Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (<em>5HT</em>) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.

In this study, p-chlorophenylalanine (pCPA), an inhibitor of tryptophan hydroxylase (the rate limiting enzyme of serotonin synthesis), was used to reduce serotonin (<em>5HT</em>) levels during early development in zebrafish embryos. One day old dechorionated embryos were treated with 25 μM pCPA for 24h and subsequently rescued. Immunohistological studies using a <em>5HT</em> antibody confirmed that <em>5HT</em> neurons in the brain and spinal cord were depleted of transmitter by 2 days post fertilization (dpf). Twenty four hours after pCPA exposure embryos were unable to burst swim and were nearly paralyzed. Movement began to improve at 4 dpf, and by 7 dpf, larvae exhibited swimming activity. Rescued larvae continued to grow in rostrocaudal length over 5 days post-rescue, but their length was always 16-21% below controls. Surprisingly, both groups displayed the same number of myotomes. To examine whether hypertonicity of myotomes in treated embryos played a role in their shorter rostrocaudal lengths, 1 dpf embryos were exposed to a combination of 25 μM pCPA and 0.6 mM of the sodium channel blocker ethyl 3-aminobenzoate methanesulfonate (MS-222). After a 24 hour exposure, the embryos exhibited the same rostrocaudal length as control embryos suggesting that myotome hypertonicity plays a major role in the decreased axial length of the treated larvae. In addition, pCPA treated 2 dpf embryos exhibited abnormal notochordal morphology that persisted throughout recovery. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the relative levels of the serotonin 1A receptor (<em>5HT</em>(1A)) transcript and the serotonin transporter (SERT) transcript in the brain and spinal cord of control and treated embryos. Transcripts were present in both brain and spinal cord as early as 1 dpf and reached maximal concentrations by 3 dpf. Embryos treated with pCPA demonstrated a decrease in the concentration of <em>5HT</em>(1A) transcript in both brain and spinal cord. While SERT transcript levels remained unaffected in brain, they were decreased in spinal cord. Five days subsequent to pCPA rescue, <em>5HT</em>(1A) transcript concentrations remained decreased in brain while SERT transcript levels were elevated in both regions. These findings suggest that reduction of <em>5HT</em> during early zebrafish development may have an adverse effect on body length, notochordal morphology, locomotor behavior, and serotonin message-related expression.

To address the hypothesis that maturation alters the contribution of K-channels to resting and agonist-induced tone in small cerebral arteries, second branch middle cerebral arteries (approximately 200 microm) were taken from term fetal (139-141 days gestation) and adult sheep, denuded of endothelium, and mounted in myographs. After determination of length-tension relations, the arteries were stretched to 55, 100, and 145% of optimum length. At each level of stretch, contractile responses to 5 mM 4-aminopyridine (4-AP, voltage-sensitive K-channel blocker), 100 nM iberiotoxin (calcium-sensitive K-channel blocker), 10 microM glibenclamide (ATP-sensitive K-channel blocker), or 10 microM Ba(2+) (inward rectifier K-channel blocker) were recorded. In separate experiments, concentration--response relations were determined for 5-HT in the presence and absence of each of the four K-channel blockers at the same concentrations. Both 4-AP and iberiotoxin produced stretch-dependent contractions of greater magnitude in adult (37% for 4-AP and 43% for iberiotoxin at 100% optimum) than in fetal (5% for 4-AP and 7% for iberiotoxin at 100% optimum) arteries. 4-AP also enhanced the pD(2) for 5-HT in adult (from 7.15 to 7.49), but not in fetal, arteries. Conversely, glibenclamide attenuated the pD(2) for 5-HT in fetal (from 7.02 to 6.71), but not in adult, arteries. Iberiotoxin enhanced the pD(2) for 5-HT in both fetal (from 7.05 to 7.51) and adult (from 7.15 to 7.75) arteries. In addition, iberiotoxin enhanced maximum responses to 5-HT (from 59 to 82%) in adult but not fetal arteries. Finally, 4-AP enhanced the maximum responses to 5-HT in both fetal (from 67 to 85%) and adult (from 59 to 79%) arteries. These results indicate that maturation modulates the contribution of K(V), K(Ca), and K(ATP), but not K(IR) channels to basal and/or <em>5HT</em>-induced cerebrovascular tone, and demonstrate that K(V) and K(Ca) channels are coupled to stretch-sensitive receptors, and that K(V) and K(Ca) limit contractile responses to 5-HT. To the extent that changes in pD(2) values reflect changes in agonist--ligand interactions, the data also suggest that K(V), K(Ca), and K(ATP) channels may possibly influence ligand--receptor binding for 5-HT.

