The interaction of antidepressant drugs with enteric 5-HT7 receptors.

Lucchelli A, Santagostino-Barbone MG, D'Agostino G, Masoero E, Tonini M.

Department of Experimental and Applied Pharmacology, School of Pharmacy, University of Pavia, Italy. adlu unipv.it

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.

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Electrophysiologic analysis of antidepressant drug effects on the GABA(A) receptor complex based upon antagonist-induced encephalographic power spectrum changes.

Matsubara M, Suzuki S, Miura K, Terashima M, Sugita S, Kimura H, Hatsuda S, Mori T, Murakami H, Hayashi T, Ohta T, Ohara M.

Department of Neuropsychiatry, Aichi Medical College, Aichi, Japan.

To better understand antidepressant drug effects on the GABA(A) receptor complex (the GABA(A) receptor, chloride ionophore and benzodiazepine receptor), we investigated how antidepressants influenced power spectrum changes induced by pentylenetetrazol (PTZ), a chloride ionophore antagonist, in the rat hippocampal electroencephalogram (EEG). In control recording, PTZ (27.5 mg/kg i. p.) increased EEG power at frequencies under 12 Hz up to five times. After rats were pretreated with imipramine, fluoxetine or trazodone for 7 days (10 mg/kg i.p., twice a day), PTZ could not increase EEG power to more than three times the power before injection; this effect was not observed after pretreatment for 3 days. These three antidepressants inhibit serotonin uptake, while two other antidepressants, desipramine and nortriptyline, that inhibit norepinephrine uptake failed to counter the PTZ effect. We concluded that antidepressants with serotonergic effects enhanced the function of the GABA(A) receptor complex. Copyright 2000 S. Karger AG, Basel

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Antidepressant medications and risk for cancer.

Dalton SO, Johansen C, Mellemkjaer L, Sorensen HT, McLaughlin JK, Olsen J, Olsen JH.

Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen.

Antidepressants appear to promote tumor growth in experimental studies; however, results from epidemiologic studies are inconclusive. We used a population-based cohort study to estimate the incidence of cancer after antidepressant treatment in 39,807 adult users of antidepressants identified in the Prescription Database of the County of North Jutland, Denmark between January 1, 1989 and December 31, 1995. Information on cancer occurrence was obtained from the Danish Cancer Registry. We categorized exposure according to use of tricyclic antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors. In the follow-up period beginning 1 year after first known prescription, there were 966 cancers among users of antidepressants; our population estimate suggested an expected number of 946 for an overall standardized incidence ratio of 1.0 (95% confidence interval = 1.0-1.1). Users of tricyclic antidepressants had an excess of non-Hodgkin's lymphoma, with the risk increasing with the number of prescriptions of tricyclic antidepressants. The standardized incidence ratio was 2.5 (95% confidence interval, 1.4-4.2) for those with five or more prescriptions. Our results provide little evidence that antidepressants promote cancer at other sites, except for a possible effect of tricyclic antidepressants and tetracyclic antidepressants on non-Hodgkin's lymphoma.

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Relationships of alcohol use, stress, avoidance coping, and other factors with mental health in a highly educated workforce.

Koopman C, Wanat SF, Whitsell S, Westrup D, Matano RA.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5718, USA.

PURPOSE: The relationships of drinking, stress, life satisfaction, coping style, and antidepressant use to mental health were examined in a highly educated workforce. DESIGN: This study used a one-time mail-out, mail-back cross-sectional survey design to examine the relationships of mental health with three kinds of stress (life events, work stress, home stress); two kinds of life satisfaction (work and home); use of avoidance coping; and antidepressant use. SETTING: This study was conducted at a large worksite in northern California in which the workforce was comprised of predominantly highly educated employees. SUBJECTS: Questionnaires were mailed to a random sample of 10% of 8567 employees, and 504 were completed and returned by participants (59%). Complete data were provided by 460 participants (53%). MEASURES: Respondents completed the Mental Health Index, the Alcohol Use Disorders Identification Test (AUDIT), and measures of coping style, work and home stress and satisfaction, stressful life events, and antidepressant use. RESULTS: Mean Mental Health Index scores were at the 32nd percentile of the U.S. population-based norms, with low percentile values associated with worse mental health. Using multiple regression analysis, the factors examined in this study were significantly related to Mental Health Index scores as the dependent variable [F(16, 443) = 27.41, p < .001, adjusted overall R2 = .48]. Poor mental health scores were significantly related to the following: age (p < .05); screening positively for current harmful or hazardous drinking (p < .05); having high levels of stress at work (p < .05) or home (p < .01); experiencing dissatisfaction with work (p < .001) or home life (p = .01); engaging in avoidance coping (p < .001); and using antidepressants (p < .001). Employees currently using antidepressants had significantly more outpatient medical and mental health visits, indicating higher health costs. Furthermore, mental health status was also significantly related to the interactions between several pairs of these variables: education and gender, age and job stress, home satisfaction and work stress, home satisfaction and avoidance coping, and home satisfaction and use of antidepressants. CONCLUSION: Mental health status was poorer on average in a highly educated workforce compared with general U.S. norms. Most of the factors that were found to be associated with poorer mental health were ones that are potentially modifiable, such as experiencing more stress and less satisfaction in work and home life and engaging in current hazardous or harmful drinking. The findings that mental health is worse among individual employees who exhibit combinations of these factors suggest that we need to better understand possible effects of these factors in the context of one another. As interpretation of these results may be limited by the single worksite that participated in this study, future research should re-examine these relationships in other worksites varying from this one in geography and demographic characteristics.

