The serotonergic (<em>5HT</em>) system plays a key role in modulating behaviors, such as appetite and anxiety and has been implicated in many human disorders of mood and mind. Recent studies have begun to identify the signaling molecules and transcriptional cascades governing <em>5HT</em> neuron development in the hindbrain. Already at early stages, local differences in requirements of <em>5HT</em> neuron development have become apparent. These studies point toward cryptic heterogeneity amongst <em>5HT</em> neurons and suggest that <em>5HT</em> neuron determination and differentiation may be more flexible and less absolute biologic processes than might have been expected. Ultimately, the intrinsic heterogeneity and environmental sensitivity of <em>5HT</em> neurons may help explain the variability observed in some human behavioral disorders, such as autism spectrum disorder, and the less predictable behavioral consequences of fetal alcohol syndrome.

The pathophysiology of obsessive-compulsive disorder (OCD) remains unknown. However, increasing attention has been paid to the putative role of the serotoninergic system, the strongest evidence being based on the widely demonstrated efficacy of serotonin (<em>5HT</em>) reuptake inhibitor antidepressants in the treatment of OCD. The therapeutic effects are correlated with changes in peripheral parameters of <em>5HT</em> function, which have been found to be altered in OCD, suggesting the possibility of reduced <em>5HT</em> reuptake capacity. This could reflect a compensatory mechanism presumably due to decreased availability of extracellular <em>5HT</em>, as evidenced by data derived from direct assessment of central <em>5HT</em> neurotransmission. The development of new neurochemical probes that explore the sensitivity of various <em>5HT</em> receptor subtypes has provided precious information. m-Chlorophenylpyperazine (m-CPP), an agonist to <em>5HT</em>1A, <em>5HT</em>1D, and <em>5HT</em>2C receptors, and which also blocks <em>5HT</em>3 receptors, exacerbates OC symptoms. In contrast, neither MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), a <em>5HT</em>1A and <em>5HT</em>2C receptor agonist, nor ipsapirone or buspirone, which acts as an agonist to <em>5HT</em>1A receptors, have any effect on OC symptom severity. This suggests the potential implication of the <em>5HT</em>1D receptor, as shown by the aggravation of OC manifestations in response to sumatriptan, a selective <em>5HT</em>1D receptor agonist. The <em>5HT</em>3 plays no specific role, given the lack of influence of the <em>5HT</em>3 antagonist ondansetron, on OC symptom intensity. Further studies are required to elucidate the pharmacological molecular determinants of the putative <em>5HT</em>1D receptor dysfunction.

The biochemical and behavioural effects of acute, 5, 15 and 25 days treatment with chlordiazepoxide (CDP, 5 mg/kg) were examined in the rat. After 5 days of drug treatment, 5-hydroxytryptamine (<em>5HT</em>) levels in the midbrain, hypothalamus and cortex were significantly higher than those of the corresponding controls, and the level of 5-hydroxyindoleacetic acid (5HIAA) was significantly lower, indicating reduced turnover. After 15 days of drug treatment, 5HIAA levels were significantly elevated, compared with the controls, possibly indicating that CDP was blocking the transport of 5HIAA from the brain. This effect appears to be independent of the reduced turnover. After 25 days of drug treatment there were no significant differences compared with the controls. There were no marked changes in noradrenaline and dopamine in any of the areas investigated. It appears that the reduction in <em>5HT</em> turnover is linked to the anxiolytic effects of CDP; the latter were found after 5 days of drug treatment, but not after 15 or 25 days, using the social interaction test of anxiety.