Tramadol (Ultram, Ultracet) is a centrally acting synthetic opioid with analgesic efficacy comparable to codeine. Antinociception is attributed to low but effective affinity for the mu-opioid receptor (μ), as well as reuptake inhibition of the monoamines norepinephrine (NE) and serotonin (<em>5HT</em>). Dual action antidepressants mirtazapine (Remeron), duloxetine (Cymbalta), and most notably venlafaxine (Effexor), which tramadol is closely related to in structure, also inhibit NE and <em>5HT</em> reuptake. These medications are proven effective antidepressants and this shared monoaminergic action resulted in the research of tramadol as a potential treatment for depression. The present article intends to substantiate the use of tramadol in this manner by analyzing several decades of research which is presented as an illustration of neuronal theories, as well as lab work and case studies of both the supporting ideas and potential hazards. Finally, the article promotes the benefits of acute action in comparison to modern antidepressants and the documentation of low abuse rates while maintaining an object view of the risks, most notably, the risk for addiction from agonist action on μ-receptors.

<em>5HT</em>(2A/2C) and <em>5HT</em>(3) receptors have an important role in cognitive behavior specially in spatial learning and memory but the literature concerning the role of these receptors in hippocampus in cognition remains controversial. In the present study a <em>5HT</em>(2A/2C) antagonist ritanserin (0, 2, 4, 8 microg/0.5 microl) and a <em>5HT</em>(3) antagonist granisetron (0.0, 0.05, 0.25, 0.5 microg/0.5 microl) were injected bilaterally into the CA1 region of rat hippocampus, 20 min before each training session in Morris Water Maze (MWM) task. Compare with control group, ritanserin (4 microg/0.5 microl) significantly reduced the escape latency and traveled distance of swimming to platform, but granisetron (0.25 microg/0.5 microl) significantly increased those parameters. Both drugs had no effect on escape latency and traveled distance of a non-spatial visual discrimination task. These results suggest a differential role of <em>5HT</em>(2A/2C) and <em>5HT</em>(3) receptors during spatial learning that ritanserin improves rat performance in spatial discrimination task whereas granisetron impairs it.

