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M Briley

Publications and source records attributed to M Briley.

At least 19 recordsLinked to original sources
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↗
PubMed1991

Platelet 3H-paroxetine binding to the serotonin transporter is insensitive to changes in central serotonergic innervation in the rat.

The serotonin transporter labeled in platelets by 3H-imipramine or 3H-paroxetine binding has been suggested to be a peripheral marker for changes in serotonin uptake in the brain that may be related to depression. The present study was designed to determine whether major changes in central serotonergic innervation modify the platelet serotonin transporter as labeled by 3H-paroxetine binding. Fifteen days after the intracerebroventricular administration of 5,7-dihydroxytryptamine (250 micrograms/animal) to rats to lesion central serotonergic neurons, serotonergic innervation was reduced by 82% in the cortex and 98% in the hippocampus as determined by endogenous serotonin levels. The maximum binding of 3H-paroxetine was reduced by 55% in the cortex and was undetectable in the hippocampus. Serotonin levels and 3H-paroxetine binding in platelets were not, however, significantly modified in the same animals. Thus, following a major serotonergic lesion in the brain, changes in the platelet serotonin transporter do not parallel serotonergic changes in the brain. The hypothesis that binding to the platelet serotonin transporter is a state-dependent marker of brain serotonergic activity therefore appears to be unlikely.

5,7-Dihydroxytryptamine↗
PubMed1990

Anticonvulsive properties of F1933 (dulozafone) on kindled seizures in the rat.

The anticonvulsive properties of a new compound: F1933 (Dulozafone) were investigated in the amygdala kindling model and compared with those of diazepam. Both drugs protected fully kindled rats against generalized seizures but failed to suppress partial ictal events (amygdala afterdischarges and limbic seizures). The anticonvulsive action of F1933, administered at the ED100, was nearly reversed by the specific antagonist of benzodiazepines receptors; R015-1788 (Flumazenil), suggesting that the effect of F1933 is mediated by this receptor. These results also emphasize the usefulness of kindling to test antiepileptic drugs and to confirm their supposed profile of action.

Acetanilides↗
PubMed1990

Serotonin autoreceptor subsensitivity and antidepressant activity.

Release of [3H]serotonin elicited by electrical stimulation from rat hypothalamus and its modulation through autoreceptors has been studied after chronic administration of two antidepressants, citalopram, specific inhibitor of serotonin uptake, and milnacipran (previously called midalcipran, F 2207) which blocks the uptake of serotonin and noradrenaline to the same extent. The amount of [3H]serotonin released by electrical stimulation was enhanced and the inhibitory effect of the agonist, LSD (lysergic acid diethylamide), reduced in rats treated with citalopram at 10 and 50 mg/kg per day for 21 days. These effects existed at both doses but were accentuated at the higher dose. Thus a chronic treatment with citalopram provokes a down-regulation of the serotonergic autoreceptor, allowing an increase of serotonin neurotransmission. After 21 days treatment with milnacipran, at 50 mg/kg per day, none of the parameters studied were modified. These data suggest that down-regulation of the serotonin autoreceptor is not a universally applicable hypothesis to explain the action of all antidepressants acting on the uptake of serotonin.

Animals↗
PubMed1990

Modulation by drugs of the release of total tritium and 3H-5-HT from rat hypothalamic slices.

The release of total tritium and 3H-5-hydroxytryptamine (5-HT) evoked by electrical stimulation from prelabelled rat hypothalamic slices was studied. Lysergic acid diethylamide (LSD) decreased white methiothepin increased both total tritium and 3H-5-HT overflow. The proportion of total tritium present as 3H-5-HT was equivalent under control conditions and in the presence of methiothepin and slightly increased in the presence of LSD. Whereas the addition of the 5-HT uptake blocker, citalopram, did not modify the evoked release of total tritium, the monoamine oxidase inhibitor, pargyline, decreased it. In the presence of either of these drugs the proportion of 3H-5-HT was increased. In the presence of citalopram, the inhibition by LSD was reduced on both the release of total tritium and of 3H-5-HT. It thus appears that changes in electrically evoked total tritium overflow in general reflect changes in 3H-5-HT release. When uptake inhibitors or monoamine oxidase inhibitors are present in the medium, the situation is, however, more complex and results from experiments measuring only the release of total tritium should be interpreted with caution.

