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Major depressive disorder (MDD) is a chronic and disabling psychiatric disorder characterized by a wide range of signs/symptoms, including cognitive dysfunction. Vortioxetine (VOR) is a multimodal antidepressant drug with pro-cognitive actions in animal models and MDD patients. The VOR-mediated blockade of 5-HT 3 -R in a subpopulation of GABA interneurons enhances pyramidal neuron activity in rat medial prefrontal cortex, an effect possibly underlying its pro-cognitive action. Brain oscillations are involved in regulation of cognitive function. We therefore examined VOR effects on oscillatory activity in four brain areas of freely-moving rats (prelimbic cortex, PrL; nucleus accumbens, NAc; dorsal hippocampus, dHPC; paraventricular thalamic nucleus, PVA), in standard and in serotonin-depleted rats showing recognition memory deficits. 4-chloro-dl-phenylalanine (pCPA) markedly reduced low frequency oscillations (LFO, mainly 1 Hz oscillations) and enhanced theta oscillations in PrL and NAc. It also reduced gamma and high frequency oscillations (HFO) in PVA. Subchronic VOR and escitalopram (ESC) treatments had little effect on oscillatory activity in standard rats. However, VOR -but not ESC- prevented recognition memory deficits in 5-HT-depleted rats, and normalized LFO and theta powers in PrL and NAc. In parallel, VOR -but not ESC- prevented the deficit in PrL-dHPC gamma coherence, but not the decrease in gamma and HFO powers in PVA. Overall, this supports a prominent role of serotonergic neurotransmission on brain oscillatory activity, particularly in cortico-striatal pathways linked to short-term recognition memory. Further, VOR prevented pCPA-induced cognitive deficits by normalizing oscillatory activity at lower frequencies in the PrL-NAc pathway, also normalizing the PrL-dHPC coherence at gamma frequencies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: Obsessive-compulsive disorder (OCD) is characterized by executive function impairment and by clinical responsivity to selective serotonin reuptake inhibitors (SSRIs). Executive planning deficits constitute a candidate endophenotype for OCD. It is not known whether this endophenotype is responsive to acute serotonin manipulation., Objective: The study aimed to investigate the effects of acute SSRI administration on executive function in patients with OCD, first-degree relatives of patients with OCD, and healthy controls., Methods: A randomized double-blind cross-over study assessed the effects of single-dose escitalopram (20 mg) and placebo on executive planning in 24 patients with OCD, 13 clinically unaffected first-degree relatives of patients with OCD, and 28 healthy controls. Performance on a Tower of London task measuring executive planning was assessed 4 h after oral administration of the pharmacological challenge/placebo and compared across and within groups using a mixed model analysis of variance., Results: On the outcome measure of interest, i.e., the mean number of choices to obtain the correct solution, there was a marginally significant effect of group (F(2, 59) = 3.1; p = 0.052), with patients (least square (LS) mean 1.43; standard error [SE] 0.06; 95% confidence interval (CI), 1.31-1.55) and their relatives (LS mean 1.46; SE 0.08; 95% CI, 1.30-1.62) performing worse than matched healthy controls (LS mean 1.26; SE 0.05; 95% CI, 1.15-1.37) on placebo. There was a trend towards a significant group × treatment interaction (F(2, 58) = 2.8, p = 0.069), with post hoc tests showing (i) patients (p = 0.009; LS mean difference 0.23; SE 0.08) and relatives (p = 0.03; LS mean difference 0.22; SE 0.10) were more impaired compared to controls and (ii) escitalopram was associated with improved executive planning in patients with OCD (p = 0.013; LS mean difference 0.1; SE 0.04), but not other groups (both p > 0.1; controls: LS mean difference - 0.03; SE 0.04; relatives: LS mean difference 0.02; SE 0.05)., Conclusion: Our findings are consistent with a view that there is impaired executive planning in OCD and that this constitutes a behavioural endophenotype. In patients with OCD, but not in relatives, acute SSRI administration ameliorated this deficit. Further investigation is needed to understand common and differential involvement of neurochemical systems in patients with OCD and their relatives.

This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Trait domains of the five-factor model are not orthogonal, and two metatraits have often been estimated from their covariation. Here, we focus on the stability metatrait, which reflects shared variance in conscientiousness, agreeableness, and (inversely) neuroticism. It has been hypothesized that stability manifests, in part, because of individual differences in central serotonergic functioning. We explored this possibility in a community sample ( N = 441) using a multiverse analysis of (a) multi-informant five-factor-model traits and (b) stability as a predictor of individual differences in central serotonergic functioning. Differences in serotonergic functioning were assessed by indexing change in serum prolactin concentration following intravenous infusion of citalopram, a selective serotonin reuptake inhibitor. Results were mixed, showing that trait neuroticism, agreeableness, and conscientiousness, as well as the stability metatrait, were significantly associated with prolactin response but that these findings were contingent on a number of modeling decisions. Specifically, these effects were nonlinear, emerging most strongly for participants with the highest levels (or lowest, for neuroticism) of the component traits.

