses to noradrenaline or sympathetic stimulation; responses to isoprenaline were enhanced by cortisol. 3. Oxytetracycline, which inhibits binding to connective tissue fibres, did not affect responses to noradrenaline or nerve stimulation. 4. 17 beta-Oestradiol, caffeine and U0521 proved to be unsuitable compounds for studying catecholamine inactivation since they non-selectively potentiated responses to noradrenaline and isoprenaline. 5. It is concluded that catecholamine inactivation processes do not modify transmitter function in sheep coronary arteries.

GABA fluxes in presynaptic nerve endings from immature rats.

Abstract— Several parameters of GABA Auxes across the synaptosomal membrane were studied using synaptosomes prepared from the brain of immature (8‐day‐old) rats. The following aspects of GABA carrier‐mediated transport were similar in immature and mature synaptosomes: (1) magnitude of [3H]GABA accumulation; (2) GABA homoexchange in normal ionic conditions; (3) GABA homoexchange in the presence of cationic fluxes (Na+ and Ca2+ influx, K+ efflux) characteristic of physiological depolarization. As in adult synaptosomes (Levi & Raiteri, 1978), in these conditions the stoichiometry of GABA homoexchange was in the direction of net outward transport (efflux > influx).The essential differences between the behaviour of 8‐day‐old and adult synaptosomes were the following: (1) β‐alanine (a glial uptake inhibitor) inhibited GABA uptake in immature synaptosomes (the inhibition being greater in crude than in purified preparations) and was without a significant effect in adult synaptosomes. DABA and ACHC (two neuronal uptake inhibitors) depressed GABA uptake more efficiently in purified than in crude immature synaptosomes, but were as effective in crude and purified nerve endings from adult animals. The data suggest a greater uptake of GABA in the‘gliosomes’contaminating the synaptosomal preparations from immature animals. (2) In immature synaptosomes prelabelled with [3H]GABA the specific radioactivity of the GABA released spontaneously or by heteroexchange (with 300 μm‐OH‐GABA) was the same as that present in synaptosomes, while in adult synaptosomes OH‐GABA released GABA with increased specific radioactivity. The data suggest a homogeneous distribution of the [3H]GABA taken up within the endogenous GABA pool in immature, but not in mature synaptosomes. (3) In immature synaptosomes the release of GABA (radioactive and endogenous) induced by depolarization with high KC was not potentiated by Ca2+, unless the synaptosomes had been previously depleted of Na+ These data suggest that, although a Ca2+ sensitive pool of GABA may be present, this pool is not susceptible to being released in normal conditions, probably because the high intrasynaptosomal Na+ level prevents a sufficient depolarization. The possible significance of these findings in terms of functional activity of GABAergic neurotransmission in the immature brain is discussed.

Inhibition of neuronal uptake of 3H-biogenic amines into rat cerebral cortex by partially and fully saturated derivatives of imipramine and desipramine : The importance of the aromatic ring in adrenergic amines—part 3

In order to assess the importance of the aromatic rings in inhibition of neuronal amine uptake produced by tricyclic antidepressant drugs, derivatives of imipramine (IMI) and dcsipramine (DMI) were prepared in which either one (IMIH, DMIH) or both (IMIH2, DMIH2) of the aromatic rings were fully reduced to cyclohexane rings. The relative abilities of these compounds to inhibit the uptake of l-[ 3 H]- norepinephrine (NE), [ 3H]-dopamine (DA) and [ 3H]-5-hydroxytryptamine (5-HT) into chopped tissue of rat cerebral cortex were determined. Reduction of one or both aromatic rings did not alter significantly the inhibition of uptake of [ 3H]-DA or [ 3H]5-HT produced by either IMI or DMI ( IC 50 values 25–80 μM). However, saturation of one or both rings abolished the selectivitv of DMI for inhibition of NE uptake ( IC 50 0.12 μM). decreasing potency 150-fold ( IC 50 18.3 μM) and 250-fold ( IC 50 29.4 μM) respectively. The effect of aromatic ring reduction on the IMI-induced inhibition of NE uptake was much less pronounced. The results suggest that hydrophobic rather than π-electron attractive forces are involved in the interaction of DMI or IMI with DA or 5-HT uptake sites. However, the loss in selectivity for inhibition of NE uptake upon reduction of DMI may reflect loss of π-electron interactions in the binding of DMI to the NE uptake site, or may reflect increased sensitivity to spatial disposition of the hydrophobic binding areas of the drug relative to that found at the DA or 5-HT amine uptake sites.

