Serotonergic Innervation Research Articles

Serotonin and Sleep: Molecular, Functional, and Clinical Aspects

Serotonin and Sleep: Molecular, Functional, and Clinical Aspects

Activation of glucocorticoid receptors increases 5-HT 2A receptor levels

Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT 2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT 2A receptor level is a state or a trait marker of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT 2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish an effect of GR activation on 5-HT 2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT 2A receptor protein levels were decreased (26.3 ± 1.6%, p < 0.05) and frontal 5-HT 2A receptor binding was decreased (20 ± 15%, p < 0.01) as compared to wild-type mice. Conversely, in over-expressing GR mice hippocampal 5-HT 2A receptor protein levels were increased (60.8 ± 4.0%, p = 0.0001) and 5-HT 2A receptor binding was increased in dorsal hippocampus (77 ± 35%, p < 0.05) as compared to wild-type mice. No difference in serotonin fibre density was observed in the GR over-expressing mice, while the GR under-expressing mice showed lower serotonergic innervation in the frontal cortex area. An effect of GR activation on 5-HT 2A receptor levels was further corroborated by the culture studies as long-term exposure of 3 μM corticosterone to organotypic hippocampal cultures increased 5-HT 2A receptor levels ( p < 0.05). The corticosterone-induced 5-HT 2A receptor up-regulation was blocked by addition of either spironolactone or mifepristone.

Serotonergic cell transplant and cervical spinal cord injury

Phrenic motor recovery following cervical hemisection (HS) positively correlates with recovery of serotonergic input to ipsilateral phrenic motoneurons (PhrMNs). In preliminary studies, we are testing the hypothesis that respiratory motor recovery following HS can be enhanced by intraspinal grafting of embryonic (E14) brainstem tissue containing serotonergic (5‐HT) neurons or their precursors. E14 dorsal raphe nucleus tissue was placed into an acute C4HS cavity in adult male rats. At 8 weeks post‐surgery histological analysis showed that donor tissue filled the cavity and robust 5‐HT immunostaining was seen in the ipsilateral spinal cord rostral and caudal to the graft. Ventilation was assessed in conscious rats with plethysmography. Normoxic breathing patterns were similar between control (C4HS only) and transplant animals. However, during hypoxic challenge (10% O2) graft rats had increased frequency and minute ventilation (both p=0.01) compared to controls. Although additional control experiments are needed to determine if graft effects are specific to DRN tissue (vs. a non‐specific effect of embryonic tissue), these preliminary findings suggest that neurotransplantation may be a viable strategy for promoting respiratory motor recovery by enhancing serotonergic innervation of PhMNs.Funding: NIH 1R01HD052682‐01A1 (DDF), NIH RO1 NS054025 (PJR), NIH T32 HD043730 (BJD)

Localization of biogenic amines in the foregut of Aplysia californica: catecholaminergic and serotonergic innervation.

This study examined the catecholaminergic and serotonergic innervation of the foregut of Aplysia californica, a model system in which the control of feeding behaviors can be investigated at the cellular level. Similar numbers (15-25) of serotonin-like-immunoreactive (5HTli) and tyrosine hydroxylase-like-immunoreactive (THli) fibers were present in each (bilateral) esophageal nerve (En), the major source of pregastric neural innervation in this system. The majority of En 5HTli and THli fibers originated from the anterior branch (En(2)), which innervates the pharynx and the anterior esophagus. Fewer fibers were present in the posterior branch (En(1)), which innervates the majority of the esophagus and the crop. Backfills of the two En branches toward the central nervous system (CNS) labeled a single, centrifugally projecting serotonergic fiber, originating from the metacerebral cell (MCC). The MCC fiber projected only to En(2). No central THli neurons were found to project to the En. Surveys of the pharynx and esophagus revealed major differences between their patterns of catecholaminergic (CA) and serotonergic innervation. Whereas THli fibers and cell bodies were distributed throughout the foregut, 5HTli fibers were present in restricted plexi, and no 5HTli somata were detected. Double-labeling experiments in the periphery revealed THli neurons projecting toward the buccal ganglion via En(2). Other afferents received dense perisomatic serotonergic innervation. Finally, qualitative and quantitative differences were observed between the buccal motor programs (BMPs) produced by stimulation of the two En branches. These observations increase our understanding of aminergic contributions to the pregastric regulation of Aplysia feeding behaviors.

