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M Briley

Publications and source records attributed to M Briley.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effect of mefenorex on 5-HT release: studies in vitro on rat hypothalamic slices and in vivo by microdialysis.

Mefenorex, used for 20 years as an anorexic drug, has not been studied so far with regard to its central mechanism of action, although its chemical structure suggests a serotonergic mechanism. In the present study, the effect of mefenorex on serotonin (5-HT) release was investigated both in vitro, on rat hypothalamic slices and in vivo, using microdialysis in the paraventricular (PVN)-ventromedian (VMH) hypothalamic area while mefenorex was applied locally by means of counterdialysis. In vitro, mefenorex increased the spontaneous release of 3H 5-HT from hypothalamic slices but not the electrically evoked release. This suggests a 5-HT releasing action of mefenorex not mediated through the terminal autoreceptor. The in vivo study confirmed the enhanced release and provided additional information. The delayed and modest increase of the 5-HT intracellular metabolite 5-HIAA may be indicative of an inhibition of reuptake. The dopaminergic system was also, but more modestly, activated by mefenorex. The increase in 5-HT release together with the inhibition of its reuptake may represent the main mechanism of action of mefenorex, and the secondary activation of the dopaminergic system may contribute in its anorexigenic effect at the level of the PVN-VMH area.

Amphetamines↗
PubMed1994

Autoradiographic characterization of binding sites for [3H]milnacipran, a new antidepressant drug, and their relationship to the serotonin transporter in rat brain.

Milnacipran is a new antidepressant drug and an equipotent inhibitor of the uptake of serotonin and noradrenaline. Quantitative autoradiography and radioligand binding studies were used to characterize recognition sites of [3H]milnacipran in rat brain. [3H]Milnacipran demonstrated saturable, reversible and nanomolar affinity binding. The binding was Na(+)-dependent, potently displaced by serotonin uptake inhibitors in all structures and moderately or weakly displaced by catecholamine uptake inhibitors (order of potency: paroxetine > fluoxetine > mazindol > desipramine > nomifensine > maprotiline). High density of recognition sites were found in structures dense in serotonergic innervation (raphe, basal ganglia, colliculi, cortex). The autoradiographic pattern of [3H]milnacipran recognition sites resembled that of [3H]paroxetine, but their distribution did not correlate well in some structures. Selective lesioning of serotonergic neurons by intracerebral injection of 5,7-dihydroxytryptamine caused a large decrease of [3H]milnacipran binding in various regions (septum, caudate, hippocampus, thalamus, ventral and dorsal hypothalamus), but in other structures, the [3H]milnacipran binding was partially affected (putamen) or even unchanged (amygdala, lateral hypothalamus). In contrast, lesion of noradrenergic neurons by intraperitoneal administration of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] did not affect the binding of [3H]milnacipran in any region. These results show that [3H]milnacipran mainly binds to the serotonin transporter and does not recognize the catecholamine transporters under the conditions used. In addition, [3H]milnacipran might also bind to other sites, serotonin transporter localized on non-serotonergic neurons or serotonergic neurons insensitive to 5,7-DHT neurotoxicity.

5,7-Dihydroxytryptamine↗
PubMed1994

Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity.

A series of 1-ar(o)yl-3-[2-(1-benzyl-4-piperidinyl)ethyl](thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridyl group. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio)urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.

Acetylcholinesterase↗
PubMed1994

Neuropharmacology of 5-hydroxytryptamine1B/D receptor ligands.

In spite of a lack of compounds acting selectively at the 5-hydroxytryptamine (5-HT)1B and 5-HT1D receptor subtypes, by cross-relating the available data, this review attempts to tentatively assign behavioural and other in vivo correlates of these receptor subtypes. In addition, a summary of data from microdialysis studies is included to develop an integrated view. Finally, a suggestion is made as to the possible pathophysiological consequences of 5-HT1D receptor dysfunction in man.

Animals↗
PubMed1994

Effect of milnacipran and desipramine on noradrenergic alpha 2-autoreceptor sensitivity.