Background: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects., Aims: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT)., Methods: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region)., Results: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change., Conclusion: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

The personality trait neuroticism is associated with increased vulnerability to anxiety and mood disorders, conditions linked with abnormal serotonin neurotransmission and emotional processing. The interaction between neuroticism and serotonin during emotional processing is however not understood. Here we investigate how individual neuroticism scores influence the neural response to negative emotional faces and their sensitivity to serotonergic tone. Twenty healthy participants performed an emotional face task under functional MRI on three occasions: increased serotonin tone following infusion of a selective serotonin reuptake inhibitor (SSRI), decreased serotonin tone following acute tryptophan depletion (ATD) protocol, and no serotonin challenge (control). During the task, participants performed a gender-discrimination task of neutral, fearful or angry facial expressions. Individual variations in neuroticism scores were associated with neural response of subgenual anterior cingulate cortex to fearful facial expressions. The association was however opposite under the two serotoninergic challenges. The fear-related response in this region and individual neuroticism scores correlated negatively during citalopram challenge and positively during ATD. Thus, neuroticism scores were associated with the relative impact of serotonin challenges on fear processing in subgenual anterior cingulate cortex. This finding may link to a neural mechanism for the variable therapeutic effect of SSRI treatment observed in clinical populations.

We report a case of a hospitalised patient who developed probable serotonin toxicity shortly after the initiation of linezolid in whom the selective serotonin reuptake inhibitor (SSRI) escitalopram had been recently discontinued. On day 2 of linezolid administration, the patient reported severe anxiety and was observed to have full body jerking and twitching motions without mental status change. Notably, the patient was concomitantly receiving the antidepressant, trazodone and the benzodiazepine, clonazepam possibly affecting the severity and manifestations of serotonin toxicity. Linezolid was discontinued after 5 days and the patient's symptoms resolved. Serotonin toxicity can present with an array of symptoms and be life threatening if left unrecognised. This report highlights the clinical lessons that discontinuation of an SSRI upon initiation of linezolid does not eliminate the risk of serotonin toxicity and that other concomitant medications may worsen or improve some of the symptoms lending delay and uncertainty to the diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Disruptions in the cortico-limbic emotion regulation networks have been linked to depression, anxiety, impulsivity, and aggression. Altered transmission of the central nervous serotonin (5-HT) contributes to dysfunctions in the cognitive control of emotions. To date, studies relating to pharmaco-fMRI challenging of the 5-HT system have focused on emotion processing for facial expressions. We investigated effects of a single-dose selective 5-HT reuptake inhibitor (escitalopram) on emotion regulation during virtual violence. For this purpose, 38 male participants played a violent video game during fMRI scanning. The SSRI reduced neural responses to violent actions in right-hemispheric inferior frontal gyrus and medial prefrontal cortex encompassing the anterior cingulate cortex (ACC), but not to non-violent actions. Within the ACC, the drug effect differentiated areas with high inhibitory 5-HT1A receptor density (subgenual s25) from those with a lower density (pregenual p32, p24). This finding links functional responses during virtual violent actions with 5-HT neurotransmission in emotion regulation networks, underpinning the ecological validity of the 5-HT model in aggressive behavior. Available 5-HT receptor density data suggest that this SSRI effect is only observable when inhibitory and excitatory 5-HT receptors are balanced. The observed early functional changes may impact patient groups receiving SSRI treatment.

We have recently reported that the serotonin (5-HT) projections from the midbrain's raphe nuclei that contains 5-HT cell bodies may play a role both in heat production and in heat loss. The purpose of the present study was to clarify the involvement of 5-HT in the ventral tegmental area (VTA), where 5-HT is suggested to participate in thermoregulation, using the combined methods of telemetry, microdialysis, and high performance liquid chromatography, with a special emphasis on regulation of the body temperature (T b ) in freely moving rats. First, we measured changes in T b , tail skin temperature (T tail ; an index of heat loss), heart rate (HR; an index of heat production), locomotor activity (Act), and levels of extracellular monoamines in the VTA during cold (5°C) or heat (35°C) exposure. Subsequently, we perfused citalopram (5-HT re-uptake inhibitor) into the VTA and measured the thermoregulatory parameters and monoamines release. Although T b , T tail , and HR changed during both exposures, significant changes in extracellular level of 5-HT (138.7±12.7% baseline, p<0.01), but not dopamine (DA) or noradrenaline (NA) were noted in the VTA only during heat exposure. In addition, perfusion of citalopram into the VTA increased extracellular 5-HT levels (221.0±52.2% baseline, p<0.01), but not DA or NA, while T b decreased from 37.4±0.1°C to 36.8±0.2°C (p<0.001),T tail increased from 26.3±0.4°C to 28.4±0.4°C (p<0.001), and HR and Act remained unchanged. Our results suggest that the VTA is a key area for thermoregulation, and 5-HT, but not DA or NA, modulates the heat loss system through action in the VTA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Serotonin has been implicated in promoting self-control, regulation of hunger and physiological homeostasis, and regulation of caloric intake. However, it remains unclear whether the effects of serotonin on caloric intake reflect purely homeostatic mechanisms, or whether serotonin also modulates cognitive processes involved in dietary decision making. We investigated the effects of an acute dose of the serotonin reuptake inhibitor citalopram on choices between food items that differed along taste and health attributes, compared with placebo and the noradrenaline reuptake inhibitor atomoxetine. Twenty-seven participants attended three sessions and received single doses of atomoxetine, citalopram, and placebo in a double-blind randomised cross-over design. Relative to placebo, citalopram increased choices of more healthy foods over less healthy foods. Citalopram also increased the emphasis on health considerations in decisions. Atomoxetine did not affect decision making relative to placebo. The results support the hypothesis that serotonin may influence food choice by enhancing a focus on long-term goals. The findings are relevant for understanding decisions about food consumption and also for treating health conditions such as eating disorders and obesity.

