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At least 55 records · Page 3Linked to original sources
PubMed2000

Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents.

The frontal cortex (FCX) plays a key role in processes that control mood, cognition and motor behaviour, functions which are compromised in depression, schizophrenia and other psychiatric disorders. In this regard, there is considerable evidence that a perturbation of monoaminergic input to the FCX is involved in the pathogenesis of these states. Correspondingly, the modulation of monoaminergic transmission in the FCX and other corticolimbic structures plays an important role in the actions of antipsychotic and antidepressant agents. In order to further understand the significance of monoaminergic systems in psychiatric disorders and their treatment, it is essential to characterize mechanisms underlying their modulation. Within this framework, the present commentary focuses on our electrophysiological and dialysis analyses of the complex and reciprocal pattern of auto- and heteroreceptor mediated control of dopaminergic, noradrenergic and serotonergic transmission in the FCX. The delineation of such interactions provides a framework for an interpretation of the influence of diverse classes of antidepressant agent upon extracellular levels of dopamine, noradrenaline and serotonin in FCX. Moreover, it also generates important insights into strategies for the potential improvement in the therapeutic profiles of antidepressant agents.

Animals↗
PubMedDate not supplied

Behavioural models for the characterisation of established and innovative antidepressant agents.

To improve the management of depressive states, it is essential to develop preclinical behavioural models for the characterisation of both conventional and new antidepressant agents. This need is illustrated in this article with two very different classes of antidepressant agents, serotonin and/or noradrenaline reuptake inhibitors (SNRIs) and neurokinin NK1 receptor antagonists. Their effects are evaluated in rodent models of (i) the detection of potential antidepressant activity via marble-burying behaviour in mice; (ii) drug discrimination procedures in rats (mechanistic); and (iii) the evaluation of potential activity on co-morbid symptoms, such as anxiety, via the social recognition test in rats and gerbils. It is concluded that behavioural assays offer a palette of techniques for the characterisation of clinically active antidepressants as well as for innovative (acting on new targets) or improved (multi-target) antidepressants. Nevertheless, for antidepressants of the future, as for established antidepressants, feedback from clinical trials are awaited to confirm the predictive value of these models.

Animals↗
PubMed1992

[Anticalcium activity of several antidepressive agents].

In experiments in white mice and rats the antidepressants pyrazidol (pirlindole), moclobemide and especially tetrindole possess anticalcium activity in tests of calcium chloride-induced lethality in mice and arrhythmia in rats. Tetrindole is as active as verapamil. Imipramine, azaphen and incazane were not active in these experiments. In vitro on isolated intestinal segments of guinea-pigs tetrindole exerts anticalcium action, but in less degree than verapamil. In all probability the anticalcium activity of tetrindole may play some role in the mechanism of action of this compound on the central nervous system.

Animals↗
PubMedDate not supplied

[Concept of 2nd generation antidepressive agents].

Since the discovery of imipramine and iproniazide, the tricyclic antidepressants (TCA) have maintained a significant role in the pharmacotherapy of depression, whereas the MAO-inhibitors play a minor role because of toxicity problems. However, even the tricyclics present problems and the research to obtain a new "second generation" of less toxic and more efficacious antidepressants have been fully justified. This research has been based on biological models of depression and/or the experimental effects of existing antidepressants. In spite of the considerable investments over 30 years, the validity of prevailing biological depression-models is uncertain. Among the experimental effects of existing antidepressants, their ability to inhibit the reuptake of noradrenaline and serotonin has attracted most attention, resulting in the development of very selective compounds. Likewise, new selective and in particular reversible MAO-inhibitors have been developed. In light of the doubious validity of the experimental models, the clinical testing remains the crucial point. However, clinical trial methodology poses a number of problems, and there is much uncertainty concerning the efficacy of the heterogenous group of "second generation" antidepressants. Therefore, they are generally considered as antidepressants of second choice.

Antidepressive Agents↗
PubMed1982

[Effect of various antidepressive agents on brain monoamine oxidase activity].

The effect of different antidepressants (MAO inhibitors, monoamine uptake inhibitors, new drugs) on the activity of bovine brain monoamine oxidase was investigated. The type A MAO activity was found to be selectively inhibited by the morpholine derivative, moclobamide (IC50-10(-5) M). Pyrazidol, inkazan, imipramine, and iproniazide also had an inhibitory effect on the enzyme activity, but their action was not selective. Zymelidine and norzymelidine (10(-4) M) slightly reduced the deamination of serotonin and 2-phenylalanine. The hydrazine derivatives, N 33 and N 34 showed the same effects. The morpholine derivative, viloxazine had no effect on the MAO activity of bovine brain. It is inferred that not only classic MAO inhibitors but also antidepressants of different structure are capable of inhibiting brain monoamine oxidase.

Animals↗
PubMed2006

Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents.