Animals↗
PubMed1990

Effect of serotonergic lesion on "anxious" behaviour measured in the elevated plus-maze test in the rat.

5,7-Dihydroxytryptamine (250 micrograms) was administered intracerebroventricularly to rats to lesion central serotonergic neurones. Fourteen days later the rats were tested in the elevated plus-maze "anxiety" model in comparison to sham lesioned animals. Twenty-four hours later, the rats were killed and serotonin levels and [3H]paroxetine binding measured in cortical and hippocampal membranes. The lesion destroyed 81% of the serotonergic innervation in the cortex and 99% in the hippocampus as determined by endogenous serotonin levels. Lesioned rats had an increased ratio of open/total arm entries in the elevated plus-maze, reflecting a decreased level of "anxiety". These results are compatible with the implication of serotonin in the control of anxiety and suggest that an anxiolytic effect may be induced by lowering the level of serotonergic activation.

5,7-Dihydroxytryptamine↗
PubMed1990

Biochemical strategies in the search for cognition enhancers.

Memory is a complex multi-event procedure which is profoundly influenced by the overall psychological state. It is thus evident that there cannot be a "memory transmitter" and that many neurotransmitter systems are implicated in different parts of the cognitive process. In general, memory effects resulting from manipulation of the catecholamine systems are a reflection of altered arousal. Modification of cholinergic transmission or that of certain neuropeptides such as vasopressin would appear, however, to involve more directly the memory process itself. This article presents a brief overview of the part played by various neurotransmitter systems in cognitive function and suggests a number of research strategies by which new cognition enhancers may be sought.

Alzheimer Disease↗
PubMed1990

Biochemical models for cognition enhancers.

Although the etiology of Alzheimer's disease includes a wide range of dysfunction, the most essential dysfunction is probably in the mesolimbic acetylcholine (ACh) system. Three novel approaches to modulating ACh function were considered, somatostatin, serotonin (5-HT) and modulation of cortical ACh tone through angiotension II. Concerning somatostatin there is no correlation between the decrease in somatostatin binding sites in brain and choline-acetyl-transferase activity suggesting that modulating somatostatin is not a promising therapeutic approach to Alzheimer's disease. With 5-HT, evidence suggests that 5-HT receptors (in particular 5HT1A) are located on cholinergic projections and behavioral evidence suggests 5-HT modulation of memory function. This area could therefore develop rapidly, particularly in view of the recent discovery of numerous subtypes of 5-HT receptor. Concerning the third approach, recent evidence has shown that angiotensin converting enzyme (ACE) inhibitors can facilitate ACh release and also possess cognition enhancing activity. The possibility was also evoked that drugs such as piracetam might prevent age-related decreases in ACh receptor density. Concerning trophic factors (e.g. glutamate-induced neuronal sprouting) most approaches have induced amnesia but the search for partial glutamate agonists may have potential. Finally, a neuronal transplant approach was considered but was thought to be very difficult in view of the global brain shrinkage associated with aging and Alzheimer's disease.

Alzheimer Disease↗
PubMed1989

Monoamine uptake inhibition by plasma from healthy volunteers after single oral doses of the antidepressant milnacipran.

In a placebo-controlled double-blind cross-over study, we gave 12 healthy male volunteers placebo or milnacipran orally, such that each volunteer received placebo and two doses of milnacipran. Blood samples taken before and at various times after dosing were analysed for plasma concentrations of unchanged milnacipran and the inhibitory effect of the plasma on the uptake of 3H-5-hydroxytryptamine (5HT) into normal human platelets or of 3H-noradrenaline into rat hypothalamus homogenate. The mean maximal inhibition of 5HT and noradrenaline uptake was correlated with drug dose. The inhibition of 5HT uptake was correlated with the inhibition of noradrenaline uptake and both were correlated with plasma concentration of unchanged drug at all times and doses tested. Thus, milnacipran, when given orally to man, circulates in a biologically active form with similar potency for the inhibition of 5HT and noradrenaline uptake.