5-hydroxytryptamine receptor 1A (5-HT1AR) is closely associated with cognitive functions. Selective serotonin reuptake inhibitors (SSRIs) can protect individuals from brain damage following ischemia/hypoxia. To investigate the function of SSRIs in vascular dementia (VD), we established a rat model of VD, and observed the effect of SSRIs on the expression of 5-HT1AR mRNA and neurotransmitters. Male SD rats (6 months) were randomly assigned into sham, model, and SSRI groups (N = 30). VD was achieved by permanent ligation of the bilateral common carotid artery. Escitalopram, a highly selective 5-HT reabsorption inhibitor, was ip injected into the rats for three consecutive weeks. The Morris water-maze was used to test learning and memory. H&E staining for neuronal injury was conducted on cortical and hippocampal tissues. HPLC was used to determine the levels of dopamine (DA), 5-HT, and norepinephrine (NE). RT-PCR was used to determine expression of 5-HT1AR mRNA. As compared to control rats, model animals demonstrated elongated escape latency, lower platform crossing times, and significant injuries to hippocampal CA1 neurons. This was accompanied by reductions in DA, 5-HT, and NE levels in hippocampal tissues, as well as reduced cortical 5-HT and decreased 5-HT1AR mRNA expression (P < 0.05). Escitalopram treatments reduced escape latency, elevated platform crossing times, improved CA1 neuronal damage, increased DA and 5-HT levels in hippocampal and cortical neurons, as well as elevated expression of 5-HT1AR mRNA (P < 0.05). Therefore, SSRIs may improve cognitive dysfunction of VD rats, possibly by stimulating expression of neurotransmitters and protecting neurons.

Dopamine and serotonin have opponent interactions on aspects of impulsivity. Therefore we wanted to test the hypothesis that dopamine and serotonin would have opposing effects on speed-accuracy trade offs in a perceptual decision making task. Unlike other behavioral measures of impulsivity, perceptual decision making allows us to determine whether decreasing premature responses, often interpreted as decreased impulsivity, corresponds to increased behavioral performance. We administered GBR-12909 (a dopamine transporter blocker), escitalopram (a serotonin transporter blocker), or saline in separate sessions to 3 rhesus macaques. We found that animals had slower reaction times (RTs) on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although nonsignificantly, on GBR than saline and had equivalent accuracy. Administration of GBR-12909 did cause animals to be faster in error trials than correct trials. Therefore, from the point of view of RTs the animals were less impulsive on escitalopram. However, the decreased accuracy of the monkeys shows that they were not able to make use of their slower response times to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of a slower information-processing rate in the perceptual inference task. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Background and Purpose: The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients., Experimental Approach: Mice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies., Key Results: The increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogenic-like/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted., Conclusions and Implications: Our data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity., Linked Articles: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc., (© 2015 The British Pharmacological Society.)

Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared with single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram (CIT) on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo (PLC)-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism. Twelve healthy subjects received PLC medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took CIT (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (CIT and PLC medication with anodal/cathodal tDCS, CIT and dextromethorphan (150 mg) with anodal/cathodal tDCS). Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.