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The use of antidepressants among injecting drug users in Sydney, Australia.

Darke S, Ross J.

National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia.

AIMS: To ascertain the prevalence and patterns of antidepressant use among IDU in Sydney and to determine any harm associated with antidepressant use. DESIGN: Cross-sectional survey. SETTING: Sydney, Australia. PARTICIPANTS: Two hundred and one Sydney injecting drug users (IDU) recruited through advertisements, needle exchanges, methadone maintenance clinics and by word of mouth. FINDINGS: Forty per cent of subjects had used antidepressants, 21% in the preceding 6 months. Similar proportions of subjects had used tricyclics (26%) and selective serotonin reuptake inhibitors (SSRIs) (24%), with 8% reporting use of a monoamine oxidase inhibitor. Recent use favoured the SSRIs; however, there was still widespread use of tricyclics. The injection of antidepressants was rare, with only three subjects reporting ever having injected the drugs. Antidepressant use was associated with higher levels of polydrug use, poorer health, higher levels of psychiatric distress and a greater risk of heroin overdose. The excess risk of overdose was specifically associated with tricyclics, rather than SSRIs. CONCLUSIONS: The study confirmed that, like other pharmaceutical products, the use of antidepressants was common among IDU in Sydney. The prescription of tricyclics to heroin users would appear to increase their risk of overdose. If it is considered appropriate to prescribe antidepressants to IDU, it would appear safer to prescribe SSRIs.

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Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor.

Wong EH, Sonders MS, Amara SG, Tinholt PM, Piercey MF, Hoffmann WP, Hyslop DK, Franklin S, Porsolt RD, Bonsignori A, Carfagna N, McArthur RA.

Neurobiology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007, USA.

BACKGROUND: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression. METHODS: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine's in vivo pharmacology. Reboxetine's antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL72 operant responding test. RESULTS: Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1,000 nmol/L)for muscarinic, histaminergic H1, adrenergic alpha1, and dopaminergic D2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL72 test. CONCLUSIONS: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.

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cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment.

Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS.

Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.

Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents.

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Antidepressant- and anxiolytic-like effects of selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole in mice.

Volke V, Wegener G, Bourin M, Vasar E.

Department of Physiology, University of Tartu, 19 Ravila Street, Estonia. vallov ut.ee

Various inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-like properties in animal models. The aim of this study was to compare the behavioural effects of NOS inhibitor 7-nitroindazole (7-NI) with the more selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) in animal models predictive of antidepressant- and anxiolytic-like activity in order to clarify the role of distinct isoforms of NOS in the regulation of depression and anxiety. Both TRIM (50 mg/kg) and 7-NI (50 mg/kg) decreased the immobility time in the forced swimming test. The magnitude of the effect was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg). The antidepressant-like effect of TRIM was counteracted by pretreatment with L-arginine (250 mg/kg). The systemic administration of TRIM (50 mg/kg), but not 7-NI (up to 50 mg/kg) increased the time spent in the light side of the apparatus in the light-dark compartment test. The anxiolytic-like effect of TRIM was antagonised by pretreatment with L-arginine. Both TRIM and 7-NI decreased the locomotion of animals in the open field and caused motor incoordination on rotarod. These motor side effects were more pronounced in the case of 7-NI and were not diminished by pretreatment with L-arginine. We conclude that neuronal NOS seems to play the key role in the antidepressant- and anxiolytic-like effects of NOS inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12644287&dopt=Abstract antidepressant