1. The effects of chronic administration with milnacipran and desipramine on the noradrenergic alpha 2-autoreceptor sensitivity in the rat hypothalamus were compared. 2. Rats were administered, in their diet, milnacipran (50 mg/kg/day for 21 days, 24 h wash-out), desipramine (35 mg/kg/day for 21 days, 24 h wash out) or desipramine (14 mg/kg/day for 21 days, 41 h wash-out). Hypothalamic slices were incubated with [3H]noradrenaline, superfused and stimulated electrically. 3. Chronic administration with milnacipran did not modify basal or electrically induced release of [3H]noradrenaline, tissue incorporation of [3H]noradrenaline or the sensitivity of the alpha 2-autoreceptor assessed by the inhibition of the stimulation-evoked release of [3H]noradrenaline by the alpha 2-adrenoceptor agonist, guanabenz, in comparison to controls. After chronic desipramine (35 mg/kg), basal and evoked release of [3H]noradrenaline were increased, tissue incorporation of [3H]noradrenaline decreased and the inhibitory effect of guanabenz was diminished. At the lower dose (14 mg/kg), chronic desipramine increased only the evoked release of noradrenaline but did not modify the sensitivity of the alpha 2-autoreceptor. 4. Desipramine at 35 mg/kg remains in the tissue after 24 h wash out, causing a reduction of uptake and complicating the interpretation of the data.

Animals↗
PubMed1993

Identification of 5-hydroxytryptamine1D binding sites in sheep caudate nucleus membranes.

Radioligand binding measurements were performed in membranes of sheep caudate nucleus using [3H]5-hydroxytryptamine (5-HT). [3H]5-HT labeled a population of high affinity binding sites with a Kd of 1.9 +/- 0.1 nM and a Bmax of 19.8 +/- 2.2 fmol/mg tissue. Combined 5-HTID/E binding sites were the predominant 5-HT1 subtype, accounting for 78% of the total population of 5-HT1 binding sites. 5-Carboxamidotryptamine (5-CT) and sumatriptan yielded inhibition curves which best fitted a two-site model with high affinity values of 0.8 and 10.1 nM, and 1000 and 206 nM for their low affinity components. The proportion of the high affinity 5-CT and sumatriptan binding sites was 79 and 72%. The binding affinity profile of 5-HT1D binding sites [5-CT > 5-HT > d-LSD > 5-MeOT > sumatriptan > RU 24,969 > metergoline > tryptamine = rauwolscine = methylsergide > yohimbine = methiothepin > TFMPP = 8-OH-DPAT > 2-methyl-5-HT > mCPP = quipazine = CP 93,129 > ketanserin > (-)-propranolol = haloperidol = ipsapirone] compares well to that reported for 5-HT1D receptor sites in human caudate and cortex (correlation coefficient: 0.99 and 0.98). The present results indicate that sheep caudate nucleus is a valid tissue for studying interaction of compounds with 5-HT1D binding sites in the relative absence of 5-HT1E binding sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice.

Injection of C57Bl/6 mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 x 10 mg/kg i.p. over 8 h) resulted in a partial (40%) striatal dopamine depletion at 7 days post-drug. Pretreatment with the selective noradrenergic neurotoxin N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine (DSP-4; 40 mg/kg i.p.), while having no effect per se on striatal dopamine levels, exacerbated the MPTP-induced dopamine deficit to 60%. Results support the hypothesis that damage to the locus coeruleus-noradrenergic system, by removing a facilitatory influence on the nigrostriatal dopamine system, interferes with the ability of the nigrostriatal pathway to compensate for or recover from injury.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Does 5-carboxamidotryptamine-induced turning in guinea-pigs involve 5-HT1D autoreceptors?

Contralateral turning induced by unilateral injection of 5-carboxamidotryptamine (5-CT) into guinea-pig substantia nigra could result from unilaterally reduced inhibition of the dopaminergic pathway as a consequence of a decreased release of inhibitory 5-hydroxytryptamine (5-HT) through stimulation of 5-HT1D autoreceptors. This hypothesis was tested by administering 5-CT unilaterally to freely moving guinea pigs through a microdialysis probe, and simultaneously measuring extracellular 5-HT in the dialysate and rotation. A concentration of 250 mN 5-CT was required to produce significant turning. This also induced a massive increase in extracellular 5-HT, introduced as an impurity of the 5-CT. The presence of high concentrations of extracellular 5-HT makes it unlikely that 5-CT-induced rotation is mediated through decreased 5-HT release resulting from 5-HT1D autoreceptor stimulation.