Current pharmacological therapies for depression, including selective serotonin reuptake inhibitors (SSRI), are far from ideal. The cannabinoid system has been implicated in control of mood and neural processing of emotional information, and the modulation of serotonin (5-HT) release in the synaptic clefts. The aim of the present study was to evaluate whether the combination of a selective SSRI (citalopram) with a selective cannabinoid CB1 receptor antagonist (rimonabant) represents a more effective strategy than the antidepressant alone to enhance serotonergic transmission. For this purpose extracellular 5-HT levels were monitored with microdialysis in forebrain (prefrontal cortex, PFC) and mesencephalic (locus coeruleus, LC) serotonergic terminal areas in freely awake rats. Rimonabant at 10 mg/kg, i.p., but not at 3mg/kg i.p. increased 5-HT in both areas. Citalopram at 3, 5 and 10 mg/kg i.p. increased 5-HT both in PFC and LC in a dose-dependent manner. The effect of citalopram (5mg/kg, i.p.) on 5-HT levels was significantly enhanced by rimonabant at 10 mg/kg, i.p. but not at 3 mg/kg i.p. in both areas. The present results demonstrate that the cannabinoid CB1 receptor antagonist rimonabant is able to enhance in an additive manner the citalopram-induced increase of 5-HT concentrations in serotonergic terminal areas. The combination of a cannabinoid antagonist and a SSRI may provide a novel strategy to increase 5-HT availability, reducing the dose of SSRIs, and potentially decreasing the time lag for the clinical onset of the antidepressant effect., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Subjects with obesity and insulin resistance display a low response to a serotonergic challenge test. One of the hallmarks of obesity and insulin resistance is elevated plasma free fatty acids (FFAs). We hypothesize that increasing plasma FFA by infusion of a lipid emulsion, may be a contributing component leading to decreased serotonergic responsivity in healthy young men. Ten lean healthy men, 23.6 ± 5.0 years and BMI 22.6 ± 1.9 kg/m(2), were included. Serotonergic responsivity was assessed using the prolactin response to infusion with citalopram, a selective serotonin reuptake inhibitor, which is a validated tool to assess serotonergic tone. All participants received a lipid/heparin emulsion (Intralipid) infusion during 6 h. Saline infusion was used as a control. To evaluate a possible effect of heparin per se on prolactin, four out of the ten subjects also received heparin only during 6 h without the serotonergic challenge test. Plasma prolactin increased by 74.3 ± 15.5% during saline infusion. Intralipid infusion increased plasma FFA from 0.5 ± 0.05 to 2.3 ± 0.2 mmol/l (p < 0.001). The increase in plasma prolactin during Intralipid infusion was significantly lower (39.3 ± 10%; p < 0.001 compared to saline infusion). Heparin infusion per se increased plasma prolactin by 14.0 ± 1.9%. We found that during the Intralipid infusion with concomitant high plasma FFA levels the serotonergic response was decreased in healthy young men. Higher FFA levels may be the mediator of the decreased serotonergic response reported in patients with insulin resistance and obesity., (Copyright © 2012 S. Karger AG, Basel.)

Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.

Positron emission tomography studies of 5-hydroxytryptamine (5-HT)(1A) receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT(1A) agonist radiotracer [(11)C]CUMI-101. This study evaluates the sensitivity of [(11)C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [(11)C]CUMI-101 intravenous bolus of 4.5 ± 1.5 mCi. Binding potential (BP(F)=B(avail)/K(D)) was measured before (n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BP(F) (P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [(11)C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BP(F) may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.

Aim: Central serotoninergic activity may modulate glucose metabolism via neuroendocrine effectors. Group Care is a clinico-pedagogic intervention that improves metabolic control and quality of life in Type 2 diabetes through lifestyle modification and, possibly, central mechanisms. The hypothesis that central serotoninergic activity is modified in patients followed by Group Care was tested by measuring their hypothalamic- pituitary-adrenal response to citalopram, a selective serotonin reuptake inhibitor., Methods and Subjects: Ten healthy controls and 17 non-obese, non-insulin-treated patients with Type 2 diabetes received, in random order, iv infusions of either 20 mg citalopram or saline. Nine patients had been longterm on Group Care and 8 had always been on traditional one-to-one care. Circulating glucose, insulin, ACTH, cortisol, DHEA, GH and PRL were measured every 15 min for 240 min. Differences between areas under the curves after citalopram and saline (Δ-AUC) were calculated., Results: Citalopram stimulated ACTH and cortisol secretion in healthy subjects (p=0.026 and p=0.011, respectively) and patients on Group Care (p=0.056 and p=0.038) but not in patients on traditional care. In healthy subjects, basal glucose correlated with growth hormone Δ- AUC (r=0.820; p=0.004) and inversely with insulin Δ-AUC (r=-0.822; p=0.003). The former correlation was preserved in the patients (r=0.637; p=0.026)., Conclusions: Diabetes may blunt the response of the hypothalamic-pituitary-adrenal axis to citalopram, but this is preserved in patients followed by a long-term intervention model that improves clinical as well as cognitive and emotional variables.

Although use of methamphetamine (MA) by smoking is the fastest growing method of administration, very limited data are available describing the effects of smoked MA. Using a murine inhalation exposure system, we explored the pulmonary effects of low-dose acute inhalation exposure to MA vapor (smoke). Inhalation of MA vapor resulted in transiently reduced pulmonary function, as measured by transpulmonary resistance, dynamic compliance, and whole-body plethysmography compared with unexposed control animals. These changes were associated with an approximately 34% reduction in serotonin (5-hydroxytryptamine [5-HT]) metabolism/inactivation to 5-hydroxyindolacetic acid, and a nearly 40% reduction in monoamine oxidase (MAO)-A activity in the lung. Pretreatment of mice with a selective 5-HT reuptake inhibitor completely ablated the MA-induced changes in pulmonary function, confirming a key role for the 5-HT transporter (serotonin transporter [SERT]) and the serotonergic system in this effect. Immunofluorescent staining of mouse lung tissue confirmed high expression of SERT in airway epithelial cells. Using mouse airway epithelial cell line, LA-4, and purified human MAO-A, it was demonstrated that MA impedes 5-HT metabolism through direct inhibition of MAO-A activity in vitro. Together, these data demonstrate that low-dose exposure to MA results in reduced pulmonary function mediated via SERT and subsequent perturbation of 5-HT metabolism in the lung. This supports a role for the serotonergic system in MA-mediated pulmonary effects.

