Immunocytochemical methods were used to define the distribution of enkephalin (ENK), substance P (SP), tyrosine hydroxylase (TH), and serotonin (5-hydroxytryptamine: <em>5HT</em>) in the rat septum. A dense plexus of axons containing enkephalin-like immunoreactivity is found in the intermediate lateral septal nucleus. This is surrounded laterally by SP-containing cell bodies and axons and medially by ENK-containing cell bodies. Both SP- and ENK-immunoreactive axons form pericellular and peridendritic terminal arbors around lateral septal neurons. TH-positive axons are distributed throughout the septum and form dense pericellular terminal baskets around scattered neurons in the medial half of the intermediate lateral septal nucleus and in the extreme lateral septum. Very few SP and TH immunoreactive axons are present in the ENK immunoreactive plexus zone. <em>5HT</em>-immunoreactive axons are most dense at the lateral edge of the ventral and intermediate lateral septal nuclei but form pericellular terminal arbors only in the dorsal lateral septal nucleus, in the septofimbrial nucleus, and in the dorsal cap of the medial septal nucleus. These results indicate that the dorsal and intermediate lateral septal nuclei include three histochemically distinct laminated subfields: (1) an ENK immunoreactive axonal plexus within the lateral aspect of the intermediate lateral septal nucleus, (2) a more medial region of scattered ENK immunoreactive perikarya and similarly scattered TH immunoreactive pericellular baskets, and (3) a dorsolateral zone occupied by SP neurons and <em>5HT</em>-containing pericellular baskets. Thus, the data suggest that SP- and ENK-containing neuronal populations in the lateral septum receive different monoaminergic inputs. Further, the somewhat exclusive laminated pericellular termination of peptide- and catecholamine-containing axons in the lateral septum predicts very different functional and pharmacological properties among zones.

To assess the effects of increased hypothalamic tryptophan (TRP) availability on 5-HT content in preoptic area on thermoregulation and work production during exercise on treadmill, 20.3 microM of L-TRP (n=7) or 0.15M NaCl (n=6) was injected into the lateral cerebral ventricle of male Wistar rats immediately before the animals started running (18 m min(-1) 5% inclination). Exercise time to fatigue (min), and workload (kgm) were analysed. Core temperature was measured by telemetry. At fatigue, brains were quickly removed and preoptic area (POA), hypothalamus (HP), frontal cortex (FC), hippocampi (HC) were rapidly dissected and frozen immediately in dry ice. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured by HPLC. TRP-exercised rats showed the highest content of 5-HT in the POA and the lowest in the hippocampi compared to the rested and SAL-exercised rats. An inverse relationship between TF and a direct correlation with body temperature changes and POA-<em>5HT</em> levels were observed. A correlation between HC 5-HT content and TF was also found. However, there was no correlation between HC 5-HT content and changes in Tb at fatigue. Finally, our results bring further evidences that increased 5-HT content in POA is involved with an increase in heat production during exercise. In addition, the direct correlation of 5-HT level in hippocampi and TF of TRP-exercised rats suggests that this brain area is also related to motor activity control during exercise. In conclusion, our data indicated that tryptophan-induced central fatigue in exercising rats is related to serotonin content in preoptic area.

BACKGROUND

Serotonin (5-hydroxytryptamine, <em>5HT</em>) is involved in hypothalamic regulation of energy consumption. Also, the gut microbiome can influence neuronal signaling to the brain through vagal afferent neurons. Therefore, serotonin concentrations in the central nervous system and the composition of the microbiota can be related to obesity.

OBJECTIVE

To examine adipokine, and, serotonin concentrations, and the gut microbiota in lean dogs and dogs with experimentally induced obesity.

METHODS

Fourteen healthy Beagle dogs were used in this study.