The neuroendocrine control of ovulation and broodiness in the domestic hen involves complex interactions between hypothalamic neuropeptides, neurotransmitters, and ovarian steroids which regulate the secretion of luteinizing hormone (LH) and prolactin. Nuclear progesterone receptor is localized in many neurons throughout the hypothalamus but is absent from LHRH neurons. Hence, the positive feedback action of progesterone on LH release is not mediated by a genomic mechanism within the LHRH neuron. Precursors of 5-hydroxytryptamine (<em>5HT</em>) and dopamine (DA) inhibit the preovulatory release of LH, while the turnover rates of these neurotransmitters in the anterior hypothalamus decrease when preovulatory levels of LH are at their highest. Further, a population of receptors for <em>5HT</em> which occurs in the anterior hypothalamus in laying birds is absent in nonlaying, incubating hens. Taken together, these observations suggest that the preovulatory surge of LH is mediated by a transitory decrease in the inhibitory action of <em>5HT</em> and possibly DA, on the secretion of LHRH. Neurons containing <em>5HT</em> may play a role in the regulation of prolactin release and, more specifically, in the control of broodiness. Drugs which enhance the function of <em>5HT</em> neurons stimulate prolactin release while increased prolactin secretion in incubating hens is associated with an increase in the turnover of <em>5HT</em> in the anterior hypothalamus. No receptors for <em>5HT</em> were demonstrable in the anterior pituitary gland, showing that the prolactin-releasing activity of <em>5HT</em> must be mediated by a prolactin-releasing factor (PRF). A candidate for a physiological PRF is vasoactive intestinal polypeptide (VIP).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of serotonin reuptake inhibitors (SRIs) is associated with sexual dysfunction. The cause of this dysfunction is unclear but may be related to stimulation of the serotonergic system. In the present article, we describe seven patients in whom iatrogenic sexual dysfunction induced by SRIs was treated with cyproheptadine, a <em>5HT</em>-2 antagonist with antihistaminergic and adrenolytic properties. Seven obsessive-compulsive male patients, aged 29-54 years, who developed sexual dysfunction following treatment with SRIs (fluoxetine, fluvoxamine, and clomipramine) were instructed to take cyproheptadine (4-12 mg) 1-2 h before commencing sexual activity. Five of the seven patients displayed improvement in sexual function, although the improvement was transitory in two. The two remaining patients did not respond. All patients exhibited sedation on the day following cyproheptadine administration. Our preliminary observation suggests that some patients with sexual dysfunction associated with SRI treatment, mainly decreased libido and anorgasmia, may benefit from cyproheptadine administration. The role of <em>5HT</em>-2 antagonists in SRI-induced sexual dysfunction merits further investigation.

The visual system of the fly's compound eye undergoes a number of cyclical day/night changes that have a circadian basis. Such responses are seen in the synaptic terminals of the photoreceptors and in their large monopolar-cell interneurons in the first optic neuropile, or lamina. These changes include, in the photoreceptor terminals, rhythms in the numbers of synapses and the vertical migration of screening pigment; and, in the monopolar cells L1 and L2, a rhythm in the transients of the electroretinogram and in the cyclical swelling of L1 and L2 lamina axons, as well as of the epithelial glia that surround these. Some of these changes are seen in both the housefly and the fruit fly, but the time-course of such changes differs between the two species. Many of the changes are influenced by the injection of various transmitter candidates, in a direction that can be reconciled with the possibility of normal endogenous release of two substances, <em>5HT</em> from the neurites of <em>5HT</em>-immunoreactive neurons, and pigment dispersing factor peptide from the neurites of PDH cells. Consistent with this interpretation, the immunoreactive varicosities of PDH cells exhibit size changes attributable to their cyclical release of peptide, or to its cyclical synthesis and/or transport from the PDH cell somata. Thus, neurotransmitter substances not only have rapid electrophysiological actions in the optic lobe, but also longer-lasting, presumably indirect, neuromodulatory actions, which are manifest as structural changes among the lamina's neurons and synapses. These actions involve an interplay between aminergic and peptidergic systems, but the exact role and especially the site of action of each has still to be elucidated.

OBJECTIVE

We examined changes in the serotonin system across the estrous cycle in trigeminal ganglia of female rodents to determine which components are present and which are regulated by the variations in levels of ovarian steroids that occur during the estrous cycle.

BACKGROUND

Migraine is 2-3 times more prevalent in women than in men and attacks are often timed with the menstrual cycle, suggesting a mechanistic link with ovarian steroids. Serotonin has been implicated in the pathogenesis of migraine, and the effectiveness of triptans, selective <em>5HT</em>-1B/D/F agonists, has provided further support for this concept. It is not known whether serotonin, its rate-limiting enzyme tryptophan hydroxylase (TPH), or its receptors are regulated by ovarian steroids in trigeminal ganglia.

METHODS

We used reverse transcription-polymerase chain reaction to examine gene expression in cycling mice, Western blots to examine protein expression, double-labeling immunohistochemistry using markers of nociceptors and nonnociceptors and confocal microscopy to identify specific types of neurons, and primary tissue culture to examine effects of estrogen on trigeminal neurons in vitro.