BACKGROUND: Aromatic anticonvulsant agents such as carbamazepine and phenytoin can induce anticonvulsant hypersensitivity syndrome (AHS) at a frequency of 1 in 10,000 to 1 in 1,000 treated patients. The hypersensitivity syndrome is a potentially life-threatening adverse drug reaction with multiorgan involvement, and incidental reexposure must be strictly avoided. Patients and treating physicians must be informed and educated about the causal drug and its potential immunologic or toxicologic cross-reactivity with other compounds. It has been well established that for future antiepileptic drug therapy, carboxamides (carbamazepine and oxcarbazepine), phenytoin, and barbiturates (phenobarbital and primidone) have to be avoided owing to their high degree of cross-reactivity. Other anticonvulsant agents, such as valproic acid, benzodiazepines, and gabapentin, may be prescribed. OBJECTIVES: To present the clinical data for and to describe the potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant agents in patients with carbamazepine- and phenytoin-induced AHS. METHODS: The knowledge of cross-reactivity among aromatic anticonvulsant agents mainly emerged from clinical experience and observations because diagnostic challenge tests are not advisable. Thirty-six patients with the diagnosis of AHS were instructed to contact our unit if the symptoms relapsed. RESULTS: Despite better knowledge of AHS, one third of the patients had avoidable recurrences after exposure to cross-reactive drugs. Besides the known cross-reactivity among aromatic anticonvulsant agents, we observed a recurrence of the hypersensitivity syndrome in 5 patients after the administration of tricyclic antidepressant agents. CONCLUSION: The important potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant drugs should be brought to the attention of treating physicians.

Adolescent↗
PubMed2003

Discriminative stimulus properties of antidepressant agents: a review.

Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine - a 5-HT2/alpha2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites - substitute for neither citalopram nor reboxetine, indicating that 'antidepressant' effects per se do not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2C antagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the alpha1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the alpha2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at alpha1- and alpha2-ARs, respectively. These observations indicate that 5-HT2C receptors and alpha1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1 and neurokinin1) receptors.

Animals↗
PubMed1999

Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents.

Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.

Animals↗
PubMed1998

Antidepressant agents: from tricyclics to serotonin uptake inhibitors.

BACKGROUND: The number of antidepressant drugs available in the market has grown rapidly in the last few years. The present paper underlines some of the pre-clinical and clinical problems that call close attention from the regulatory authorities when approving new drugs. METHODS: We present here a review of the literature. RESULTS: A wide heterogeneity in the action of the various antidepressants precludes any single theory about the pathogenesis and therapy of depression. Antidepressant activity, in fact, may be achieved by acting on a number of different monoaminergic mechanisms. The variety in the neurochemical effects of antidepressants is not reflected in clinical trials, which tend to stereotypy. In many cases clinical trials aim at demonstrating equivalence rather than differences in efficacy. Regulatory authorities should, therefore, pay attention in accepting the equivalence of effects of a new drug in relation to a reference one: most clinical trials of new antidepressant drugs do not have the power to detect clinically relevant differences. CONCLUSIONS: Unconventional new pre-clinical tests are needed to generate antidepressants with a different mechanism of action. Clinical studies are needed to promote objective comparative evaluation of the cost, benefits and toxic effects of new antidepressants.

Antidepressive Agents↗
PubMed1984

[Neurological complications of tricyclic antidepressive agents].

The tricyclics are antidepressive drugs in widest use today. They are one of the most effective of the psychotropic agents and would be used more often if it was not for the complications. In this article we consider the neurological stimulation that results in undesirable cardio-vascular responses that are the main side-effects of these drugs. First, a brief statement is made about the action of the antidepressive drugs on the synapses for both their therapeutic effects and their side-effects are produced at this level. Despite the many patterns of complications that can occur, it is important to remember that these drugs are still very useful in managing depression and they should be the treatment of choice in depressive syndromes.

Antidepressive Agents, Tricyclic↗
PubMed1997

Pharmacology of amineptine, an antidepressant agent acting on the dopaminergic system: a review.

Amineptine is a tricyclic antidepressant agent with a unique capacity to reduce dopamine uptake selectively in vitro: this effect is also obtained in vivo. In vivo, amineptine increases striatal homovanillic acid without affecting the levels of other metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine. However, relatively high doses of amineptine preferentially lower the extracellular DOPAC level, assessed by pulse voltammetry, in the nucleus accumbens but not in the striatum. Microdialysis techniques confirm an increase in extracellular dopamine in various brain areas (striatum, nucleus accumbens and frontal cortex) and an increase in extracellular noradrenaline in the frontal cortex and dorsal hippocampus. Chronic treatment with amineptine induces downregulation of dopamine D2, beta- and alpha 2-adrenergic receptors. Amineptine enters the brain and its pharmacological effects are probably induced by the unchanged drug, rather than its two main metabolites.

Animals↗
PubMedDate not supplied

[Interaction between cotrimoxazole and antidepressive agents].

The association cotrimoxazole-tricyclic antidepressants seems to involve a rapid relapse of the depressive states continuously treated with the latter drugs. Five cases are reported. Mechanisms of this unknown drug interaction are discussed. The hypothesis of an enzymatic induction is not the most probable. A central inhibition of the tricyclic antidepressants seems to be possible but needs to be supported by further evidence.

Anti-Infective Agents↗