Sertraline is a new, selective serotonin (<em>5HT</em>) uptake inhibitor with antidepressant activity. The effect of chronic administration of sertraline on <em>5HT</em>-2 receptors in rat cortex was compared with that of the tricyclic antidepressant, amitriptyline. <em>5HT</em>-2 receptors were evaluated in binding assays using [3H]-ketanserin and in functional assays of transmembrane signaling, hydrolysis of phosphoinositides. The daily injection of 17 mg/kg sertraline induced a desensitization of <em>5HT</em>-2-mediated phosphoinositide hydrolysis after 28, but not 21, days. The administration of 1.2 mg/kg/day via continuous release pumps caused a more rapid desensitization. Amitriptyline administered chronically also produced a desensitization of the <em>5HT</em>-2-mediated phosphoinositide hydrolysis response. A decrease in the density of <em>5HT</em>-2 binding sites accompanies the functional desensitization after amitriptyline, but changes in <em>5HT</em>-2 binding sites were not detected after chronic sertraline administration. Studies of the mechanism of action of sertraline show that the desensitization of the phosphoinositide hydrolysis response is homologous in nature, and that it is not secondary to changes in the synthesis of precursor lipids. Other possibilities such as alterations in coupling efficiency or in the activity of effector enzymes are currently being considered. The present results suggest a new postsynaptic action of antidepressant drugs at central <em>5HT</em>-2 receptors (i.e., changes in <em>5HT</em>-2 signal transduction at a site distal to the cell surface binding site) and illustrate the importance of studies of receptor signaling pathways to complement radioligand binding.

Spontaneous cellular reorganisation at the lesion site has been investigated following massive spinal cord compression injury in adult rats. By 2 days post operation (p.o.), haemorrhagic necrosis, widespread axonal degeneration, and infiltration by polymorphnuclear granulocytes and OX42-positive macrophages were observed in the lesion site. By 7 days p.o., low affinity nerve growth factor receptor-positive Schwann cells, from activated spinal roots, were identified as they migrated far into the lesion. Between 7 and 14 days p.o., the overlapping processes of Schwann cells within the macrophage-filled lesion formed a glial framework which was associated with extensive longitudinally orientated ingrowth by many neurofilament-positive axons. Relatively few of these axons were calcitonin gene-related peptide (CGRP)-, substance P (SP)-, or serotonin (<em>5HT</em>)-positive; however, many were glycinergic or gamma aminobutyric acid (GABA)ergic. At 21 and 28 days p.o. (the longest survival times studied), a reduced but still substantial amount of orientated Schwann cells and axons could be detected at distances of up to 5 mm within the lesion. Glial fibrillary acidic protein (GFAP) immunoreactivity demonstrated the slow formation of astrocytic scarring which only became apparent at the lesion interface between 21 and 28 days p.o. The current data suggest the possibility of developing future therapeutic strategies designed to maintain or even enhance these spontaneous and orientated regenerative events.

Multi-channel, multi-neuron recording procedures were used to monitor simultaneously the spike train activity of single neurons (n=7-16 cells/animal) in the dorsal raphe (DR) nucleus of the awake, freely moving rat. Putative serotonergic and non-serotonergic neurons were distinguished from one another on the basis of established criteria, i.e. waveform shape and duration, firing pattern and firing frequency. As a group, presumed serotonergic neurons exhibited low tonic discharge rates, depressed firing after serotonin (<em>5HT</em>)-1a agonist administration, and, except for the transition from sleep to waking, a general insensitivity to specific sensory or motor events. By contrast, non-serotonergic cells in midline and lateral wing sub-regions of the nucleus displayed responses to a variety of sensorimotor events including locomotion, grooming, head movement, chewing, auditory stimuli, and whisker movement (both passive and active). However, within this latter group, the sensorimotor response repertoire of individual cells was not uniform. Likewise, non-<em>5HT</em> cells with diverse response profiles were identified in both medial and lateral sub-regions of the nucleus. Cells categorized as non-serotonergic also had varied responses to <em>5HT</em>1a agonist administration. These results emphasize the diverse input/output relationships of individual DR neurons and underscore the need for a more comprehensive analysis of such properties under waking conditions in order to obtain a better understanding of the role of the DR nucleus in brain function.

A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (P < 0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, <em>5HT</em>(2A), and <em>5HT</em>(2C) polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (P < 0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype.