The inhibitory effect of some monovalent cations on the stimulation by Na+ of the neuronal uptake of noradrenaline.

1. Vasa deferentia obtained from reserpine-pretreated rats were incubated (after inhibition of both monoamine oxidase and catechol O-methyltransferase) in media containing 1.1 μmol·l−13H-(−)noradrenaline and various concentrations of Na+ (0–140 mmol·l−1; isosmolality maintained by sucrose or by several monovalent cations). Initial rates of neuronal uptake were determined in each single vas from the difference between “total” and “cocaine-resistant” uptake of 3H-noradrenaline. 2. The “cocaine-resistant” uptake (i.e., the distribution of 3H-noradrenaline observed in the presence of 100 μmol·l−1 cocaine) was considered to be nonneuronal. It was entirely independent of both the external Na+ concentration and the substance used to replace Na+ (or NaCl) in the medium. 3. The neuronal uptake of 3H-noradrenaline was virtually absent in Na+-free medium and was progressively stimulated by increasing Na+ concentrations. The stimulation of uptake by low Na+ concentrations was most pronounced when Tris+ was used to replace Na+; i.e., all other substitutes tested here (including sucrose, Li+, choline+ and K+) inhibited neuronal uptake when compared with Tris+. 4. While the Na+-dependent stimulation of neuronal uptake followed Michaelis-Menten kinetics in Tris+- or Li+-containing media, the kinetics of uptake stimulation by Na+ were rather complex in media containing choline+ or K+ as the substitute cation. 5. Li+ and K+ acted as competitive inhibitors with respect to Na+, whereas the inhibition of neuronal uptake by choline+ was the more pronounced, the higher the concentration of external Na+. 6. At concentrations higher than 25 mmol·l−1, the impairment of neuronal uptake by K+ exceeded that predictable from competitive inhibition of the action of Na+. This was due to the fact that high external K+ concentrations decelerated net uptake very early in the time course of amine accumulation, so that initial rates of uptake are likely to be underestimated under these conditions. 7. Thus, apart from maintaining isosmolality, several substances used to replace Na+ in the medium have inhibitory effects which must be considered in experiments designed to examine the role of Na+ in membrane transport of noradrenaline.

Frequency-dependence of the metabolism of 3H-noradrenaline released from rabbit isolated aorta: effects of a combination of cocaine and corticosterone or hydrocortisone.

Abstract The effect of cocaine (neuronal uptake inhibitor) in combination with either hydrocortisone or corticosterone (extraneuronal uptake inhibitors) on the metabolism of 3H‐noradrenaline (3H‐NA) released spontaneously or by electrical‐field stimulation was studied on the isolated rabbit aorta preloaded with 3H‐NA. In the spontaneous outflow 3H‐O‐methylated and deaminated metabolites (3H‐OMDA) accounted for 41% of the total radioactivity whereas 3H‐NA represented only 22%. Cocaine (3 × 10‐5M) + hydrocortisone (10‐4 M) neither changed the spontaneous outflow of total tritium nor the distribution of the 3H‐outflow on 3H‐NA and its 3H‐metabolites. However, cocaine (3 × 100‐5M) + corticosterone (4 × 10‐5M) enhanced the passive 3H‐outflow, increased the percentage recovered as 3H‐3,4‐dihydroxyphenylglycol (3H‐DOPEG), and reduced the percentage of 3H‐OMDA + 3H‐NMN. The effect of field‐stimulation was investigated during and ofter stimulation at two frequencies: 3 and 10 Hz. The stimulation‐induced 3H‐overflow consisted mainly of unmetabolized 3H‐NA and 3H‐OMDA in the sample collected during stimulation. The ratio between 3H‐NA and 3H‐OMDA was strongly dependent on the frequency of stimulation, Thus it was 1:2 at 3 Hz, but 3:1 at 10 Hz. These ratios were about the same during the poststimulation period. On the other hand, whereas the formation of 3H‐DOPEG from 3H‐NA released during stimulation at both frequencies was small, it increased rapidly in the poststimulation sample. At 3 Hz, inhibition of neuronal and extraneuronal uptake by cocaine + steroids did not change the stimulation‐induced 3H‐overflow, but the distribution on 3H‐NA and 3H‐metabolites was markedly altered. Thus the percentage of 3H‐N A was doubled, 3H‐OMDA was halved, and 3H‐DOPEG was almost abolished. At 10 Hz, however, cocaine + corticosterone decreased the stimulation‐induced 3H‐overflow, but did not change the proportions of 3H‐NA and 3H‐OMDA. Only the formation of 3H‐DOPEG was markedly reduced. It is concluded that the distribution of stimulation‐induced 3H‐overflow on 3H‐NA and its 3H‐metabolites and the effect of neuronal and extraneuronal uptake inhibition on this is strongly influenced by the frequency of stimulation. Furthermore, inhibition of both neuronal and extraneuronal uptake does not fully prevent metabolism of 3H‐NA released by electrical‐field stimulation.