METHODS

Seven Beagle dogs in the obese group were fed commercial food ad libitum, over a period of 6 months to increase their weight and seven Beagle dogs in lean group were fed a restricted amount of the same diet to maintain optimal body condition over a period of 6 months. Peripheral leptin, adiponectin, <em>5HT</em>, and cerebrospinal fluid (CSF-<em>5HT</em>) levels were measured by ELISA. Fecal samples were collected in lean and obese groups 6 months after obesity was induced. Targeted pyrosequencing of the 16S rRNA gene was performed using a Genome Sequencer FLX plus system.

RESULTS

Leptin concentrations were higher in the obese group (1.98 ± 1.00) compared to those of the lean group (1.12 ± 0.07, P = .025). Adiponectin and 5-hydroytryptamine of cerebrospinal fluid (CSF-<em>5HT</em>) concentrations were higher in the lean group (27.1 ± 7.28) than in the obese group (14.4 ± 5.40, P = .018). Analysis of the microbiome revealed that the diversity of the microbial community was lower in the obese group. Microbes from the phylum Firmicutes (85%) were predominant group in the gut microbiota of lean dogs. However, bacteria from the phylum Proteobacteria (76%) were the predominant group in the gut microbiota of dogs in the obese group.

CONCLUSIONS

Decreased <em>5HT</em> levels in obese group might increase the risk of obesity because of increased appetite. Microflora enriched with gram-negative might be related with chronic inflammation status in obese dogs.

Signalling by receptors coupled to heterotrimeric G proteins primarily involves intermediates (G-protein subunits and second messengers) that can reach their targets by diffusion either through the cytosol or within the plane of the membrane. However, in many cases additional proteins have been identified which, by providing a scaffold, link several components of a signal transduction pathway in order to control speed and specificity of signalling. Scaffolding proteins such as PSD-95 or shank/ProSAP proteins organise rather large signalling complexes. Recent proteomic approaches have now been used to study the molecular composition of receptor complexes in detail, for example glutamate receptors and <em>5HT</em>(2C) receptors, providing a much more complicated picture of G-protein-coupled receptor signalling than previously anticipated.

Monoaminergic neurons are present in small numbers and in multiple distinct locations of the vertebrate CNS. They are involved in important functions such as movement coordination, motivation, and the response to environmental stress. However, the mechanisms involved in their subtype specification are not well understood. In this study, we examined the states of forebrain dopaminergic (DA) and serotonergic (<em>5HT</em>) neurons in larval and adult zebrafish of wild type and the too few mutant. The majority of DA and <em>5HT</em> neuronal subgroups that were found in adults were established in the 6-day old larval zebrafish. Rather than affecting all monoaminergic neurons in the forebrain, selective subgroups of these neurons are reduced in the too few mutant, starting from the larval stage. Taken together, our study establishes that similar to DA neurons, distinct subtypes of <em>5HT</em> neurons exist in larval as well as adult zebrafish. The development of a subset of these monoaminergic neurons is dependent on the too few gene product. Thus, this mutant is potentially important for understanding the development as well as the function of forebrain DA and <em>5HT</em> neurons.

BACKGROUND

The serotonergic system has been implicated in emotional processing in animals and humans. Although the contribution of different receptor subtypes has been hypothesised, there have been few direct tests of this in human subjects.

OBJECTIVE

The current study aimed to explore the involvement of the serotonin type 3 (5HT3) receptor subtype in a battery of emotional processing tasks previously found to be sensitive to SSRI administration.

METHODS

Healthy volunteers were randomised to receive the 5HT3 antagonist, ondansetron (12 mg, oral), or placebo in a double blind between groups design. Emotional processing was assessed using three tasks: affective modulation of the startle reflex, emotional categorisation and memory and facial expression recognition. Subjective state ratings, blood pressure and pulse were also collected before and after ondansetron and placebo.

RESULTS

Ondansetron was well tolerated and did not affect subjective measures of mood, anxiety or well-being in these healthy volunteers. However, the emotion potentiated effect was abolished in the volunteers receiving ondansetron. Facial expression recognition and emotional memory were not significantly affected.