Clinical studies indicate that addition of bupropion to selective serotonin (5-HT) reuptake inhibitors (SSRIs) provides incremental benefit over SSRI monotherapy in depression. This study was designed to investigate the effects of co-administration of bupropion with escitalopram on the firing rate of 5-HT and norepinephrine (NE) neurons in anesthetized rats. Escitalopram (10 mg/kg/day x 2 days), given via subcutaneously (s.c.) implanted minipumps, decreased the firing of 5-HT and NE neurons by 70% and 55%, respectively. The firing of 5-HT neurons, unlike that of NE neurons, recovered after the 14-day escitalopram regimen. Bupropion, injected once daily (30 mg/kg/day, s.c. x 2 days), did not increase 5-HT firing but decreased that of NE by 55%. After 14 days of repeated bupropion administration, 5-HT firing was increased by 50%, and NE firing was back to baseline. Co-administration of escitalopram and bupropion doubled 5-HT firing after 2 and 14 days, whereas NE neurons were inhibited by 60% after 2 days, but partially recovered after 14 days. The responsiveness of 5-HT(1A) autoreceptors was significantly attenuated in the combination-treated rats after 2 days, indicating an early desensitization. These results provide support for contributions from 5-HT and NE mechanisms for enhanced effectiveness of combination of SSRI and bupropion treatment.

Rationale: The role of serotonin (5-HT) in attention is not fully understood yet., Objective: We aimed to investigate whether attention is modulated after treatment with escitalopram, a selective serotonin reuptake inhibitor (SSRI)., Methods: We administered 10 mg of escitalopram to 20 healthy subjects in a placebo-controlled, double-blind cross-over design for 1 day or to another 20 participants for a period of 7 days. Attention was assessed at time of plasma peak escitalopram concentration using the computerised Attention Network Test (ANT), which is a combined flanker and cued reaction time task., Results: The results showed differential effects of serotonergic manipulation on attention depending on sequence of intake. For the acute treatment, we found significant differences between escitalopram and placebo for all warning conditions dependent of sequence of intake: participants receiving escitalopram as first treatment showed significant slower reaction times in all warning conditions as compared with placebo while participants receiving escitalopram as second treatment showed significant faster reaction times as compared with placebo. For the sub-chronic treatment, we found significant differences between escitalopram and placebo depending on sequence of intake, but only for the flanker condition: participants receiving escitalopram first had significant slower reaction times in incongruent trials with escitalopram as compared with placebo while participants starting with placebo had significant shorter reaction times in incongruent trials with escitalopram., Conclusions: Thus, the results showed a differential effect of escitalopram in cognition, especially in attention, and are discussed with regard to an interaction between serotonin and familiarity with the attention test.

Motor excitability is increased in both hemispheres in stroke patients during motor recovery. Pharmacologically controlled changes of cortical excitability might be beneficial for synaptic plasticity and therefore facilitate functional recovery after a brain lesion. In particular, it has been suggested that antidepressant drugs can modulate motor excitability. Several recent reports suggest the possibility of monitoring pharmacological effects on brain excitability through transcranial magnetic stimulation (TMS). The aim of this study was to investigate motor area excitability in patients with stroke after oral administration of citalopram. We conducted a prospective randomised placebo controlled study. Twenty patients with unilateral stroke were included in the study: ten patients treated by antidepressive drug and ten patients with placebo. A selective serotonergic drug (citalopram) or a placebo was administered using a mean dosage of 10 mg/day in combination with physiotherapy. Motor cortex excitability was studied by single and paired transcranial magnetic stimulation. TMS recording was tested before (T1) and 1 month after (T2) beginning drug treatment. Patients treated by the serotonergic drug, compared to patients that received a placebo, showed a significant improvement in neurological status as measured by NIHSS and a decrease of motor excitability over the unaffected hemisphere, while no differences were observed over the affected hemisphere. Our findings suggest that treatment with serotonergic drugs can bring about a significant decrease of the motor cortex excitability in stroke patients with effects on both the affected and unaffected hemispheres associated with a better motor recovery.

Rationale: Paliperidone (9-OH-risperidone) is the main metabolite of the atypical antipsychotic risperidone. While both drugs are potent dopamine (D)2 antagonists, they have quantitative differential affinities for serotonin (5-HT) and norepinephrine (NE) receptor binding sites., Objectives: The present study aimed to determine if paliperidone exerts distinct effects on 5-HT and NE neuronal activity from those of risperidone., Materials and Methods: Risperidone and paliperidone were administered to Sprague-Dawley rats. Neuronal activity of 5-HT and NE neurons was assessed using in vivo electrophysiology., Results: Acute administration of risperidone but not paliperidone inhibited the firing of 5-HT neurons, as previously reported. This inhibition was partially antagonized by the NE reuptake inhibitor desipramine, by the 5-HT(1A) receptor antagonist WAY 100635, and completely reversed when both drugs were given consecutively. Risperidone inhibited the firing of 5-HT neurons after 2 and 14 days of administration, with or without escitalopram. Paliperidone did not alter the firing rate of NE neurons by itself, but it reversed the suppression of NE neurons induced by escitalopram, as it was previously reported for risperidone., Conclusion: These results indicate that although risperidone and paliperidone share a qualitatively similar receptor binding profile in vitro, they differentially alter the firing of 5-HT and NE neurons in vivo. The capacity of paliperidone to reverse the selective serotonin reuptake inhibitor (SSRI)-induced inhibition of NE neuronal firing, without interfering with the effect of SSRIs of 5-HT neuronal activity, suggests that paliperidone may be a very effective adjunct in SSRI-resistant depression.

