A Transcriptome-Based Drug Discovery Paradigm for Neurodevelopmental Disorders.

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.

A novel MIP-ECL sensor based on RGO-CeO2NP/Ru(bpy)32+-chitosan for ultratrace determination of trimipramine.

A novel molecularly imprinted polymer (MIP)-electrochemiluminescence (MIP-ECL) sensor based on CeO2NP-RGO/Ru(bpy)32+-MIP-chitosan was introduced for the ultrasensitive and ultraselective detection of trimipramine (TRI). TRI-MIP was synthesized via the precipitation polymerization process. A nanocomposite of reduced graphene oxide decorated with ceria (CeO2NP-RGO) was synthesized through a facile sonochemical process. CeO2NP-RGO was utilized for modifying the surface of an electrode which consequently led to an excellent electrical conductivity, enhanced electrochemical and ECL characteristics of Ru(bpy)32+. Electrochemical and ECL behaviors of the MIP-ECL sensor were evaluated. Accordingly, the ECL intensity was significantly enhanced via TRI molecule adsorption on the MIP composite film. The prepared MIP-ECL sensor demonstrated high sensitivity and selectivity as well as good reproducibility and stability for TRI determination under the applied optimal conditions. The assays response for TRI concentration was linear in the range of 0.2-100 pM with a 0.995 correlation coefficient. The limit of detection (LOD) was as small as 0.025 pM (S/N = 3). The recoveries between 91-107% for human serum (RSDs < 4.1%) and 94-104.6% for human urine (RSDs < 3.4%) approve that the MIP-ECL sensor can be used for precise detection of TRI in complex biological matrices. Ultimately, this sensor was utilized successfully for the analysis of TRI in human serum and urine samples without any special pretreatment.

In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury-Lessons Learned.

We developed a pipeline for the discovery of transcriptomics-derived disease-modifying therapies and used it to validate treatments in vitro and in vivo that could be repurposed for TBI treatment. Desmethylclomipramine, ionomycin, sirolimus and trimipramine, identified by in silico LINCS analysis as candidate treatments modulating the TBI-induced transcriptomics networks, were tested in neuron-BV2 microglial co-cultures, using tumour necrosis factor α as a monitoring biomarker for neuroinflammation, nitrite for nitric oxide-mediated neurotoxicity and microtubule associated protein 2-based immunostaining for neuronal survival. Based on (a) therapeutic time window in silico, (b) blood-brain barrier penetration and water solubility, (c) anti-inflammatory and neuroprotective effects in vitro (p < 0.05) and (d) target engagement of Nrf2 target genes (p < 0.05), desmethylclomipramine was validated in a lateral fluid-percussion model of TBI in rats. Despite the favourable in silico and in vitro outcomes, in vivo assessment of clomipramine, which metabolizes to desmethylclomipramine, failed to demonstrate favourable effects on motor and memory tests. In fact, clomipramine treatment worsened the composite neuroscore (p < 0.05). Weight loss (p < 0.05) and prolonged upregulation of plasma cytokines (p < 0.05) may have contributed to the worsened somatomotor outcome. Our pipeline provides a rational stepwise procedure for evaluating favourable and unfavourable effects of systems-biology discovered compounds that modulate post-TBI transcriptomics.

Cytochrome P450-mediated inhibition of venlafaxine metabolism by trimipramine.

OBJECTIVE: The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample. METHODS: Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V0 (n = 905), and a group of patients co-medicated with trimipramine, VTRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann-Whitney U test with a significance level of 0.05. RESULTS: Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the VTRIM group (1.15 vs. 2.37, P = 0.012). CONCLUSION: Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug-drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients' safety.

Identification of small molecules that promote human embryonic stem cell self-renewal.