RESULTS

In C57/BL6 mice mRNA levels of TPH-1, the rate-limiting enzyme in serotonin synthesis, were over 2-fold higher and protein levels were 1.4-fold higher at proestrus, the high estrogen stage of the cycle than at diestrus, the low estrogen stage. TPH protein also was present in primary trigeminal cultures obtained from female Sprague-Dawley rats, but levels were not affected by 24-hour treatment with physiological levels (10(-9) M) of 17beta-estradiol. Gene expression of <em>5HT</em>-1B and <em>5HT</em>-1D receptors in trigeminal ganglia was not regulated by the estrous cycle. Serotonin was present in trigeminal neurons containing CGRP, a potent vasoactive neuropeptide, peripherin, an intermediate filament present in neurons with unmyelinated axons, neurofilament H, which is present in neurons with myelinated axons, and in neurons binding IB4, a marker of nonpeptidergic nociceptors. Serotonin was also present in neurons containing <em>5HT</em>-1B. The serotonin-positive population was significantly larger in diameter than the serotonin-negative population. Conclusions.-Expression of the rate-limiting enzyme required for serotonin synthesis is regulated during the natural estrous cycle, and serotonin is present in larger trigeminal neurons of all the major subtypes. Colocalization of serotonin with <em>5HT</em>-1B suggests that this receptor functions as an autoreceptor to regulate serotonin release. Cyclical changes in serotonin levels in trigeminal ganglia could contribute to the pathogenesis of menstrual migraine.

Pseudomonas fluorescens is a commensal bacterium present at low level in the human digestive tract that has also been reported in many clinical samples (blood, urinary tract, skin, lung, etc.) and sometimes associated with acute opportunistic infections. It has recently been found that the human β-defensin-2 can enhance the pathogenic potential of P. fluorescens. In this study, we evaluated the effect of other intestinal molecules (<em>5HT</em>, SP and Epi) on growth and virulence of the clinical strain P. fluorescens MFN1032. We found that P. fluorescens MFN1032 growth was not mainly affected by these factors, but several modifications in the virulence behavior of this bacterium were observed. <em>5HT</em>, SP and Epi were able to modulate the motility of P. fluorescens MFN1032. <em>5HT</em> and SP had an effect on pyoverdin production and IL-8 secretion, respectively. Infection of Caco-2/TC7 cells with P. fluorescens MFN1032 pretreated by SP or Epi enhanced the permeability of the monolayers and led to a partial delocalization of F-actin to the cytoplasm. These findings show that some intestinal molecules can modulate the pathogenic potential of P. fluorescens MFN1032. We can hypothesize that this dialogue between the host and the human gut microbiota may participate in health and disease.

Differential pulse voltammetry was performed in the suprachiasmatic nucleus (SCN) of anaesthetised rats. Peripheral administration of RU24969 (10 mg/kg) a <em>5HT</em>1 receptor agonist, decreased the size of the 5HIAA oxidation peak whereas it was increased by the non-selective <em>5HT</em> receptor antagonist methiothepin (10 mg/kg). The effects of RU24969 were attenuated by methiothepin while the <em>5HT</em>2 receptor antagonist ketanserin (5 mg/kg i.p.) did not affect the response to RU24969. The results suggest that in vivo <em>5HT</em> release and metabolism in the SCN is probably under the influence of the <em>5HT</em>1 receptor.

Studies in humans suggests that airway inflammation may modulate nonspecific airway responsiveness. We studied in a rat model the effect of the inhalation of endotoxin on the cellular composition of the bronchoalveolar lavage (BAL) fluid and airway responsiveness. The exposure to an aerosol of endotoxin caused a rapid influx of neutrophils in the airways. The neutrophils persisted up to 24 h after exposure. Elastase activity in lavage fluid became detectable 30 min after the endotoxin exposure and peaked 9 h later. The exposure to the endotoxin aerosol was followed 1 to 2 h later by a significant increase in the airway responsiveness to 5-hydroxytryptamine (<em>5HT</em>). However, the increase in responsiveness disappeared, and 9 to 12 h following the end of the exposure a significant decrease in airway <em>5HT</em> responsiveness was observed at the moment that more than 80% of the cells contained in the BAL fluid were neutrophils. The effect of endotoxin on airway responsiveness and inflammation was dose dependent. We also compared in three different inbred rat strains the effect of endotoxin inhalation. The aerosol exposure induced in all three strains a comparable neutrophil influx in the airways, but only two of the three strains became hyperresponsive to <em>5HT</em>. We conclude that the inhalation of endotoxin causes a neutrophilic airway inflammation in rats. The relationship between this airway inflammation and airway responsiveness is dependent on the time following the exposure and the animal strain used.