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT(1A) receptor antagonist WAY-100,635 (20-100 microg/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA(3) pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT(1A) receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED(50)=58 and 254 mug/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 microg/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 microg/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT(1A) autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.

The authors investigated whether different types of aggression relate to the A779C tryptophan hydroxylase (TPH) polymorphism and to serotonergic activity in volunteers. A factor analysis of the Buss-Durkee Hostility Inventory yielded 2 factors representing Neurotic Hostility (NH) and Aggressive Hostility (AH). The authors used a neuroendocrine challenge with Citalopram in 48 volunteers and increased cortisol concentrations only in those with high levels of AH. Finally, an association study with 58 volunteers revealed that the A779C TPH polymorphism significantly relates to AH, with the highest aggression levels for the genotype AA and the lowest aggression levels for the genotype CC, but not to NH. Results are discussed with respect to inconsistent findings in the literature, which may be explained by this distinction of types of aggression., (Copyright 2005 APA.)

1 Microdialysis was used to study the acute and chronic effects of escitalopram (S-citalopram; ESCIT) and chronic citalopram (CIT), together with the 5-HT1A receptor antagonist WAY100,635 (N-[2-[methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on extracellular 5-hydroxytryptamine (5-HT) levels in the rat prefrontal cortex. 2 Extracellular 5-HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg(-1) ESCIT. No further increase was observed at 2.5 mg kg(-1) ESCIT (290%). 3 The effect of 13-day s.c. infusion of 10 mg kg(-1) day(-1) ESCIT on extracellular 5-HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5-HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S-citalopram in rats infused with CIT for 13 days were lower than after 2 days. 4 Acute treatment with 2.5 mg kg(-1) ESCIT or 5 mg kg(-1) CIT raised extracellular 5-HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg(-1) day(-1)) or CIT (20 mg kg(-1) day(-1)) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5-HT. WAY100,635 (0.1 mg kg(-1) s.c.) increased extracellular 5-HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5-HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively. 5 8-OH-DPAT (0.025 mg kg(-1)) reduced extracellular 5-HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days. 6 This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5-HT1A receptors, regulating the release of 5-HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5-HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5-HT.

The tricyclic antidepressant amitriptyline is the only documented and most widely used prophylactic drug for chronic tension-type headache (CTTH). However, it is not fully clarified whether the serotonin (5-HT) reuptake inhibition plays a major role for the analgesic effect of amitriptyline. To explore the importance of 5-HT reuptake inhibition for mechanism of action of the analgesic effect of amitriptyline we investigated platelet 5-HT levels during preventive treatment of CTTH with amitriptyline, the selective serotonin reuptake inhibitor citalopram, and placebo. Thirty-four patients with CTTH were given preventive treatment with amitriptyline 75 mg/day, the selective 5-HT reuptake inhibitor citalopram 20 mg/day, and placebo in a 32-week, double-blind, placebo-controlled, three-way crossover trial. Blood samples were collected in the last week of each treatment period. Platelet 5-HT was used as a measure of 5-HT reuptake inhibition and determined by high performance liquid chromatography. Area under the headache curve was 308 (157-715) (median with quartiles in parentheses) with amitriptyline and significantly lower than 377 (158-1121) with citalopram (P = 0.04) and 441 (178-1408) with placebo (P = 0.002). There was no difference between citalopram and placebo (P = 0.23). Platelet 5-HT was 0.4 (0.3-0.7) x 10(-18)mol/platelet with citalopram, which was significantly lower than 1.7 (1.2-2.4) x 10(-18)mol/platelet with amitriptyline (P < 0.001), and 3.5 (2.8-4.3) x 10(-18)mol/platelet with placebo (P < 0.001). The lower platelet 5-HT during treatment with citalopram than amitriptyline indicates that 5-HT reuptake was most effectively inhibited by citalopram. In contrast, amitriptyline was most effective in reduction of headache. This suggests that the analgesic effect of amitriptyline in CTTH is not solely due to 5-HT reuptake inhibition and that other mechanisms such as norepinephrine reuptake inhibition, NMDA receptor antagonism, blockade of muscarinic receptors and ion channels should be addressed in the future research.