Human embryonic stem cells (hESCs) and induced pluripotent cells have the potential to provide an unlimited source of tissues for regenerative medicine. For this purpose, development of defined/xeno-free culture systems under feeder-free conditions is essential for the expansion of hESCs. Most defined/xeno-free media for the culture of hESCs contain basic fibroblast growth factor (bFGF). Therefore, bFGF is thought to have an almost essential role for the expansion of hESCs in an undifferentiated state. Here, we report identification of small molecules, some of which were neurotransmitter antagonists (trimipramine and ethopropazine), which promote long-term hESC self-renewal without bFGF in the medium. The hESCs maintained high expression levels of pluripotency markers, had a normal karyotype after 20 passages, and could differentiate into all three germ layers.

Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters.

RATIONALE: The antidepressant trimipramine shows an atypical pharmacological profile and its mechanism of action is still obscure. OBJECTIVES: The present study investigated whether trimipramine and three of its metabolites interact with targets of other antidepressants, namely, the human monoamine transporters for noradrenaline (hNAT), serotonin (hSERT), and dopamine (hDAT), and with the human organic cation transporters (hOCT1, hOCT2, and hOCT3) which are expressed in the brain and are known to be involved in the uptake of monoamines. METHODS: HEK293 cells heterologously expressing the abovementioned transporters were used to determine the inhibition of [(3)H]MPP(+) uptake by trimipramine and its main metabolites. RESULTS: At concentrations up to 30 µM, all transporters, except hOCT3, were inhibited by all examined substances. With IC(50) values between 2 and 10 µM, trimipramine inhibited hSERT, hNAT, hOCT1, and hOCT2, whereas clearly higher concentrations were needed for half-maximal inhibition of hDAT. Desmethyl-trimipramine showed about the same potencies as trimipramine, whereas 2-hydroxy-trimipramine was less potent at hNAT, hSERT, and hOCT1. Trimipramine-N-oxide preferentially inhibited hSERT. CONCLUSIONS: Neither trimipramine nor its metabolites are highly potent inhibitors of the examined monoamine transporters. However, since at a steady state the sum of the concentrations of the parent compound and its active metabolites is almost two times higher than the plasma concentration of trimipramine and since it is known that tricyclic antidepressants accumulate in the brain (up to tenfold), at least partial inhibition by trimipramine and its metabolites of hSERT and hNAT (but not of hOCT3) may contribute to the antidepressant action of trimipramine.

The effect of trimipramine on dream recall and dream emotions in depressive outpatients.

Trimipramine is a sedating tricyclic antidepressant which is not only effective in the treatment of depression but also in primary insomnia. In contrast to most other antidepressants, trimipramine does not affect rapid eye movement sleep. In a large sample of depressive outpatients (N = 3926), the effect of trimipramine on dream recall and dream emotions was studied. The effect of trimipramine on dream recall was small and might be explained by the reduction of negatively toned dreams. The 4-week treatment with trimipramine yielded a considerable shift in dream emotions towards the positive end of the scale, which is paralleled by the decrease of symptom severity. The present findings support the continuity hypothesis of dreaming by demonstrating a close link between waking-life symptomatolgy and negative dream emotions. Future studies should analyze dream content in order to support the hypothesis that improvement in day-time symptoms is reflected in patients' dreams.

Receptor occupancy of mirtazapine determined by PET in healthy volunteers.