Although numerous animal procedures have been employed in the study of antidepressants (ADs) in anxiety, the results following acute administration remain highly variable. The present study investigated the effect of the SSRI paroxetine (4, 8, and 16 mg/kg, IP) in two tests of anxiety in mice: the light/dark test paradigm, and the four plates test (FPT). In both tests, it was found that paroxetine resulted in an anxiolytic-like effect at doses that did not modify motor performance (at the doses of 4 and 8 mg/kg in the light/dark test and at the doses of 4, 8, and 16 mg/kg in the four plates test). In the light/dark paradigm, both doses of buspirone significantly potentiated paroxetine, while in the four plates only one dose of buspirone (a <em>5HT</em>(1A) partial agonist) (0.06 mg/kg) increased the anxiolytic-like effect of paroxetine. Prior administration of 1-PP was without effect in the light/dark paradigm but antagonized the effect of paroxetine (at the dose of 0.06 and 0. 5 mg/kg) in the FPT. The results suggested that a balance between pre- and postsynaptic 5-HT(1A) receptor was implicated in the anxiolytic-like effect of paroxetine. Buspirone seemed to emphasize the role of paroxetine in 5-HT(1A) receptor modulation and exerted a biphasic influence in the two tests.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that serves as a survival factor for neurons. Agomelatine is a novel antidepressant as well as a potent agonist of melatonin (MT), MT1 and MT2 receptor types and an antagonist of the serotonin (<em>5HT</em>), 5-HT2C receptor. The study herein established whether treatment with agomelatine alters hippocampal BDNF protein expression under chronic unpredictable mild stress (CUMS) condition. Twenty-one day treatment with agomelatine, fluoxetine or vehicle was assessed in 52 Sprague-Dawley rats undergoing CUMS. Ten naïve control rats were also evaluated after 21 days. The behavioral effects of treatments were studied using the open field test (OFT) on day 0, 7 and 21 and sucrose preference test on day 21. Hippocampal BDNF protein expression was measured using immunohistochemistry. The effect of the interventions on hippocampal neurons was histologically examined after H&E staining. Agomelatine mitigated the reduction in rearing behavior by CUMS in the OFT on day 7 as well as sucrose preference on day 21. The mean optical density value of BDNF was significantly higher in the CUMS + agomelatine group than the CUMS and CUMS + fluoxetine groups. The CUMS + agomelatine group had a significantly higher number of BDNF positive cells compared to naïve controls and CUMS group. Histology showed that hippocampal neurons in the CUMS + agomelatine and CUMS + fluoxetine groups were intact and few of them demonstrated karyopyknosis. Agomelatine-a novel antidepressant, but not fluoxetine, increased hippocampal BDNF level and of BDNF positive neurons in rats subject to CUMS.

Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites--or nodes--where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks.

Mice deficient in the serotonin transporter (<em>5HT</em>T) display highly elevated extracellular <em>5HT</em> levels. <em>5HT</em> exerts ist effects via at least fourteen different cloned <em>5HT</em> receptors located pre- and postsynaptically. In contrast to the other <em>5HT</em> receptors, the <em>5HT</em>3 receptor is a ionotropic receptor with ligand-gated cation channel function. Since G-protein-coupled <em>5HT</em> receptors show extensive adaptive changes in <em>5HT</em>T-deficient mice, we investigated whether <em>5HT</em>3 receptors are also altered in these mice. Using quantitative autoradiography, we found that <em>5HT</em>3 receptors are upregulated in frontal cortex (+46%), parietal cortex (+42%), and in stratum oriens of the CA3 region of the hippocampus (+18%) of <em>5HT</em>T knockout mice. Changes in <em>5HT</em>3 receptor mRNA expression, as determined by quantitative in situ hybridisation, were less pronounced. The adaptive changes of <em>5HT</em>3 receptor expression constitute a part of the complex regulatory pattern of <em>5HT</em> receptors in <em>5HT</em>T knockout mice.