To further evaluate the effects and mechanism of action of the putative serotonin agonist m-chlorophenylpiperazine (m-CPP) in humans, changes in plasma prolactin, cortisol, growth hormone, ACTH and body temperature were studied in a group of 10 healthy volunteers following oral administration of m-CPP (0.75 mg/kg), before and after pretreatment with the serotonin receptor antagonist metergoline (MTG). M-CPP produced transient significant increases in plasma prolactin, cortisol, ACTH and in body temperature, but did not significantly alter plasma growth hormone concentration. Moreover, pretreatment with the <em>5HT</em> antagonist metergoline blocked the m-CPP-induced hormonal and temperature changes. These findings provide strong support for m-CPP's effects in humans being mediated through an interaction with <em>5HT</em> receptors, and thus support the usefulness of m-CPP as a pharmacologic tool for studying disease and drug-induced alterations in serotonin function in man.

Serotonin (<em>5HT</em>) transporters (SERTs) couple to existing ion gradients to transport <em>5HT</em> into presynaptic terminals. In mammalian SERTs, the transport cycle is reported as electroneutral, with a translocation of zero net charge, and <em>5HT</em> uptake is independent of membrane voltage. Yet mammalian SERTs exhibit <em>5HT</em>-induced currents, and Drosophila SERTs (dSERTs) show voltage-dependent uptake. Thus, the relationship between uptake and current remains controversial; furthermore, the number of <em>5HT</em> molecules translocated per ion channel event is unknown. To investigate this, we have used heterologous expression of cloned dSERTs to measure <em>5HT</em> flux and dSERT currents concurrently under voltage clamp, and we have used fluctuation analysis to measure the size of the elementary ionic events in the same cells. RNA-injected Xenopus oocytes accumulate <em>5HT</em>, and paroxetine or desipramine inhibit this uptake. RNA-injected oocytes also display paroxetine-sensitive <em>5HT</em>-induced currents and <em>5HT</em>-independent leak currents. Na replacement decreases the uptake and the induced currents. <em>5HT</em>-induced current and <em>5HT</em> uptake both increase at negative potentials, where <em>5HT</em> carries approximately 5% of the induced current. Recently, several groups have reported similar phenomena for other transporters, in which transmitter-induced currents exceed the predictions of coupled transport. We now provide evidence that in dSERT, approximately 500 <em>5HT</em> molecules are translocated per channel opening, which, at -20 mV, carries approximately 10,000 electronic charges. These data support a model in which 500 SERT cycles occur for each <em>5HT</em>-induced channel opening or a model in which 500 <em>5HT</em> molecules and 10,000 electronic charges pass through a common pore.

We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5-HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X-ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5-HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand-binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT-<em>5HT</em> and hSERT-escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies.

Serotonin (<em>5HT</em>) and substance P (SP) are colocalized in terminals within the nucleus tractus solitarius (NTS). The purpose of the present study was to determine the origin of these terminals. <em>5HT</em>- and SP-immunoreactivities (IR) were visualized using dual-colour immunofluorescence histochemistry with amino-4-methylcoumarin-3-acetic acid- and fluorescein isothiocyanate-conjugated secondary antisera, while NTS-afferent neurons were visualized by retrograde labelling with rhodamine beads. Extensive colocalization of <em>5HT</em>- and SP-IR was seen in NTS-afferent neurons located in the nucleus raphe pallidus, nucleus raphe obscurus, nucleus raphe magnus, and in the parapyramidal region. Over 80 per cent of the SP-IR NTS-afferent neurons contained <em>5HT</em>-IR, while 68 per cent of the <em>5HT</em>-IR neurons contained SP-IR. Thus, <em>5HT</em>- and SP-IR are extensively colocalized in NTS-afferent neurons in the medullary raphe nuclei and associated areas of the ventral medulla.

The modulation of synaptic plasticity by serotonin type II (5-hydroxytryptamine type II (5-HT(2)))-receptor stimulation was explored using intracellular, field potential and Fura-2 fluorescence image recordings in a rat amygdala slice preparation. Bath application of <em>5HT</em>(2) receptor agonist 1-(2,5)-dimethoxy-4-iodophen-2-aminopropane (DOI) transformed theta-burst-stimulated (TBS) synaptic plasticity from short-term potentiation to long-term potentiation. DOI enhanced N-methyl-D-aspartate (NMDA) receptor-mediated potentials and calcium influx without affecting the resting membrane potential or input resistance of the neurons. In contrast, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor-mediated excitatory synaptic responses were unaffected by DOI. The facilitating effects of DOI were blocked by the 5-HT(2) receptor antagonist, ketanserin, and by the 5-HT(2C)-receptor selective antagonist, RS102221. These results indicate that 5-HT(2)-receptor activation enhances NMDA receptor-mediated synaptic function in the basolateral amygdala (BLA).