RATIONALE: Molecular tools are needed for assessing anti-depressant actions by positron emission tomography (PET) in the living human brain. OBJECTIVES: This study determined whether [(11)C]mirtazapine is an appropriate molecular tool for use with PET to estimate the magnitude of neuroreceptor occupancy produced by daily intake of mirtazapine. METHODS: This study used a randomised, double-blind, placebo-controlled, parallel-group, within-subject design. Eighteen healthy volunteers were PET-scanned twice with [(11)C]mirtazapine; once under baseline condition and again after receiving either placebo or mirtazapine (7.5 or 15 mg) for 5 days. We determined kinetic parameters of [(11)C]mirtazapine in brain regions by the simplified reference region method and used binding potential values to calculate receptor occupancy produced by mirtazapine. RESULTS: Serum concentrations of mirtazapine ranged from 33 to 56 nmol/l after five daily doses of 7.5 mg mirtazapine and were between 41 and 74 nmol/l after 15 mg mirtazapine. Placebo treatment failed to alter the binding potential of [(11)C]mirtazapine from baseline values, whereas daily intake of mirtazapine markedly decreased the binding potential in cortex, amygdala and hippocampus. Receptor occupancy ranged from 74 to 96% in high-binding regions of the brain after five daily doses of 7.5 mg or 15 mg mirtazapine, whereas 17-48% occupancy occurred in low-binding regions. CONCLUSIONS: [(11)C]Mirtazapine together with PET can determine the degree of receptor occupancy produced by daily doses of mirtazapine in regions of the living human brain.

Shifts in metabolic parameters surrounding glucose homoeostasis resulting from tricyclic antidepressant therapy: implications of insulin resistance?

This study displayed the physiological effects the tricyclic antidepressants amitriptyline or trimipramine have on glucose homoeostasis in male Wistar rats. An insulin secreting cell line (INS-1) was also used to determine effects tricyclic antidepressants have on insulin secretion and insulin displacement. Thirty rats each received a 1 mg kg-1 dose of amitriptyline or trimipramine for a period of 14 weeks; another 14 rats served as the control group. Blood glucose, serum insulin and muscle and liver glycogen levels were determined. Kidney, liver and muscle insulin degradation was measured and compared with insulin degrading enzyme concentrations in the latter two tissues. INS-1 cells were used to determine the effect 1 microM amitriptyline has on insulin secretion. Displacement studies for [3H]glibenclamide by amitriptyline or trimipramine were undertaken on INS-1 cells. A significant increase in blood glucose (P<0.01) was found for both test groups after 6 and 14 weeks of receiving the medication, which may be related to a significant decrease in liver and muscle glycogen levels (P<0.001). Serum insulin levels remained unchanged, although a significant increase in insulin degradation was observed in the muscle, liver and kidney, which may be related to a significant increase in insulin degrading enzyme (P<0.001) that was found. A significant increase in insulin secretion was observed for the INS-1 cells treated with amitriptyline, although no significant displacement for the [3H]glibenclamide was evident for amitriptyline or trimipramine. The significant alterations in glucose homoeostasis observed, as well as the significant changes associated with insulin secretion and degradation associated with amitriptyline or trimipramine treatment, imply that prolonged use of these medicines may lead to insulin resistance and full blown diabetes.

The involvement of endogenous opioid mechanisms in the antinociceptive effects induced by antidepressant drugs, desipramine and trimipramine.

The present study was designed to investigate the involvement of endogenous opioid systems in the antinociception induced by the antidepressant drugs, desipramine and trimipramine. For this purpose, the antinociceptive effects of desipramine (7.5 and 15.0 mg/kg i.p.) and trimipramine (5.0 and 10.0 mg/kg i.p.) were compared to that induced by morphine (0.2 and 2.0 mg/kg i.p.) in the tail-clip model in mice. Naloxone (0.3 and 3.0 mg/kg i.p.), a non-specific opioid receptor antagonist, inhibited morphine-induced antinociception in mice, whereas the antinociceptive effects of antidepressant drugs were found to be resistant to naloxone blockade to some extent, since only the higher concentration of naloxone (3.0 mg/kg i.p.) caused significant inhibition of the effects of antidepressant drugs. In contrast, naltrindole (1.0 mg/kg i.p.), a specific delta-receptor antagonist, inhibited antinociception induced by desipramine and trimipramine in this test, while it inhibited the antinociceptive effect of morphine only partly. None of the opioid antagonists produced a significant effect in the tail-clip experiment when they were injected alone. Based on these findings, we concluded that endogenous opioids are involved in the antinociceptive effects of the antidepressant drugs using different mechanisms.

Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study.

In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have provided scientific support for this approach in treating primary insomnia. In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics. Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia. Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo. After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal. This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.

Effects of the atypical antidepressant trimipramine on neuronal excitability and long-term potentiation in guinea pig hippocampal slices.

Acute effects of the atypical tricyclic antidepressant (TCA) trimipramine on long-term potentiation (LTP) were investigated in this study. Electrically evoked population spikes (PS) were tested under the influence of trimipramine in the CA1 region of the hippocampus. A concentration of 10 microM trimipramine reduced PS amplitudes to 85.1 +/- 8.8%. They were reduced to 12.2 +/- 8.5% with 50 microM trimipramine. In experiments with LTP, trimipramine 10 microM was applied. Only 8 of 10 tested slices showed LTP. These potentiations were smaller than in the control experiments. LTP could not be induced with 50 microM trimipramine. In conclusion, the influence of trimipramine on LTP is similar to other TCA. It is contended that this contributes to the antidepressant effect of the drug.

Effects of chronic antidepressant treatments on 5-HT and NA transporters in rat brain: an autoradiographic study.

Tricyclic antidepressants and serotonin (5-HT) uptake inhibitors rapidly block uptake sites, or transporters; however, their therapeutic effects are only seen after 2-3 weeks of treatment. Thus, direct blockade of 5-HT and noradrenaline (NA) transporters cannot account entirely for their clinical efficacy, and other long-term changes may be involved. Adult Sprague-Dawley rats were treated for 21 days with daily injections of either desipramine, trimipramine, fluoxetine, or venlafaxine; a fifth group that was used as a control, received daily saline injections. Identified cortical areas, hippocampal divisions and nuclei raphe dorsalis, raphe medialis and locus coeruleus were examined by quantitative autoradiography using either [3H]citalopram to label 5-HT transporters, or [3H]nisoxetine for NA uptake sites. Increases in [3H]nisoxetine binding were found in the cingulate, frontal, parietal, agranular insular, entorhinal and perirhinal cortices as well as in the hippocampal divisions CA1, CA3, dentate gyrus and subiculum, and in nucleus raphe dorsalis of trimipramine-treated animals compared to the control rats. Also, densities of NA transporters decreased in temporal cortex, CA2 and nucleus raphe dorsalis in fluoxetine-treated rats as compared to the controls. Also, there was a decrease in NA transporters in the locus coeruleus of the desipramine-treated animals as compared to the densities measured in the control group. Chronic treatment with desipramine or trimipramine, which do not directly inhibit 5-HT uptake, compared to fluoxetine and venlafaxine, lead to increases in 5-HT transporter densities in cingulate, agranular insular and perirhinal cortices. The present study shows differential region-specific effects of antidepressants on 5-HT and NA transporters, leading to distinct consequences in forebrain areas.

Clomipramine and related structures as inhibitors of the skeletal sarcoplasmic reticulum Ca2+ pump.

The Ca2+-pumping activity of skeletal sarcoplasmic reticulum vesicles is half-maximally inhibited by 120 microM clomipramine, 250 microM desipramine, and 500 microM imipramine or trimipramine. The inhibition is attributed to the dihydrodibenzazepine moiety, since 3-(dimethylamino)propionitrile, reproducing the aliphatic amine chain, has no inhibitory action. The inhibition is shown as a marked decrease of Ca2+ binding at equilibrium in the absence of ATP and as a reduction of phosphorylation of the Ca2+-free conformation by inorganic phosphate. Therefore, the drug effect is consistent with preferential interaction of tricyclic antidepressants with the Ca2+-free conformation of the nonphosphorylated enzyme. An additional decrease in the apparent rate constant of enzyme dephosphorylation, i.e., in the release of phosphate from ATP during enzyme cycling was also noticed.

Trimipramine fails to exert antimanic efficacy: a case of the discrepancy between in vitro rationale and clinical efficacy.