CONCLUSIONS

These results suggest an involvement of 5HT3 receptors in certain aspects of fear processing in humans. These effects are consistent with anxiolytic actions of 5HT3 antagonism in animal models and suggest that the 5HT3 receptor may play a role in the effects of serotonergic manipulations on fear and anxiety.

Homo- and heterodimerization is becoming an assessed concept in G-protein coupled receptor (GPCR) pharmacology, and the notion that GPCRs may dimerize or oligomerize is allowing for a reinterpretation of some inconsistencies or anomalies and is providing medicinal chemists with potentially relevant novel molecular targets for a variety of therapeutic conditions. Recently, it has been reported that two unrelated GPCRs, namely class C metabotropic glutamate receptor type-2 (mGluR2) and class A <em>5HT</em>(2A) serotoninergic receptor, can heterodimerize at the transmembrane domain level. We performed a 40 ns molecular dynamics simulation of the mGluR2/<em>5HT</em>(2A) heterocomplex constructed around a TM4/TM5 interface and embedded in an explicit phospholipidic bilayer surrounded by water molecules. In a separate experiment, the monomeric <em>5HT</em>(2A) receptor was simulated for additional 40 ns under the same conditions. The analysis and the comparison of the two simulations allowed us to clearly identify a cross-talk between the two protomers and to put forward an effect of the heterodimerization on the shape of the binding pocket of <em>5HT</em>(2A). This result provides the first molecular explanation for the reported allosteric effect of mGluR2 on <em>5HT</em>(2A)-mediated response and suggests that the heterocomplex can be a more suitable target for in silico screening than the monomeric protomers.

BACKGROUND

The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin <em>5HT</em>(2A) receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically (and prospectively) tested the hypothesis that <em>5HT</em>(2A) antagonism alone results in enhanced cognitive function.

OBJECTIVE

The purpose of this study was to evaluate the selective 5-HT(2A) antagonist, 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function.

METHODS

Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age=9.2 years) and eight aged rhesus macaques (mean age=24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task.

RESULTS

Depending on dose, EMD 281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals.

CONCLUSIONS

These experiments, conducted in a non-human primate model, suggest that selective <em>5HT</em>(2A) antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.

The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of Egr3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (<em>5HT</em>(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of Egr3(-/-) mice. Radioligand binding revealed nearly 70% reduction in <em>5HT</em>(2A)R expression in the prefrontal cortex of Egr3(-/-) mice compared with controls. Egr3(-/-) mice also exhibit a decreased head-twitch response to <em>5HT</em>(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of Egr3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that <em>5HT</em>(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical <em>5HT</em>(2A)R in Egr3(-/-) mice aligns with numerous studies reporting decreased <em>5HT</em>(2A)R levels in the brains of schizophrenia patients, and the gene encoding the <em>5HT</em>(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia.

Antidepressant-sensitive serotonin (5-hydroxytryptamine, <em>5HT</em>) transporters (SERTs) clear the amine from extracellular spaces in the CNS and periphery as a mechanism for transmitter inactivation and recycling. Although it is known that SERTs are preferentially expressed on basolateral domains in transfected epithelial cells, details of the transporter's membrane localization in vivo are lacking. <em>5HT</em> and <em>5HT</em> receptors have been identified in the rodent adrenal gland. Using SERT antagonist autoradiography, we establish the presence of antidepressant-sensitive transport sites in the rat adrenal medulla. Immunofluorescence experiments using antibodies specific for the SERT COOH and NH2 termini, for <em>5HT</em>, or for catecholamine biosynthetic enzymes suggest that SERT mediates intra-cellular <em>5HT</em> accumulation by epinephrine-secreting chromaffin cells. Using confocal microscopy, we establish that SERT expression is nonuniformly distributed along the plasma membrane of chromaffin cells. Notably, SERT immunoreactivity is largely absent from plasma membranes bordering smooth muscle that surrounds vascular sinusoids. Rather, SERT is highly expressed in membranes adjoining other chromaffin cells, consistent with a role for <em>5HT</em> and SERT in autocrine or paracrine control of chromaffin cell physiology. SNAP-25, a t-SNARE protein implicated in neurotransmitter release, was found to colocalize with SERT. In contrast, Na,K ATPase and NCAM are uniformly distributed along the entire perimeter of chromaffin cell membranes. These findings underscore a role for <em>5HT</em> and SERT in adrenal physiology, reveal unrecognized polarity of chromaffin cell plasma membranes, and warrant a consideration of common targeting mechanisms localizing amine transporters near release sites.