Some evidence would indicate that a serotonergic deficit may be involved in epileptogenesis. A preliminary trial of citalopram, a selective inhibitor of serotonin reuptake, was carried out. Citalopram 20mg/day was given to 11 non-depressed patients with poorly controlled epilepsy as an add on treatment with an open label design for 8-10 months. The median seizure frequency dropped by 55.6% in the whole group, with nine patients improving by at least 50%. No adverse reactions occurred with the exception of mild drowsiness. There were no changes of post-treatment as compared to pre-treatment AED serum concentrations. Although controlled studies are required to confirm the anticonvulsant effect of citalopram, these findings may be regarded as an indirect evidence of serotonergic impairment in human epileptogenesis.

Microdialysis was used to assess the involvement of postsynaptic 5-hydroxytryptamine(1A) (5-HT(1A)) receptors in the regulation of extracellular 5-HT in the amygdala. Local infusion of the 5-HT(1A) receptor agonist flesinoxan (0.3, 1, 3 microM) for 30 min into the amygdala maximally decreased 5-HT to 50% of basal level. Systemic administration of citalopram (10 micromol/kg) increased 5-HT to 175% of basal level. Local infusion of 1 microM of the 5-HT(1A) receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5-HT level. 5-HT(1A) receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 microM flesinoxan for 30 min into the amygdala, which showed a significant 63% reduction in response (area under the concentration-time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 micromol/kg), which increased 5-HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 microM WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the flesinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5-HT(1A) receptor-mediated feedback in the amygdala, which diminishes following chronic citalopram treatment.

We investigated the effect of citalopram [a selective serotonin (5-HT) reuptake inhibitor; SSRI] and MKC-242 (a selective 5-HT1A agonist), following treatment with subchronic lithium (p.o., 1 week) on extracellular 5-HT concentrations in the medial prefrontal cortex (mPFC). Acute treatment with citalopram (3 and 30 mg/kg) led to significant increases in extracellular 5-HT concentrations. The subchronic lithium group showed significantly higher basal levels of extracellular 5-HT than normal diet controls. Acute citalopram (3 and 30 mg/kg) treatment together with subchronic lithium treatment showed significant increases in the extracellular 5-HT concentrations, compared with citalopram treatment alone. Acute MKC-242 (1 mg/kg) treatment showed significant decreases in extracellular 5-HT concentrations, in both the normal diet and lithium diet groups to the same extent. The addition of lithium did not change the effect of the 5-HT1A agonist on extracellular 5-HT concentrations. This study suggests that lithium augmentation of the antidepressant effect of SSRI is mediated by the additional increases in extracellular 5-HT concentrations following the co-administrations of lithium and SSRI.

THE NMDA receptor antagonist phencyclidine (PCP) has low micromolar affinity for the 5-HT reuptake site, but it is uncertain whether PCP blocks 5-HT reuptake when given systemically to rats in behaviourally stimulating doses. We here report for the first time that systemically administered PCP (5 mg/kg, s.c.) increases extracellular 5-HT levels in the rat medial prefrontal cortex (to 322%) and dorsal hippocampus (to 233%). Increases were found also when citalopram (1 microM) was included in the perfusion medium (to 184 and 180%, respectively). Extracellular 5-HIAA concentrations increased during both conditions, and extracellular GABA decreased in the dorsal hippocampus. It is concluded that systemic PCP treatment elevates extracellular 5-HT levels, probably through mechanisms other than a blockade of 5-HT reuptake.

To clarify the serotonergic mechanisms involved in the protection against ischemic neuronal damage, ZD-211 (citalopram HBr), a serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitor, or buspirone, a 5-HT1A agonist, was locally administered into the hippocampus of gerbils. Additionally, to clarify the role of the 5-HT nervous system in the hippocampus during ischemic neuronal damage, animals were subjected to the local administration of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neurotoxin, before ischemia challenge. Gerbils received intrahippocampal administration of ZD-211 (200 nmol/animal) or buspirone (20 nmol/animal) before 5-min ischemia. 5,7-DHT was intrahippocampally administered 7 days before a 2-min non-lethal ischemia challenge. In vehicle-treated animals subjected to 5 min of ischemia, almost all hippocampal CA1 pyramidal neurons were lost. The treatment with ZD-211 or buspirone showed a significant protective effect, and the number of neurons was significantly increased compared to vehicle-treated animals. Pretreatment with NAN-190, a 5-HT1A antagonist, completely abolished the protective effect of ZD-211 or buspirone. In the 5,7-DHT-treated animals, the number of neurons was significantly reduced following 2 min of ischemia compared to vehicle-treated animals in which this period of ischemia is non-lethal. Thus, intrahippocampal treatment with ZD-211 or buspirone can protect neuronal damage following transient ischemia in gerbils. These effects of ZD-211 and buspirone were mediated through the 5-HT1A receptor in the hippocampus. Furthermore, the destruction of the 5-HT nervous system in the hippocampus aggravated ischemic neuronal damage. Therefore, this study showed that the enhanced activity of the 5-HT nervous system in the hippocampus may protect against neuronal damage following cerebral ischemia.