Animals↗
PubMed1993

The benzodiazepine antagonist flumazenil blocks the effects of CCK receptor agonists and antagonists in the elevated plus-maze.

Peripheral administration of the unsulphated cholecystokinin octapeptide (CCK-8us) led to an anxiogenic-like action in the elevated plus-maze model of anxiety in rats. Devazepide and L-365,260 showed potent anxiolytic-like effects at similar doses. The fact that devazepide is 1000 times more potent as a CCK-A receptor antagonist than L-365,260, whereas the two compounds are nearly equipotent at the CCK-B receptor subtype, suggests that CCK-B rather than CCK-A receptors are involved in these effects. Similar results were obtained in mice using the two-compartment test. In the elevated plus-maze, the benzodiazepine antagonist, flumazenil, which was inactive when given alone, significantly antagonized the anxiogenic-like activity of CCK-8us and the anxiolytic-like effects of devazepide and L-365,260. These results suggest a complex interaction between benzodiazepine and CCK receptor mechanisms in the regulation of anxiety states.

Animals↗
PubMed1993

Neuropharmacology of a new potential anxiolytic compound, F 2692, 1-(3'-trifluoromethyl phenyl) 1,4-dihydro 3-amino 4-oxo 6-methyl pyridazine. 1. Acute and in vitro effects.

F 2692 [1-(3'-trifluoromethyl phenyl) 1,4-dihydro 3-amino 4-oxo 6-methyl pyridazine] exhibited dose-dependent "anxiolytic" properties in the elevated plus-maze and the punished drinking tests in rats. It was also active in the two-compartment test in mice. The "anxiolytic" effects were antagonised by the benzodiazepine antagonists, flumazenil and ZK 93426. The compound exhibited anticonvulsant, sedative, myorelaxant and amnesic effects at doses 3-30 times higher than those required for "anxiolytic" activity. F 2692 has a very low affinity for benzodiazepine binding sites in vitro and in vivo (about 1000 and 160 fold lower than diazepam respectively). In addition it displayed no affinity for GABAA, alpha 2-adrenergic, 5-HT1A or 5-HT2 receptors. These data suggest that F 2692 may be a potential anxiolytic compound with an unusual mechanism of action.

Animals↗
PubMed1993

Neuropharmacology of a new potential anxiolytic compound, F 2692, 1-(3'-trifluoromethyl phenyl) 1, 4-dihydro 3-amino 4-oxo 6-methyl pyridazine. 2. Evaluation of its tolerance and dependence producing potential and of its effects on benzodiazepine withdrawal in the elevated plus-maze test in rats.

After 21 days administration, diazepam (0.3-3 mg/kg/day) exhibited, 30 min after the last injection, tolerance to the sedative effect and "anxiolytic" activity as recorded in the elevated plus-maze test in rats. A dose-dependent increase of "anxiety" was also observed 24 h after withdrawal from 21 or 90 days of diazepam treatment. In contrast, under the same experimental conditions, F 2692 [1-(3'-trifluoromethyl phenyl) 1,4-dihydro 3-amino 4-oxo 6-methyl pyridazine] (3-30 mg/kg/day) exhibited no tolerance to either the sedative effect or the "anxiolytic" activity and showed no "anxiogenic rebound" response after withdrawal. Chronic diazepam pretreatment for 21 days modified neither the sedative effect nor the dose-dependent "anxiolytic" effect of F 2692. Furthermore, F 2692 could reverse the anxiogenic response after withdrawal from 21 days administration of diazepam. Finally, administration of diazepam for 3 weeks followed by a daily administration of F 2692 for a week induced no increase of "anxiety" 24 h after withdrawal.

Animals↗
PubMed1993

Neurobiological mechanisms involved in antidepressant therapies.