Previous findings suggest differences in the neuroanatomical substrates of short- (seconds) vs longer-duration (minutes) fear responses. We now report that phasic and sustained fear can also be differentiated pharmacologically, based on their response to several treatments that either are or are not clinically effective anxiolytics. For these experiments, short- or long-duration clicker stimuli were paired with footshock. Acoustic startle amplitude was later measured in the absence of the clicker, or within seconds (phasic fear) or minutes (sustained fear) of its onset. Before testing, rats received a single injection of vehicle, the benzodiazepine chlordiazepoxide, the <em>5HT</em>(1A) agonist and dopamine D2 antagonist buspirone, the selective serotonin reuptake inhibitor fluoxetine, or a 3-week treatment with either vehicle or fluoxetine. Chlordiazepoxide blocked sustained, but not phasic startle increases. Acute buspirone, which is not anxiolytic in human beings, did not affect sustained startle increases, but did disrupt phasic increases. Chronic fluoxetine blocked sustained startle increases and unreliably reduced phasic increases; acute fluoxetine affected neither. The results indicate that phasic and sustained fear responses can be pharmacologically dissociated, further validating this distinction, and suggest that sustained startle increases may be especially useful as anxiety models and anxiolytic screens.

Cannabinoid (CB) receptors are expressed in the enteric nervous system (ENS) and CB(1) receptor activity slows down motility and delays gastric emptying. This receptor system has become an important target for GI-related drug development such as in obesity treatment. The aim of the study was to investigate how CB(1) ligands and antagonists affect ongoing activity in enteric neurone networks, modulate synaptic vesicle cycling and influence mitochondrial transport in nerve processes. Primary cultures of guinea-pig myenteric neurones were loaded with different fluorescent markers: Fluo-4 to measure network activity, FM1-43 to image synaptic vesicles and Mitotracker green to label mitochondria. Synaptic vesicle cluster density was assessed by immunohistochemistry and expression of CB(1) receptors was confirmed by RT-PCR. Spontaneous network activity, displayed by both excitatory and inhibitory neurones, was significantly increased by CB(1) receptor antagonists (AM-251 and SR141716), abolished by CB(1) activation (methanandamide, mAEA) and reduced by two different inhibitors (arachidonylamide serotonin, AA-<em>5HT</em> and URB597) of fatty acid amide hydrolase. Antagonists reduced the number of synaptic vesicles that were recycled during an electrical stimulus. CB(1) agonists (mAEA and WIN55,212) reduced and antagonists enhanced the fraction of transported mitochondria in enteric nerve fibres. We found immunohistochemical evidence for an enhancement of synaptophysin-positive release sites with SR141716, while WIN55,212 caused a reduction. The opposite effects of agonists and antagonists suggest that enteric nerve signalling is under the permanent control of CB(1) receptor activity. Using inhibitors of the endocannabinoid degrading enzyme, we were able to show there is endogenous production of a CB ligand in the ENS.