Rats were administered the selective serotonin (5-HT) uptake blocker citalopram or saline for 14 days to determine if prolonged treatment would lead to changes in extracellular 5-HT or autoreceptor sensitivity. One day after drug withdrawal, dialysis probes were implanted in the frontal cortex and dorsal hippocampus. Dialysis experiments were carried out using chloral hydrate anesthetized rats. The experimental protocol comprised the administration of three consecutive drug challenges: (1) After stable baseline levels were obtained, citalopram was infused through the dialysis probes to locally block uptake in the forebrain. (2) Subsequently, a 5-HT1B receptor agonist (RU24969 or CP93,129) was infused through the probe to test for changes in terminal autoreceptor sensitivity. (3) Last, citalopram was administered systemically to test the effect of indirect activation of somatodendritic autoreceptors. Under these conditions, with uptake already blocked locally in the forebrain, systemic citalopram produces a decrease in extracellular 5-HT, an effect that can be inhibited by pretreatment with antagonists of 5-HT1A receptors. The results indicate that during local infusion of citalopram extracellular 5-HT was significantly higher in the dorsal hippocampus of the chronic citalopram as compared to saline treatment group. This difference persisted throughout the full time course of the experiment. However, the decreases in 5-HT levels produced by local infusion of a 5-HT1B receptor agonist or after systemic citalopram administration were not significantly different between the chronic citalopram and saline treated groups. There were no significant differences between chronic citalopram and saline treated animals in frontal cortex. These results suggest that prolonged inhibition of 5-HT uptake may produce a selective change in the regulation of release from median raphe 5-HT neurons, but this change could not be clearly linked to a change in nerve terminal or somatodendritic autoreceptor sensitivity.

In animals given citalopram (10 mg/kg) twice daily for 14 days a further dose of 1 mg/kg, administered 24 h after the last dose, markedly increased cortical dialysate serotonin (5-hydroxytryptamine, 5-HT), but had no effect in control animals. The effect on dialysate 5-HT in the dorsal raphe was not increased by the chronic treatment. At 25 micrograms/kg, 8-hydroxy-2-(di-n-propylamino)tetralin, an agonist at 5-HT1A receptors, reduced cortical 5-HT output in controls but not in animals treated chronically with citalopram whereas 50 micrograms/kg reduced 5-HT output in both groups. These findings suggest that somatodendritic 5-HT1A receptors are desensitized after chronic treatment with citalopram and this results in facilitation of its effect on cortical dialysate 5-HT. These results also agree with the concept that the effect of 5-HT re-uptake inhibitors on increasing 5-HT output in the frontal cortex is attenuated by their simultaneous ability to activate somatodendritic 5-HT1A receptors via an increase of endogenous 5-HT in the raphe region.

Prolonged (14 days, twice daily), but not acute, application of imipramine and (+)-oxaprotiline (10 mg/kg) induced sensitization of hippocampal CA1 neurons to the inhibitory effect of 5-hydroxytryptamine (5-HT), as studied ex vivo in the rat hippocampal slice preparation. Attenuation of the population spike, recorded in the CA1 pyramidal cell layer in response to stimulation of the Schaffer collateral-commisural pathway, was used to asses the sensitivity of neurons to 5-HT. Prolonged and acute administration of the selective 5-HT reuptake blocker citalopram did not change the responsiveness of hippocampal neurons to 5-HT. Since imipramine and (+)-oxaprotiline share the inhibitory effect on the norepinephrine reuptake, our results may indicate that long-term alterations in the noradrenergic system lead to modifications in postsynaptic serotonergic receptors.

The authors investigated the mechanism of action of the antidepressant serotonin (5-HT) reuptake blocker citalopram in the rat by means of an in vivo electrophysiologic paradigm. In control animals, the acute intravenous administration of citalopram reduced the firing rate of dorsal raphe nucleus serotonergic neurons with an ED50 of 230 micrograms/kg. Rats were treated with citalopram (20 mg/kg/day i.p.) for 2, 7, and 14 days. Two-day treatment was accompanied by a marked reduction of the firing activity of serotonergic neurons; there was a partial recovery after 7 days of treatment, and a complete one following 14-day citalopram administration. The response of serotonergic neurons to intravenously administered lysergic acid diethylamide (LSD), a somatodendritic 5-HT autoreceptor agonist, was reduced in rats treated with citalopram for 14 days, suggesting that such a treatment reduces the sensitivity of the somatodendritic autoreceptor. Fourteen-day citalopram treatment also markedly enhanced the efficacy of the stimulation of the afferent serotonergic pathway in suppressing the firing activity of postsynaptic CA3 dorsal hippocampus pyramidal neurons. This enhanced efficacy of serotonergic synaptic transmission was not the result of an increased sensitivity of postsynaptic neurons to serotonin, as the effect of the direct microiontophoretic application of serotonin onto these same neurons was not modified. That serotonin reuptake blockade per se was responsible for this enhancement could also be ruled out, as the acute intravenous administration of citalopram (1 mg/kg) in control rats failed to enhance the efficacy of the stimulation. To determine an involvement of the 5-HT terminal autoreceptor, methiothepin (1 mg/kg), a terminal autoreceptor antagonist, was injected intravenously in control and citalopram-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)