Selective serotonin reuptake inhibitors (SSRIs) are effective in alleviating the symptoms of depression. However, clinical improvement is only obtained after several weeks of treatment. SSRIs, when administered acutely to animals, have little effect on synaptic levels of serotonin. This suggests the existence of one or more regulatory mechanisms controlling serotonergic neurotransmission. The firing rate of dorsal raphe serotonergic neurons is under the control of somatodendritic 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, the release of serotonin from nerve terminals is under the control of 5-HT autoreceptors (5-HT1B subtype in rodents, 5-HT1D in other species), whereas the control of the activity of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis, is complex, involving 5-HT1A but possibly other 5-HT receptors including the 5-HT1B/D subtype. During prolonged administration with a SSRI, these three feedback systems become desensitized and their regulatory effects on serotonergic neurotransmission are weakened or lost. This has the effect of allowing the synaptic levels of serotonin to rise with a consequently increased stimulation of one or more types of postsynaptic 5-HT receptor. Thus, it is only after prolonged administration that the pharmacological activity of SSRI is fully expressed in terms of synaptic serotonin levels. This may explain the latency of antidepressant action seen with these drugs in humans. Various other classes of antidepressant therapies (tricyclic antidepressants and monoamine oxidase inhibitor drugs, electroconvulsive therapy) have long-term effects on one or more of the feedback mechanisms such that an increase in synaptic concentrations of serotonin may be a common mechanism of many antidepressant therapies.

Animals↗
PubMed1992

Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats.

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P less than 0.10) to reduce the amnesia.

Amnesia↗
PubMed1992

Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat.

Most antidepressants produce changes in monoamine receptors in brain after chronic administration in animals. The most commonly described alterations are a decreased density and function of beta-adrenergic receptors and have been postulated to be the mechanisms by which antidepressants exert their therapeutic effect. Milnacipran (previous name midalcipran) is a new, clinically-effective antidepressant, which inhibits the uptake of both serotonin and noradrenaline but has no affinity for any pre- or postsynaptic receptor studied. When given either orally at 7.5 mg/kg twice daily for 3 days, at 30 mg/kg once daily for 3 weeks, by osmotic mini-pump at 30 mg/kg/day for 27 days, or in drinking water at approximately 15 mg/kg/day for 6 weeks and after a washout period of 24 hr, milnacipran produced no down-regulation of beta-adrenoceptors. In addition, there were no alterations of alpha 1- or alpha 2-adrenoceptors, 5-HT1, 5-HT2 receptors or benzodiazepine binding sites. Moreover, uptake and accumulation of serotonin and noradrenaline were unmodified. In addition, the potency for milnacipran to inhibit monoamine uptake in vitro in the cortex was not altered in treated rats, compared to control animals. Thus, in spite of its action on both the uptake of serotonin and noradrenaline, milnacipran appears to be without long-term action on beta-adrenoceptors or the other receptors studied, suggesting that, at least for this antidepressant, these modifications are not essential for clinical activity.

Animals↗
PubMed1992

Effect of antidepressant drugs on monoamine synthesis in brain in vivo.

The activity of tryptophan and tyrosine hydroxylase were estimated in vivo by measuring the accumulation during 30 min of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA), respectively, after inhibition of aromatic amino acid decarboxylase by administration of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). Whereas the activity of tyrosine hydroxylase in the dopamine-rich striatum was sensitive to haloperidol, which caused a significant increase in accumulation of DOPA, there was no effect of haloperidol in the predominantly noradrenergic frontoparietal cortex, confirming that the activity of tyrosine hydroxylase, measured in the frontoparietal cortex, is essentially localized in noradrenergic neurones. In the frontoparietal cortex of the rat the in vivo activity of tryptophan and tyrosine hydroxylase were equipotently attenuated by imipramine, while the selective blocker of the uptake of noradrenaline, desipramine and the selective blocker of the uptake of serotonin, citalopram, reduced only tyrosine or tyrosine hydroxylase respectively. Milnacipran, an antidepressant which inhibits the uptake of both monoamines to a similar extent, decreased the synthesis of both monoamines equipotently. The monoamine oxidase inhibitor, clorgyline, also reduced the synthesis of both monoamines. Thus, the in vivo inhibition of the synthesis of monoamines would appear to be mediated by an increase in synaptic concentration of monoamines, resulting from the inhibition of the uptake or catabolism of monoamines. Chronic administration of citalopram led to a significant increase of the basal synthesis of 5-hydroxytryptamine (5-HT). Milnacipran, given chronically, significantly enhanced the basal synthesis of both 5-HT and noradrenaline (NA).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