BACKGROUND

The cholinergic system is profoundly impaired in senile dementia of Alzheimer type (SDAT) and replacement therapy produces only modest clinical benefits. The serotonergic system is also impaired and may contribute both to cognitive and non-cognitive symptoms in SDAT. To investigate this further we assessed the effects of lowering brain serotonin using the technique of acute tryptophan depletion on cognitive function in patients with SDAT and in age matched control subjects.

METHODS

Sixteen patients with probable SDAT and 17 healthy elderly subjects received two amino acid drinks in a within subject, double-blind, placebo-controlled, counterbalanced, crossover design. One of the drinks was nutritionally balanced and contained tryptophan (placebo), the other was identical but contained no tryptophan. A battery of detailed neuropsychological tests was performed between 4 and 6 h after the drink. Mood rating scales and other ratings of behavioural and emotional symptoms were also performed on both occasions.

RESULTS

Acute tryptophan depletion resulted in impairment on tasks of working memory in both groups. There was no group specific effect. Female SDAT subjects performed better on a task of pattern recognition during acute tryptophan depletion compared with placebo. There were no changes in behavioural symptoms during acute tryptophan depletion in either group.

CONCLUSIONS

Compromised serotonergic function may be an important contributor to cognitive decline in SDAT and in ageing. Strategies targeting specific <em>5HT</em> receptors may be helpful in SDAT.

Acute SSRI (selective serotonin reuptake inhibitor) treatment has been shown to attenuate the abuse-related effects of cocaine; however, SSRIs have had limited success in clinical trials for cocaine abuse, possibly due to neurobiological changes that occur during chronic administration. In order to better understand the role of serotonin (<em>5HT</em>) in cocaine abuse and treatment, we examined the effects of chronic treatment with the SSRI fluoxetine at clinically relevant serum concentrations on cocaine-related neurobiology and behavior. Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans. Self-administration and reinstatement were monitored throughout the treatment and washout period. In vivo microdiaylsis was used to assess changes in dopaminergic and serotonergic neurochemistry. Positron emission tomography was used to assess changes in the <em>5HT</em> transporter and 2A receptor binding potential (BP). Functional output of the <em>5HT</em> system was assessed using prolactin levels. Cocaine-primed reinstatement and cocaine-elicited dopamine overflow were significantly suppressed following chronic fluoxetine treatment. <em>5HT</em>2A receptor BP was increased in the frontal cortex following treatment while prolactin release was blunted, suggesting desensitization of the <em>5HT</em>2A receptor. These effects persisted after a 6-week washout period. Measures of pre-synaptic serotonergic function and cocaine self-administration were unaffected. These data demonstrate that acute and chronic fluoxetine treatments exert different effects on cocaine-related behavior. Furthermore, chronic fluoxetine treatment causes alterations in <em>5HT</em>2A receptors in the frontal cortex that may selectively disrupt cocaine-primed reinstatement. Fluoxetine may not be useful for treatment of ongoing cocaine abuse but may be useful in relapse prevention.

Blood platelets are thought to be a useful peripheral model for investigating the central serotoninergic mechanisms associated with the serotonin transporter (SERT). On the other hand, an in vivo investigation of SERT in the human brain has been made possible by the development of several promising SPECT radioligands, such as [123I]-ADAM. The aim of the present study was to investigate the possible correlation between the SERT measurements in the brain and those in platelets. Forty-four subjects (14 healthy subjects and 30 patients with the diagnosis of major depression or schizoaffective disorder) were examined. The [123I]-ADAM binding was assessed 4h after injection using MR-guided regions of interest (ROIs) in the midbrain and cerebellum. In a parallel investigation, serotonin (<em>5HT</em>) concentration and kinetic characteristics of <em>5HT</em> uptake activity (Vmax and Km) were determined in platelet-rich plasma. Overall, there was no significant correlation between the V(max) of <em>5HT</em> uptake in platelets and the specific to nonspecific partition coefficient of [123I]-ADAM (V''3) in the midbrain. However, low but significant Pearson correlation coefficients were found for V(max) and normalised activities measured in the midbrain (r=0.310, p=0.043). The correlation was stronger and significant in females (n=20, r=0.629, p=0.003) but low and non-significant in the 24 males (r=0.104). Although confirmation is necessary, it seems that the relationship between different indices of [123I]-ADAM binding in the brain and <em>5HT</em> uptake characteristics in platelets is complex, nonuniform, and possibly gender-specific.