The excitability of hypoglossal (XII) motoneurons innervating genioglossal muscles is markedly suppressed during the rapid-eye-movement (REM) stage of sleep. This may contribute to airway obstructions in sleep apnea patients. Based on our earlier studies in decerebrate cats using injections of carbachol into the pons to induce a REM sleep-like atonia and microinjections of serotonin (<em>5HT</em>) into the XII motor nucleus, we hypothesized that a sleep-related withdrawal of the serotonergic excitatory input to XII motoneurons may play a major role in these processes. To test one aspect of this hypothesis, we inserted microdialysis probes into the XII nucleus region of decerebrate, paralyzed, vagotomized and artificially ventilated cats. The probes were perfused without or with the addition of a <em>5HT</em> reuptake blocker, clomipramine. The levels of <em>5HT</em> and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined using HPLC and electrochemical detection in dialysate samples collected over successive 20 min periods under four successive experimental conditions: control (at least 2 h after probe insertion); during the postural atonia and respiratory depression produced by pontine microinjection of carbachol; recovery from the effects of carbachol produced by pontine microinjection of atropine; and, to verify that the presence of <em>5HT</em> in the dialysate was related to the activity of serotonergic cells of the brainstem, following administration of 8-OH-DPAT, a <em>5HT</em> 1A receptor agonist known to suppress activity in the serotonergic cells of the raphe system. After correcting for recovery rates of individual probes, the mean control <em>5HT</em> level in the extracellular space of the XII nucleus region was 7.9 +/- 4.4 nM (S.D.) in eight experiments without reuptake blockers. During the carbachol-induced depression, it was reduced to 70 +/- 20% of the pre-carbachol level. It increased to the original control level 98 +/- 27% after pontine injection of atropine. 8-OH-DPAT reduced the <em>5HT</em> level to 43 +/- 14% of the post-atropine level. Changes in the 5HIAA level were not as consistent as for <em>5HT</em> and did not reach statistical significance under any of the experimental conditions. Thus, a functionally significant amount of <em>5HT</em> is present in the extracellular space within the XII nucleus region, and its decrement during carbachol-induced, REM sleep-like atonia is likely to reflect that occurring during natural REM sleep; this may contribute to the decreased tone of upper airway muscles and airway patency.

BACKGROUND

Genetic polymorphisms that influence serotonin (5-hydroxytryptamine, <em>5HT</em>) neurotransmission are candidates for contributing to susceptibility to posttraumatic stress disorder (PTSD). The objective of our study was to determine if a variable length polymorphism for the promoter regions of the <em>5HT</em> transporter (<em>5HT</em>TLPR), and/or a substitution polymorphism in the promoter region for the <em>5HT</em>2A receptor, would be associated with PTSD in a trauma exposed population of adult African-Americans.

METHODS

Using a case control design, 118 participants recruited from the primary care clinics and the campus of a historically black university who met inclusion criteria including trauma exposure provided blood samples for genomic DNA. PTSD criteria were determined by the Clinician Assessment of PTSD Scale (CAPS) and criteria for other psychiatric disorders by the Structured Clinical Interview for DSM-IV (SCID). <em>5HT</em>TLPR and <em>5HT</em>2A-1438A/G were genotyped using established methods. Associations of genotypes with lifetime PTSD, and models testing associations of allele "dose", were analyzed.

RESULTS

Fifty-five (47%) participants met lifetime criteria for PTSD and 26 (22%) met criteria for (mostly comorbid) major depression. The <em>5HT</em>2A (lower expressing) G allele was significantly associated with PTSD. We did not find significant associations with <em>5HT</em>TLPR.

CONCLUSIONS

Our findings suggest a relationship between genetic variation in the <em>5HT</em>2A promoter region and PTSD.