The rostral ventromedial medulla (RVM) is an important mediator of the supraspinal component of opioid antinociception. Previous studies have suggested that activation of the cloned mu- and delta-opioid receptors (MOR1 and DOR1 respectively) in the RVM produces the antinociception mediated by spinally projecting neurons. In the present study, we investigated the expression of mRNA encoding either MOR1 or DOR1 in the RVM of rats. In addition, we examined quantitatively the expression of MOR1 and DOR1 mRNAs in spinally projecting RVM neurons including serotonergic (<em>5HT</em>) cells by using in situ hybridization, immunocytochemistry, retrograde tract-tracing, and the physical disector. Brainstem neurons were labeled in 14 male Sprague-Dawley rats by applying Fluoro-Gold (FG) topically to the dorsal surface of the lumbosacral spinal cord. Five-micrometer-thick cryostat sections were cut and in situ hybridization was performed by using full-length cRNA probes labeled with 35S-UTP. We found that 43% of RVM projection neurons expressed MOR1 mRNA and 83% of RVM projection neurons expressed DOR1 mRNA. Of 192 retrogradely labeled cells in the RVM, 51 cells (27%) were immunoreactive for <em>5HT</em>. Of this population, half appeared to be labeled for the mRNA encoding MOR1 and over three-fourths appeared to be labeled for the mRNA encoding DOR1. Thus, we conclude that bulbospinal neurons express MOR1 and DOR1; moreover, MOR1 and DOR1 are expressed by significant proportions of <em>5HT</em> neurons projecting to or through the dorsal spinal cord.

An invertebrate glutamate-gated chloride channel (GluCl) has recently been crystallized in an open-pore state. This channel is homologous to the human Cys-loop receptor family of pentameric ligand-gated ion channels, including anion-selective GlyR and GABAR and cation-selective nAChR and <em>5HT</em>(3). We implemented molecular dynamics (MD) in conjunction with an elastic network model to perturb the X-ray structure of GluCl and investigated the open channel stability and its ion permeation characteristics. Our study suggests that TM2 helical tilting may close GluCl near the hydrophobic constriction L254 (L9'), similar to its cation-selective homologues. Ion permeation characteristics were determined by Brownian dynamics simulations using a hybrid MD/continuum electrostatics approach to evaluate the free energy profiles for ion transport. Near the selectivity filter region (P243 or P-2'), the free energy barrier for Na(+) transport is over 4 k(B)T higher than that for Cl(-), indicating anion selectivity of the channel. Furthermore, three layers of positivity charged rings in the extracellular domain also contribute to charge selectivity and facilitate Cl(-) permeability over Na(+). Collectively, the charge selectivity of GluCl may be determined by overall electrostatic and ion dehydration effects, perhaps not deriving from a single region of the channel (the selectivity filter region near the intracellular entrance).

In the present study, we have evaluated the visceral analgesic property of buspirone, a <em>5HT</em>(1A) receptor partial agonist, on colorectal distension-induced mean arterial pressure and behavioral changes in anesthetized and awake Wistar rats, respectively. The selection of the rat strain was based on the observation that anesthetized Wistar rats exhibited a more prominent mean arterial pressure change in response to colorectal distention when compared to other strains (Sprague-Dawley, Wistar-Kyoto and Spontaneously Hypertensive). Buspirone dose-dependently (0.1-1 mg/kg, i.v.) antagonized mean arterial pressure change over a range of distensions (10-90 mmHg). In parallel studies conducted in awake animals, buspirone (1-5 mg/kg, s.c.) attenuated the abdominal withdrawal response, a nociceptive behavior, in response to colorectal distension. This effect was antagonized by co-administration of the 5-HT(1A) receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide (WAY-100635) (5 mg/kg, s.c.). We conclude that buspirone exhibits significant visceral analgesic property in two models of abdominal nociception.