X-Ray Crystallographic and 1H NMR Spectroscopic Investigations of (3RS, 4SR)-4-Hydroxypiperidine-3-carboxylic Acid, an Inhibitor of Neuronal and Glial GABA Uptake.

X-Ray Crystallographic and 1H NMR Spectroscopic Investigations of (3RS, 4SR)-4-Hydroxypiperidine-3-carboxylic Acid, an Inhibitor of Neuronal and Glial GABA Uptake.

On the correlation between alpha-adrenoceptor blockade and inhibition of neuronal uptake of 3H-noradrenaline

Summary A correlation study has been made into the structural requirements in a series of benzodioxanes for the blockade of pre- and post-synaptic alpha adrenoceptors and the inhibition of neuronal uptake of 3 H-noradrenaline in isolated rat vas deferens. All the compounds investigated exhibited some degree of uptake inhibition, but their order of potency, in this respect, bore no correlation with their order of potency as inhibitors of alpha adrenoceptors, as previously determined.

The action of DL-2,4-diaminobutyric acid on the cataleptogenic effects of pilocarpine and alpha-flupenthixol in rats.

The existence of a strionigral GABA-ergic pathway having an inhibitory effect on the nigrostriatal dopaminergic system has been proposed. The work reported in this paper was undertaken to investigate whether modification of the GABA-eric system by the GABA neuronal uptake inhibitor DL-2,4-diaminobutyric acid (DABA) would affect cholinergic (pilocarpine) and/or neuroleptic alpha-flupenthixol (alpha-FPT) induced catalepsy. DABA pretreatment was shown to enhance significantly both alpha-FPT and pilocarpine induced catalepsy. DABA alone had no cataleptic activity. The results are interpreted as supporting the existence of an inhibitory strionigral GABA-ergic pathway.

Effects of cocaine and nortriptyline on contractile responses in rabbit aorta

The effects of cocaine and nortriptyline on contractile responses to field stimulation, (−)-noradrenaline and methoxamine in the rabbit aorta were studied. The method used allowed detection of changes in maximal responses. Cocaine (3.3 × 10 −5 M) potentiated all, responses, including maximal responses, to field stimulation, (−)-noradrenaline and methoxamine. Nortriptyline (10 −6 M) had no effect on maximal responses to field stimulation, (−)-noradrenaline and methoxamine. The submaximal responses in the presence or absence of nortriptyline were plotted either as a percentage of an initial maximal response to (−)-noradrenaline in the absence of the drug or as a percentage of the maximal response of the individual maximal response. Depending on the method used to express the results, nortriptyline (10 −6 M) had no effect or potentiated submaximal responses to field stimulation and had no effect or inhibited submaximal responses to (−)-noradrenaline; this matter is discussed. Nortriptyline (10 −6 M) inhibited submaximal responses to methoxamine. The results illustrate that, in the rabbit aorta, inhibition of neuronal uptake is an insufficient explanation of the potentiating effect of cocaine on maximal responses and, furthermore, support the suggestion that cocaine has a postsynaptic action in this tissue.