Monocyte chemotactic protein-1 (MCP-1) and MCP-3, the most active and representative compounds of the CC chemokine family, are proinflammatory cytokines that attract and activate specific types of leucocytes. We have used highly purified isolated rat peritoneal mast cells (RPMC) cultured for different lengths of time with and without MCP-1 (200, 100, 50 and 25 nM). Our data clearly show that MCP-1 (200 nM) causes a marked release of [3H]serotonin ([3H]<em>5HT</em> and histamine, which reach a peak at 40 min of incubation (56.6 +/- 5.3 and 34.7 +/- 6 above the control, respectively). In dose-response experiments, MCP-1 (200, 100, 50, 25, 12.5, 6.25 and 3.12 nM) provoked a dose-dependent release of [3H]<em>5HT</em> and histamine from RPMC, which was maximum at 200 nM. After preparation of the histidine decarboxylase (HDC) probe, a Northern blot analysis was determined for HDC mRNA. After 4 hr, steady-state levels of HDC mRNA were induced in a dose-dependent manner by MCP-1 (200-25 nM), compared to the controls. However, MCP-1 failed to prime RPMC in [3H]<em>5HT</em> and histamine release when C48/80 (0.05 micrograms/ml) or anti-IgE was used. In contrast, murine interleukin-3 (IL-3) in combination with MCP-1 (200 and 100 nM) provoked a greater release of histamine and [3H]<em>5HT</em> than the compounds alone. Moreover, RPMC treated with MCP-1 (200 nM) showed, under light microscopy (20x), greater clump formation, a phenomenon absent in the controls (untreated cells). The electron microscope studies revealed that treatment with MCP-1 (200 nM) promoted binding of RPMC and clearly demonstrated a communication between the cytoplasms of adjacent mast cells. Our report describes additional biological activities for MCP-1, suggesting for the first time that this human monocyte chemoattractant plays a fundamental role in histamine and serotonin release and cell aggregation in rat peritoneal mast cells.

In the rat inferior vena cava preincubated with 3H-noradrenaline, the effects of nine serotonin (5-HT) receptor agonists and of eight antagonists (including two beta-adrenoceptor blocking agents) on the electrically evoked 3H overflow were determined. 1. 5-HT, 5-carboxamido-tryptamine, 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (RU 24969), 5-methoxytryptamine, N,N-dimethyl-<em>5HT</em>, tryptamine and 5-aminotryptamine inhibited the evoked 3H overflow. The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for 5-HT1B binding sites, but not with their affinities for 5-HT1A, 5-HT1C or 5-HT2 binding sites. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, and ipsapirone, a partial agonist at these receptors, did not inhibit overflow. 2. Cyanopindolol facilitated the evoked 3H overflow, an effect which was abolished by propranolol. The maximum inhibition of overflow obtainable with 5-HT was diminished by cyanopindolol. 3. The concentration-response curve for 5-HT was shifted to the right by metitepine, metergoline, quipazine, 6-chloro-2-(1-piperazinyl)pyrazine (MK 212) and propranolol which, given alone, did not affect 3H overflow. The apparent pA2 values of these antagonists tended to be correlated with their affinities for 5-HT1B (but not 5-HT1A, 5-HT1C or 5-HT2) binding sites. Ketanserin, a 5-HT2 receptor antagonist, and spiperone, which blocks 5-HT2 and 5-HT1A but not 5-HT1B or 5-HT1C receptors, failed to antagonize the effect of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

IBS is a complex disorder that encompasses a wide profile of symptoms. Current drug treatments for irritable bowel syndrome (IBS) are of limited value. Many target specific symptoms only. Tegaserod, a <em>5HT</em>(4) partial agonist, represents a novel mechanism of action in the treatment of IBS.

OBJECTIVE

The objective of this review was to evaluate the efficacy and tolerability of tegaserod for the treatment of IBS in adults and adolescents aged 12 years and above.

METHODS

MEDLINE 1966-November 2002 and EMBASE 1980-November 2002 were searched. The text and key words used included "tegaserod", "HTF 919", "irritable bowel", and "colonic diseases, functional". The Cochrane Central Register of Controlled Trials, the Inflammatory Bowel Disease Review Group Specialized Trials Register, and Science Citation Index were also searched. Proceedings from the British Society of Gastroenterology Annual Meeting, and Digestive Disease Week (1998-2002) were hand searched. The manufacturer of tegaserod was contacted. Relevant articles were retrieved, and their reference lists were also reviewed.