Adult↗
PubMed1989

Muscarinic receptor plasticity in rats lesioned in the nucleus basalis of Meynert.

The present study investigated the effects of chronic treatment with scopolamine (10 mg/kg i.p. for 21 days) on the muscarinic acetylcholine receptors in the frontoparietal cortex of rats, lesioned at the level of the nucleus basalis of Meynert. Ibotenic acid (25 nmol in 0.5 microliters) was injected bilaterally or unilaterally into the area of this nucleus and produced a major impairment of the cortical cholinergic system. These lesions depleted specifically frontoparietal cortical choline acetyltransferase activity. Sham-operated rats were similarly operated but no neurotoxin was injected. The chronic treatment with scopolamine caused a significant increase in the binding of [3H](-)quinuclidinylbenzilate to muscarinic receptors in the frontoparietal cortex of control and sham-operated rats but not in lesioned animals. This increase was due to an up-regulation in the number of muscarinic acetylcholine receptors, without significant change in their affinity. These results suggest that a functional presynaptic cholinergic terminal is necessary for the plasticity of muscarinic receptors in the central nervous system.

Animals↗
PubMed1988

Scopolamine induces up-regulation of nicotinic receptors in intact brain but not in nucleus basalis lesioned rats.

The effect of chronic scopolamine treatment on muscarinic and nicotinic receptors in frontoparietal cortex in rats was investigated. Administration of the muscarinic antagonist, scopolamine (10 mg/kg i.p./day) for 21 days, produced a significant increase in the density of both muscarinic and nicotinic receptors by 27.7% and 12.1% respectively as measured by the specific binding of (-)-[3H]quinuclidinylbenzilate and (-)-[3H]-nicotine. There was no modification in the affinities for these ligands. Rats, bilaterally lesioned with ibotenic acid at the level of nucleus basalis of Meynert, which innervates the frontoparietal cortex, showed no up-regulation of cortical nicotinic receptors after chronic scopolamine treatment, suggesting the importance of the synaptic integrity in the regulation mechanism.

Animals↗
PubMed1988

Sensitivity of the response of 5-HT autoreceptors to drugs modifying synaptic availability of 5-HT.

The effect of midalcipran, an equipotent inhibitor of the uptake of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), on the inhibition of release of 5-HT induced by lysergic acid diethylamide (LSD), was investigated by studying the overflow of transmitter from slices of hypothalamus from the rat prelabelled with [3H]5-HT. The (Z)-enantiomer of midalcipran, at 0.1 microM, displaced to the right the concentration-effect curve of inhibition of release of [3H]5-HT elicited by electrical stimulation induced by LSD. In contrast, the (E)-enantiomer, which does not inhibit the uptake of monoamines, was devoid of any antagonizing effect. The inhibitory effect of 0.1 microM LSD was not modified in the presence of maprotiline, bupropion or mianserin at 1 microM. The results of this study show that the interaction between the 5-HT autoreceptor and the inhibitors of the uptake of 5-HT is related exclusively to their potency at inhibiting the uptake of 5-HT. The effect of the monoamine oxidase inhibitor, pargyline (1-10 microM), was also studied on the field-stimulated release of [3H]5-HT. The inhibitory effect of this drug was antagonized by methiothepin at 0.1 and 1 microM, by phentolamine 1 microM and 10 microM and by the inhibitor of the uptake of 5-HT, citalopram at 0.1 and 1 microM. The action of pargyline appeared to be mediated through the activation of the serotonergic autoreceptor and of the presynaptic alpha-adrenoceptor located on serotonergic nerve terminals. The results obtained with pargyline are consistent with the hypothesis of an interaction between the 5-HT autoreceptor and the uptake site for 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