These studies confirm and extend the recent work suggesting that [3H]lysergic acid diethylamide (LSD) labels two distinct binding sites in rat brain resembling serotonin (<em>5HT</em>) receptors. Although Scatchard analyses of [3H]LSD binding to membranes prepared from cortex/hippocampus were linear, the heterogeneity of the [3H]LSD binding sites was clearly demonstrated in displacement studies. The displacement curves for both <em>5HT</em> and spiperone were bisigmoidal with the concentration required to saturate the high affinity components nearly 3 orders of magnitude lower than the concentration necessary to saturate the low affinity components. Additivity studies suggested that the sites with high affinity for <em>5HT</em> and spiperone are different, independent sites. These sites are referred to as <em>5HT</em>, and <em>5HT</em>2, respectively. Regional analyses showed, that in the frontal cortex, the density of the <em>5HT</em>2 site was slightly greater than the <em>5HT</em>1 site, whereas the <em>5HT</em>1 site was predominant in all other brain areas, including the spinal cord. The pharmacological properties of the two sites have features in common with <em>5HT</em> receptors; however, electrolytic lesions of the midbrain raphe nuclei did not change the densities or binding constants of the two apparent <em>5HT</em> receptor subtypes, even though the number of high affinity <em>5HT</em> uptake sites was markedly reduced.

Previous studies have demonstrated that multiple methamphetamine (METH) administrations rapidly and reversibly decrease dopamine transporter activity assessed in striatal synaptosomes. A role for reactive oxygen species was suggested by findings that: (1) METH treatment increases the formation of oxygen radicals in vivo; and (2) oxygen radicals, generated by the enzyme xanthine oxidase, attenuate dopamine uptake in vitro. To test the selectivity of transporter responses, the present study examined effects of METH and xanthine oxidase on [3H]serotonin ([3H]<em>5HT</em>) and [3H]glutamate transport into striatal synaptosomes. Multiple doses of METH, or incubation with xanthine oxidase, rapidly attenuated [3H]<em>5HT</em> transport; an effect attributable to a decrease in Vmax. The METH-induced decrease in transport activity completely recovered by 24 h, but was decreased again 1 week later. In contrast, [3H]glutamate transport was essentially unchanged after METH treatment or incubation with xanthine oxidase. These findings indicate that: (1) METH causes a rapid and reversible decrease in <em>5HT</em> transporter activity; and (2) glutamate transporters are less susceptible than <em>5HT</em> transporters to effects of reactive species or METH treatment.

Prior work has demonstrated that spinal cord neurons, isolated from the brain through a spinal transection, can support learning. Spinally transected rats given legshock whenever one hindlimb is extended learn to maintain the shocked leg in a flexed position, minimizing net shock exposure. This capacity for learning is inhibited by prior exposure to an uncontrollable stimulus (e.g., intermittent tailshock). The present experiments examined whether spinal cord neurons are more vulnerable to the adverse effects of uncontrollable stimulation after spinal cord injury. Experiment 1 confirmed that uncontrollable shock inhibits subsequent learning in transected rats. Rats that received uncontrollable stimulation prior to transection did not exhibit this effect, suggesting that brain systems exert a protective effect. Experiment 2 showed that this protective effect was removed if subjects received a dorsolateral funiculus lesion prior to shock exposure. Subsequent experiments were designed to determine the identity of the neurochemical systems that protect spinal plasticity. Intrathecal application of serotonin (5-HT) or a 5-HT 1A/7 agonist (8-OH DPAT) in transected rats had a protective effect that blocked the adverse effect of uncontrollable stimulation (Experiment 3). The alpha-2 noradrenergic agonist, clonidine, also protected plasticity (Experiment 4), but this effect was linked to cross-reactivity at the 5-HT 1A receptor (Experiment 5). Microinjection of a <em>5HT</em> 1A antagonist (WAY 100635) into the spinal cord before intact rats received uncontrollable stimulation blocked the brain-dependent protection of spinal cord neurons. The findings indicate that serotonergic systems normally protect spinal cord plasticity from the deleterious effects of uncontrollable stimulation.