METHODS

Randomised or quasi-randomised controlled trials comparing tegaserod with placebo, no treatment or any other intervention (pharmacological or non-pharmacological) in subjects aged 12 years and above with a diagnosis of IBS, focusing on clinical endpoints were considered for review.

METHODS

Study inclusion and exclusion, data extraction and quality assessment was undertaken by two reviewers independently. Meta-analysis was performed where study populations, designs, outcomes, and statistical reporting allowed combination of data in a valid way, using the summary statistic relative risk with 95% CI. Eight short-term placebo-controlled studies fulfilled our inclusion criteria. These were predominantly conducted in women. Seven studies evaluated the efficacy of tegaserod on global gastrointestinal (GI) symptoms in patients with constipation-predominant IBS (C-IBS). One small study evaluated safety in patients with diarrhoea-predominant IBS.

RESULTS

The relative risk (RR) of being a responder in terms of global relief of GI symptoms was significantly higher with tegaserod 12 mg (RR 1.19, 95% CI 1.09, 1.29) and tegaserod 4 mg (RR 1.15, 95% CI 1.02, 1.31) compared with placebo, with a number needed to treat (NNT) of 14 and 20 respectively. When all tegaserod doses were combined and compared with placebo (n=4040), the RR of being a responder was 1.17 (95% CI 1.08, 1.27), with a NNT of 17. Although the pooled results indicate statistically significant benefit with tegaserod, the a priori minimal clinically important differences set in two of the four pooled studies were not reached. Tegaserod did not significantly improve the patients' individual symptoms of abdominal pain and discomfort although bowel habit showed a statistically significant improvement with tegaserod 4 mg and there was a non-significant trend in favour of tegaserod 12 mg. When GI symptoms were assessed separately, those indicative of GI motility such as number of bowel movements and days without bowel movements were generally improved with tegaserod although the proportion of patients experiencing diarrhoea was significantly higher in the tegaserod 12 mg group compared with placebo (RR 2.75, 95% CI 1.90, 3.97), with a number needed to harm (NNH) of 20. Effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies.

CONCLUSIONS

Tegaserod appears to improve the overall symptomatology of IBS but there are currently few data on its effect on quality of life. In addition, more information is needed about its efficacy in men. It would also be of interest to know whether treatment with tegaserod leads either directly, or indirectly, to changes in visceral sensitivity or psychopathology, which are also considered important in the pathophysiology of this condition.

The neurotoxic properties of 6-hydroxydopamine and 5,7-dihydroxytryptamine are reviewed. The neurochemical responses of the dopaminergic and serotonergic systems after methamphetamine (METH) are reported. METH decreased activities of tyrosine hydroxylase and tryptophan hydroxylase; concentrations of dopamine (DA) and 5-hydroxytryptamine (<em>5HT</em>) and their respective metabolites were decreased in parallel with the decline in activity of the enzymes. When a variety of pharmacologic or surgical procedures were used to decrease DA content prior to administration of METH, the effects of METH were attenuated. From these data it is inferred that DA is essential for the METH-induced response. 3,4-Methylenedioxymethamphetamine (MDMA) produced similar effects which were also DA-dependent. Evidence for a role of glutamate and oxidative stress in the neurotoxicity of the amphetamines is presented.

In the tobacco hornworm, Manduca sexta, 5-hydroxytryptamine (<em>5HT</em>) acting at the level of the antennal lobes contributes significantly to changing the moth's responsiveness to olfactory stimuli. <em>5HT</em> targets K(+) conductances in the cells, increasing the excitability of central olfactory neurons and their responsiveness to olfactory cues. Effects of <em>5HT</em> modulation are apparent not only at the single cell level, but also in the activity patterns of populations of neurons that convey olfactory information from antennal lobes to higher centers of the brain. Evidence suggests that <em>5HT</em>-induced changes in activity within neural circuits of the antennal lobes might also drive structural plasticity, providing the basis for longer-term changes in antennal lobe function.