Muscimol uptake, release and binding in rat brain slices.

Abstract— The GABA analogue, muscimol, was taken up relatively inefficiently compared to GABA by slices of rat cerebral cortex at 37 C. Muscimol uptake followed saturation kinetics (Km ImM. Vm 0.1 μmol g mini and showed an absolute dependence on sodium ions. The relative susceptibilities of muscimol uptake and GABA high affinity uptake to a variety of inhibitors, including (‐)‐nipecotic acid. (+)‐2.4‐diaminobutyric acid and arecaidine, and the stimulation of muscimol efflux by 50μM‐GABA, suggest that muscimol and GABA share some common transport carriers. Since L‐histidine inhibited muscimol uptake hut not GABA high affinity uptake, at least part of the observed muscimol uptake may be mediated by the 'small basic’amino acid transport system. Muscimol appeared to he taken up into nerve terminals, since uptake was inhibited by the neuronal uptake inhibitor cis‐3‐aminocyclohexanecarboxylic acid but not by the glial uptake inhibitor β‐alanine. Muscimol efflux was stimulated in a calcium‐dependent manner by an increased potassium ion concentration.Sodium‐independent binding of muscimol was observed in slices of rat cerebral cortex at 4 C. Binding could be inhibited by a variety of substances. including GABA, isoguvacine and (+)‐bicuculline methochloride, which are known to inhibit the binding of muscimol to putative GABA receptors associated with synaptic membranes purified from rat brain.

MECHANISMS OF INACTIVATION OF NORADRENALINE IN THE IRIS SPHINCTER, TRACHEAL MUSCLE AND FACIAL ARTERY OF CATTLE: IMPLICATIONS FOR β‐ADRENOCEPTOR‐MEDIATED RESPONSES

1 The role of neuronal and extraneuronal pathways of amine inactivation in regulating the inhibitory actions of noradrenaline was investigated in three bovine smooth muscle preparations in which the primary adrenoceptor is of the beta-type.2 The extraneuronal uptake inhibitor, 17beta-oestradiol, sensitized the inhibitory responses to noradrenaline in the facial artery, the iris sphincter and in tracheal muscle preparations, indicating a major role for non-neuronal processes in agonist-inactivation in all three preparations. Cocaine also increased responses to noradrenaline, pointing to a role for neuronal uptake either as a terminating mechanism or as a process limiting access of exogenous agonist molecules to their site of action.3 Cocaine did not enhance significantly responses to isoprenaline, a potent beta-adrenoceptor agonist which is not taken up neuronally. Further, relaxations to metaraminol, a sympathomimetic amine which is taken up extraneuronally, but much less so than noradrenaline, were also less enhanced by 17beta-oestradiol in the three preparations tested. These findings support the specificity of action of cocaine and 17beta-oestradiol as neuronal and extraneuronal uptake inhibitors in the present experiments.4 Studies of the uptake of [(3)H]-noradrenaline revealed that 17beta-oestradiol reduced the uptake of amine in the presence of cocaine, confirming a cocaine-resistant site of action for the steroid in all three preparations.5 It is concluded that extraneuronal uptake sites are located sufficiently close to the beta-adrenoceptors to modulate the concentration and duration of action of noradrenaline at these sites of action. It is proposed that in smooth muscles which contain a preponderance of beta-receptors, extraneuronal metabolism is a key event in terminating the inhibitory effects produced.

The role of GABA in the substantia nigra

STRIATONIGRAL GABAergic fibres are widely believed to exert a tonic inhibitory influence on the dopamine (DA)-containing cells of the substantia nigra (SN), and contraversive and ipsiversive circling behaviour can be explained in terms of a greater or lesser activity of the dopaminergic neurones, respectively1,2. However, the blockade of γ-aminobutyric acid (GABA) receptors with intranigral picrotoxin occasionally stimulates rats to turn ipsiversively3,4, rather than evoking the more commonly observed response in the opposite direction5. Similarly, injections of GABA agonists into the SN sometimes trigger an atypical contraversive turning syndrome3,4,6,7. We describe here a study which sought to reconcile these paradoxical phenomena by investigating the effects on circling behaviour of decreasing the influence of GABA within the SN with picrotoxin, and of potentiating the action of GABA with cis-1,3-aminocyclohexane carboxylic acid (ACHC)8, a neuronal GABA uptake inhibitor. We show that the same drugs are capable of producing opposite turning responses when injected into the rostral and caudal parts of the SN. Moreover, behaviour patterns influenced by the anterior SN are accompanied by significant changes in homovanillic acid (HVA) levels in the striatum and require an intact DA system, whereas turning responses initiated by caudal drug injections are apparently not mediated by the dopaminergic nigrostriatal pathway.