BACKGROUND

Central serotonin (<em>5HT</em>) plays a major role in emotional processing. We used functional neuroimaging (fMRI) to investigate the effects of experimental manipulation of central <em>5HT</em> levels on the regional neural response to happy and sad facial expressions.

METHODS

Ten healthy participants (eight men and two women) were scanned during an implicit emotional processing task after receiving a tryptophan-free (acute tryptophan depletion, ATD) or a balanced amino acid drink in a double-blind design.

RESULTS

ATD lowered total plasma tryptophan concentration by 80%. There was no significant effect on subjective mood ratings, on response accuracy and on reaction times. Compared to sham depletion, ATD attenuated activation in the right medial/inferior frontal gyrus, the posterior cingulate cortex, the occipital and parietal cortex bilaterally, the right hippocampus, claustrum and insula. Conversely, ATD was associated with relatively increased activation in the left inferior frontal gyrus. ATD had differential effects on activation during the processing of happy and sad faces in the right putamen and in the left superior temporal gyrus.

CONCLUSIONS

In both cortical and sub-cortical regions, the neural response associated with processing emotional faces is significantly modulated by <em>5HT</em> manipulation resulting from ATD. Moreover, in certain areas, this effect of <em>5HT</em> depends on the emotional valence of the stimulus.

Previous work has suggested that the serotonergic system plays a key role in "popularity" or likeability. A polymorphism within the <em>5HT</em>-sub(2A) serotonin receptor gene (-G1438A) has also been associated with popularity, suggesting that genes may predispose individuals to particular social experiences. However, because genes cannot code directly for others' reactions, any legitimate association should be mediated via the individual's behavior (i.e., genes->>behaviors->>social consequences), a phenomenon referred to as an evocative gene-environment correlation (rGE). The current study aimed to identify one such mediating behavior. The author focused on rule breaking given its prior links to both the serotonergic system and to increased popularity during adolescence. Two samples of previously unacquainted late-adolescent boys completed a peer-based interaction paradigm designed to assess their popularity. Analyses revealed that rule breaking partially mediated the genetic effect on popularity, thereby furthering our understanding of the biological mechanisms that underlie popularity. Moreover, the present results represent the first meaningfully explicated evidence that genes predispose individuals not only to particular behaviors but also to the social consequences of those behaviors.

Changes in representative dopamine (D(1), D(2), and D(4)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D(1) receptors in the medial and lateral caudate-putamen (22% and 23%, respectively) and increased <em>5HT</em>(1A) receptor binding in the medial-prefrontal (26%) and dorsolateral-frontal cortex (30%). No changes in D(1) or <em>5HT</em>(1A) receptors were detected in other brain regions. These findings suggest that downregulation of striatal D(1) receptors and upregulation of cortical <em>5HT</em>(1A) receptors may contribute to PCP-induced impairment of cognitive functions in rats. Subchronic PCP treatment did not alter levels of D(2), D(4), and <em>5HT</em>(2A) receptors in all brain regions examined, which suggests a minimal role for these receptors in mediating subchronic actions of PCP in adult rats.