The influence of endothelium on relaxation induced by glyceryl trinitrate (GTN) and isoprenaline (I) has been studied in isolated rabbit aortic ring preparations, in the resting state and after constriction with 5-hydroxytryptamine (<em>5HT</em>). In resting preparations relaxant responses to GTN and I were smaller in the presence of endothelium. In preparations constricted with <em>5HT</em> relaxant responses to GTN and I were conversely greater in the presence of endothelium. These paradoxical findings are discussed in relation to basal release of endothelium derived relaxant factor.

Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT(1) and 5-HT(2) receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate l-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3x150mg/kg, i.p.) partially attenuated TRIM (50mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3mg/kg i.p, a 5-HT(2) receptor antagonist) or ketanserin (5mg/kg i.p, a <em>5HT</em>(2A/2C) receptor antagonist) prevented the effect of TRIM (50mg/kg) in the FST. WAY 100635 (0.1mg/kg i.p, a selective 5-HT(1A) receptor antagonist) and GR 127935 (3mg/kg i.p, a selective 5-HT(1B/1D) receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT(2) receptors while non-significant effects were obtained with 5-HT(1) receptors.

The feasibility of in vivo serotonin <em>5HT</em>(2) receptor binding measurement using [18F]altanserin as a radioligand has been well established. In this study, the postsynaptic receptor binding potential of this ligand was examined as a possible indicator of synaptic serotonin content after pharmacological challenge. Studies were performed in 11 subjects with a history of recurrent major depression. Six of them received serotonergic antidepressive treatment at the time of the experiment, the other five patients were untreated. Two PET measurements were carried out in each subject within 2 or 3 days. Before one of the measurements, 25 mg of the serotonin re-uptake inhibitor clomipramine were given intravenously, the other measurement was done without pharmacological challenge. The data were analyzed using non-linear least-square regression and Logan's graphical method. In the whole group of subjects, binding potential and distribution volume of altanserin decreased following clomipramine challenge. The decrease was between 14 (P=0.03) and 23% (P=0.004). This effect was mainly seen in subjects not on antidepressive medication. Clomipramine challenge probably increased the synaptic serotonin level, which competed with altanserin leading to the lowered binding potential. The paradigm might, thus, be useful to estimate serotonin release in vivo. Pretreatment with serotonergic antidepressants reduces the effect of clomipramine.

BACKGROUND

Selective serotonin reuptake inhibitors (SSRIs) alleviate many affective disturbances in human clinical populations and are used in animal models to study the influence of serotonin (5-HT) on aggressive behavior and impulsivity.

OBJECTIVE

We hypothesized that long-term SSRI treatment may reduce aggressive behavior escalated by alcohol consumption in mice. Therefore, aggression was tested in male CFW mice to determine whether repeated citalopram (CIT) administration reduces alcohol-heightened aggression.

METHODS

Resident male mice self-administered alcohol by performing an operant response on a panel placed in their home cage that delivered a 6% alcohol solution. Mice repeatedly confronted an intruder 15 min after self-administration of either 1 g/kg alcohol (EtOH) or water (H(2)O). Aggressive behaviors were higher in most mice when tests occurred after EtOH intake relative to H(2)O. Once baseline aggression was established, animals were injected (i.p.) twice daily with 10 mg/kg CIT or saline (SAL) for 32 days. Every 4 days throughout the CIT treatment period, aggressive encounters occurred 6 h after CIT injections, with testing conditions alternating between EtOH and H(2)O intake.

RESULTS

Aggression was only modestly affected by CIT in the first 2 weeks of treatment. However, by day 17 of CIT treatment, alcohol-heightened aggressive behavior was abolished, while baseline aggression remained stable. These data lend support for the role of the 5-HT transporter in the control of alcohol-related aggressive behavior, and the time course of effects suggests that a change in density of <em>5HT</em>(1A) autoreceptors is necessary before antidepressant drugs produce beneficial outcomes.