Standard mood stabilizers, such as lithium and haloperidol, and anticonvulsants show effectiveness in a maximum of 60%-70% of acutely manic patients. Obviously, there is a clinical need to evaluate other treatment options. Current pathophysiologic concepts suggest that substances with an ameliorating effect on dopaminergic hyperfunction, serotonergic hypofunction, or GABAergic hypofunction might be useful, as may be substances with calcium-antagonistic effects. In vitro, the antidepressant trimipramine exerts dopamine- and calcium-antagonistic properties. Therefore, we conducted an open trial to screen it for antimanic action. We found no clinical benefit in four acutely manic patients receiving up to 400 mg/d of trimipramine. It is concluded that, at least in the case of trimipramine, the pharmacologic profile is not helpful in predicting potential effectiveness in mania.

Effects of the atypical antidepressant trimipramine on field potentials in the low Mg2+-model in guinea pig hippocampal slices.

Trimipramine has been classified as an atypical tricyclic antidepressant, because only weak inhibitory effects on serotonin and/or noradrenaline reuptake have been found. Since some antidepressive drugs (e.g. imipramine) and other agents used in the treatment of affective disorders (e.g. carbamazepine) modulate neuronal calcium channels, trimipramine was tested on field potential changes (fp) in the low Mg2+-model of epilepsy which has been shown to be affected by calcium antagonists. Trimipramine reduced the frequency of occurrence of fp in a dose dependent manner (5-100 microM). The threshold concentration of trimipramine which did not decrease the firing rate was approximately 1 microM. Simultaneous application of subthreshold concentrations (2 microM) of the organic calcium antagonist verapamil with trimipramine decreased the firing rate to 37.0+/-22.7% (means+/-SEM, n=7) with respect to baseline values. In contrast, no additive effects of N-methyl-D-aspartate antagonists and trimipramine were observed. In conclusion, the data suggests that the antidepressive effects observed with trimipramine treatment may be due to its inhibitory action on neuronal calcium channels.

Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics.

Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.

Repeated trimipramine induces dopamine D2/D3 and alpha1-adrenergic up-regulation.

Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce beta-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and alpha1-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (+)-7-hydroxy-dipropyloaminotetralin (dopamine D2 and D3 effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an alpha1-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D2 and D3 (locomotor activity but not stereotypy) as well as alpha1-adrenergic receptors to their agonists. A question arises whether the reuptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity.

Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response.

It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.

Male reproductive systems under chronic fluoxetine or trimipramine treatment.

Adult male Long-Evans rats (n = 9 per group) received daily exposure for 4 weeks to fluoxetine (0.75 mg FLUOX/kg body weight) or trimipramine (1.6 mg TRIMI/kg body weight). Separate tests of copulation, sexual motivation, and intermale aggressive behaviors were used to evaluate functional changes during chronic exposure to either typical or atypical antidepressant drugs with more or less serotonin specificity. Circulating hormones, primary and secondary sex structures, and concentrations of dopamine (DA) and serotonin (5-HT) from mesolimbic tissue were assessed at necropsy. Results of tests with estrous females and untreated males revealed progressive disruption to sexual performance and aggressive responsiveness over time of treatment with TRIMI and, to a lesser extent, with FLUOX. By contrast, motivation, testosterone, and all measures of reproductive physiology were indistinguishable from controls. Ratios of transmitter metabolites relative to the parent compounds indicated similar reductions of 5-HT turnover with FLUOX and TRIMI. However, influences on DA turnover were significantly less with FLUOX than with TRIMI. Conclusions are that long-term intervention with antidepressant drugs may disrupt sociosexual exchanges without compromising male rats' interest in sexual contact or integrity of their reproductive physiology. Lessened disruption of sociosexual behaviors with this regimen of chronic FLUOX treatment may be related to the greater selectivity on serotonin relative to dopamine turnover.