The distribution of retinohypothalamic projections and the organization of the suprachiasmatic region of the hypothalamus was investigated in the house sparrow (Passer domesticus). Retinohypothalamic projections (RHT) were studied by two anterograde tracing methods, and hypothalamic organization was investigated immunohistochemically with antisera against a number of substances known to be present in the mammalian suprachiasmatic nucleus (SCN): bombesin (BBS), glutamic acid decarboxylase (GAD), 5-hydroxytryptamine (<em>5HT</em>), neuropeptide Y (NPY), neurotensin (NT), somatostatin (SS), substance P (SP), vasoactive intestinal polypeptide (VIP), and arginine vasopressin (AVP). Observations from these experiments were analysed within the framework of a cytoarchitectural study using Nissl-stained material. From this study, we have identified an area in the anterior hypothalamus which we believe is an avian homologue of the mammalian SCN. This area contains a nucleus located in close apposition to the optic chiasm between the dorsal supraoptic decussation (DSD) and the ventral lateral geniculate body (GLv) for much of its rostrocaudal extent. The central portion of this nucleus contains neurons that exhibit GAD- and BBS-like immunoreactivity and is the terminal field for the RHT. For this reason, we term this nucleus the visual SCN. It also contains axon plexuses exhibiting <em>5HT</em>-like, SP-like, and NPY-like immunoreactivity and is bordered ventrally by AVP-like, SP-like, and NT-like immunoreactive cells and medially by VIP-like and SS-like immunoreactive cells. Although it is not established that these cell groups together compose a single suprachiasmatic nucleus, the organization in the avian brain of a nuclear complex with a retinorecipient area surrounded by nonvisual components would be very similar to that of the mammalian SCN.

Plasma membrane serotonin transporters (SERTs) regulate serotonin (<em>5HT</em>) levels in brain and are a site of action of antidepressants and psychostimulant drugs of abuse. Syntaxin 1A is a component of the synaptic vesicle docking and fusion apparatus and has been shown to interact with multiple plasma membrane neurotransmitter transporters including SERT. Previously, we showed that syntaxin 1A regulates the transport stoichiometry of SERT. When not bound to syntaxin 1A, SERT shows both substrate-independent Na(+) fluxes and substrate-dependent Na(+) fluxes of variable stoichiometry; these fluxes are eliminated in the presence of syntaxin 1A as Na(+) flux becomes strictly coupled to <em>5HT</em> uptake. However, not known are the endogenous signaling molecules that determine the conducting states that SERT exhibits. In the present experiments, we show that inhibitors of calcium/calmodulin-dependent kinase II (CaM kinase II) modulate the stoichiometry of <em>5HT</em> flux and that this effect requires syntaxin 1A. The modulation correlates with a shift in the affinity of SERT for syntaxin 1A binding. The regulation by CaM kinase II is eliminated by a mutation in the N-terminal domain of SERT. In neonatal thalomocortical neurons that endogenously express SERT and syntaxin 1A, inhibition of CaM kinase II reveals SERT-mediated currents. These data suggest that calcium-mediated signals can serve as a trigger for regulating protein-protein interactions that control SERT conducting states.

R- and S-enantiomers of fluoxetine lowered food intake in meal-fed rats and in 2-deoxyglucose-induced hyperphagic rats. In both feeding paradigms, the S-enantiomer was slightly more potent. The potency of the two enantiomers of fluoxetine in producing anorectic effects paralleled their potency as inhibitors of 5-hydroxytryptamine (<em>5HT</em>) uptake in vivo. Both enantiomers were selective inhibitors of <em>5HT</em> uptake in vitro and showed only weak affinity for <em>5HT</em>-1, <em>5HT</em>-1A and <em>5HT</em>-2 receptors or for other receptors in rat brain. The anorectic effect of fluoxetine in meal-fed rats was not reversed by either centrally or peripherally acting <em>5HT</em>-2 receptor antagonists (ritanserin, LY53857, xylamidine, BW 501C67) or a nonspecific <em>5HT</em> receptor antagonist, metergoline. However, the serotonergic mechanism involved in the anorexic effect of fluoxetine is discussed.