Catecholamine uptake by isolated coronary arteries and atria of the kitten.

Kitten coronary arteries and atria incubated with [3H]-(-)-noradrenaline or [3H]-(+/-)-isoprenaline showed concentration- and temperature-dependent accumulation of amines (unchanged and/or as metabolites). In addition, coronary arteries incubated with [3H]-(+/-)-isoprenaline showed temperature-insensitive amine accumulation due to binding to connective tissue fibres. 2 With low concentrations of [3H]-(-)-noradrenaline (20 ng/ml) accumulation of radioactivity in both tissues was neuronal since it was reduced by desipramine, metaraminol or cocaine but not by the extraneuronal inhibitor, cortisol. 3 In coronary arteries incubated with [3H]-(+/-)-isoprenaline (5 microgram/ml) for 1 or 10 min, uptake was extraneuronal since it was inhibited by cortisol, 17beta-oestradiol or phenoxybenzamine. 4 Atria incubated with (+/-)-isoprenaline (5 to 1000 microgram/ml) showed non-neuronal, biphasic accumulation of amine. There was a high capacity, low affinity initial uptake process (apparent Km 136 micron) which was resistant to steroidal extraneuronal uptake inhibitors but which could be abolished by phenoxybenzamine. A slower uptake occurred after 2 min which was sensitive to steroidal and other extraneuronal uptake inhibitors. 5 Inhibition of uptake processes did not alter sensitivity of coronary arteries to dilator effects of catecholamines. However, experiments with extraneuronal uptake inhibitors were limited by the relaxant effects of cortisol and 17beta-oestradiol themselves. 6 In atria inhibition of neuronal uptake by desipramine or cocaine led to supersensitivity to (-)-noradrenaline but not to (-)-adrenaline or (+/-)-isoprenaline. Chronotropic responses to (-)-noradrenaline were increased five fold and inotropic responses three fold.

Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols.

A series of alpha-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline and 5-hydroxytryptamine. Some of the compounds are potent and very selective in blocking the 5-hydroxytryptamine uptake, as evidenced by biochemical data and behavioral tests. The most promising agent, alaproclate [2-(4-chlorophenyl)-1,1-dimethylethyl 2-aminopropanoate hydrochloride (I, IV)], was selected for further studies as a potential antidepressant agent. A discussion on structure--activity relationships (SAR) is given. In an attempt to explain the selective action on the mechanism of 5-hydroxytryptamine uptake by the new inhibitors, their structures are compared with those of the two neurotransmitters. From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties.

The influence of an extraneuronal compartment on the relaxation of the cat nictitating membrane in vivo.

1 Contractions of the cat nictitating membrane were elicited on stimulation of the internal carotid nerve, and the effects were studied of desipramine and two inhibitors of catechol-O-methyltransferase, U-0521 and pyrogallol, on the subsequent relaxation of the muscle. 2 The relaxation of the nictitating membrane occurred in at least two phases. The late phase of relaxation was prolonged after increase in the period of nerve stimulation and the duration of this phase was further prolonged after treatment with pyrogallol. 3 After inhibition of neuronal uptake of noradrenaline with desipramine both the early and late phases of relaxation were increased in duration, and subsequent administration of pyrogallol or U-0521 caused a further increase in the duration of the late phase of relaxation. 4 The results suggest that the late phase of relaxation of the nictitating membrane is influenced by efflux of noradrenaline from an extraneuronal pool.

A conformational study of R-alaproclate, a new selecetive inhibitor of neuronal 5-hydroxytryptamine uptake

A conformational study of R-alaproclate, a new selecetive inhibitor of neuronal 5-hydroxytryptamine uptake