The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioural and psychological symptoms of Alzheimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, <em>5HT</em>, and dopamine.

Neonatal exposures to organophosphates that are not acutely symptomatic or that produce little or no cholinesterase inhibition can nevertheless compromise the development and later function of critical neural pathways, including serotonin (<em>5HT</em>) systems that regulate emotional behaviors. We administered parathion to newborn rats on postnatal days (PN) 1-4 at doses spanning the threshold for detectable cholinesterase inhibition (0.1 mg/kg/day) and the first signs of loss of viability (0.2 mg/kg/day). In adolescence (PN30), young adulthood (PN60) and full adulthood (PN100), we measured radioligand binding to <em>5HT</em>(1A) and <em>5HT</em>(2) receptors, and to the <em>5HT</em> transporter in the brain regions comprising all the major <em>5HT</em> projections and <em>5HT</em> cell bodies. Parathion caused a biphasic effect over later development with initial, widespread upregulation of <em>5HT</em>(1A) receptors that peaked in the frontal/parietal cortex by PN60, followed by a diminution of that effect in most regions and emergence of deficits at PN100. There were smaller, but statistically significant changes in <em>5HT</em>(2) receptors and the <em>5HT</em> transporter. These findings stand in strong contrast to previous results with neonatal exposure to a different organophosphate, chlorpyrifos, which evoked parallel upregulation of all three <em>5HT</em> synaptic proteins that persisted from adolescence through full adulthood and that targeted males much more than females. Our results support the view that the various organophosphates have disparate effects on <em>5HT</em> systems, distinct from their shared property as cholinesterase inhibitors, and the targeting of <em>5HT</em> function points toward the importance of studying the impact of these agents on <em>5HT</em>-linked behaviors.

Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (<em>5HT</em>) subtype 2B receptors (<em>5HT</em>2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting <em>5HT</em>2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these <em>5HT</em> and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

Nicotinic receptors containing alpha7 subunits are widely distributed in the central nervous system and are thought to be involved in a number of functions. However, it has been difficult to study alpha7-containing receptors in vivo because of a paucity of selective agonists. A new spirooxazolidinone compound, AR-R17779, was recently described as potent agonist at alpha7 receptors, but electrophysiological studies at other types of nicotinic receptors have not been carried out. We characterized the activity of AR-R17779 at alpha7, alpha4beta2, alpha3beta4, alpha3beta2, alpha3beta2alpha5 receptors expressed in Xenopus oocytes. In addition, since there is significant homology between nicotinic alpha7 and serotonin <em>5HT</em>(3) receptors, the activity of AR-R17779 at expressed <em>5HT</em>(3a) receptors was also examined. Finally, actions of tropisetron and ondansetron, two <em>5HT</em>(3) antagonists, were explored. AR-R17779 was found to activate alpha7 receptors, but had no activity at other types of nicotinic receptors, and also had no activity at <em>5HT</em>(3a) receptors. Tropisetron activated, while ondansetron acted as an antagonist, at alpha7 nicotinic receptors. The two <em>5HT</em>(3) antagonists also acted as antagonists at alpha4beta2 and alpha3beta4 nicotinic receptors. Thus, AR-R17779 was confirmed to be a selective nicotinic alpha7 receptor agonist and to be without activity at <em>5HT</em>(3) receptors. In contrast, the actions of tropisetron and ondansetron on nicotinic receptors were complex.

Rats, subjected chronically (10-12 weeks) to a variety of mild, unpredictable stressors, showed a decrease in their consumption of weak sucrose solutions; normal behavior was restored by chronic (5-9 weeks) treatment with the tricyclic antidepressant imipramine. Acute administration of the dopamine receptor antagonist pimozide or the specific dopamine D2 receptor antagonist raclopride had no effect in nonstressed animals and in vehicle-treated stressed animals, but both drugs selectively reversed the improvement of performance in imipramine-treated stressed animals. The <em>5HT</em> antagonist metergoline increased sucrose consumption in all groups. The data suggest that the mechanism of action of imipramine in this model is an increase in functional activity at dopamine (DA) synapses.