Chronic low‐level lead exposure affects the monoaminergic system in the mouse superior olivary complex

Low-level lead (Pb) exposure is associated with behavioral and cognitive dysfunction, but it is not clear how Pb produces these behavioral changes. Pb has been shown to alter auditory temporal processing in both humans and animals. Auditory temporal processing occurs in the superior olivary complex (SOC) in the brainstem, where it is an important component in sound detection in noisy environments and in selective auditory attention. The SOC receives a serotonergic innervation from the dorsal raphe, and serotonin has been implicated in auditory temporal processing within the brainstem and inferior colliculus. Because Pb exposure modulates auditory temporal processing, the serotonergic system is a potential target for Pb. The current study was undertaken to determine whether developmental Pb exposure preferentially changes the serotonergic system within the SOC. Pb-treated mice were exposed to no Pb, very low Pb (0.01 mM), or low Pb (0.1 mM) throughout gestation and through 21 days postnatally. Brainstem sections from control and Pb-exposed mice were immunostained for the vesicular monoamine transporter 2 (VMAT2), serotonin (5-HT), and dopamine-beta-hydroxylase (DbetaH; a marker for norepinephrine) in order to elucidate the effect of Pb on monoaminergic input into the SOC. Sections were also immunolabeled with antibodies to vesicular glutamate transporter 1 (VGLUT1), vesicular gamma-aminobutyric acid (GABA) transporter (VGAT), and vesicular acetylcholine transporter (VAChT) to determine whether Pb exposure alters the glutaminergic, GABAergic, or cholinergic systems. Pb exposure caused a significant decrease in VMAT2, 5-HT, and DbetaH expression, whereas VGLUT1, VGAT, and VAChT showed no change. These results provide evidence that Pb exposure during development alters normal monoaminergic expression in the auditory brainstem.

Repeated Cocaine Administration Decreases 5-HT2A Receptor-Mediated Serotonergic Enhancement of Synaptic Activity in Rat Medial Prefrontal Cortex

Neural adaptations in the medial prefrontal cortex (mPFC) are thought to be crucial in the development and maintenance of addictive behaviors. The mPFC receives a dense serotonergic (5-hydroxytryptamine, 5-HT) innervation from raphe nuclei and 5-HT exerts complex actions on mPFC pyramidal neurons. The present study, using a rat model of behavioral sensitization to cocaine, was designed to determine whether repeated cocaine exposure in vivo is capable of altering 5-HT-induced regulation of glutamatergic transmission in the mPFC. In layer V pyramidal neurons of the mPFC, application of 5-HT, through activation of 5-HT(2A) receptors, induced a massive enhancement of spontaneous excitatory postsynaptic currents (sEPSCs). Repeated cocaine administration for 5 days resulted in an attenuation in the ability of 5-HT to enhance sEPSCs. This effect was prevented when cocaine was co-administered with the selective 5-HT(2A) receptor antagonist ketanserin and was mimicked by repeated 5-HT(2A) receptor agonist (-)4-iodo-2,5-dimethoxyphenylisopropylamine administration. Repeated cocaine administration is not associated with any changes in the levels of 5-HT(2A) receptors or regulator of GTP-binding protein signaling 4. These results suggest that cocaine-induced inhibition of 5-HT(2A) receptor-mediated enhancement of glutamatergic transmission in the mPFC may be caused, at least in part, by the impairment of coupling of 5-HT(2A) receptors with GTP-binding proteins during cocaine withdrawal. These alterations in 5-HT(2A) receptor responsiveness in the mPFC may be relevant to the development of behavioral sensitization and withdrawal effects following repeated cocaine administration.

Serotonergic and SCPb-like innervation of the atrial complex in Gyratrix hermaphroditus (Platyhelminthes, Kalyptorhynchia) revealed with CLSM

The platyhelminth reproductive system is a complex series of canals, glands, and sclerotic components that figure prominently in our understanding of reproductive physiology, taxonomy, and evolution of the Platyhelminthes. Yet, there is limited information on its innervation, especially for free-living species of Rhabdocoela, the most speciose and ecologically diverse assemblage. Here, innervation of the reproductive system in the common marine kalyptorhynch, Gyratrix hermaphroditus, is studied using confocal laser scanning microscopy (CLSM), fluorescent phalloidin, and antibodies to serotonin (5HT) and small cardioactive peptide b (SCPb). Results show that portions of the female atrial system (uterus, female gonopore) are innervated by peptidergic (SCPb) neurons that may function to control muscles involved in egg movement. In contrast, portions of the male atrial system (male atrium, male gonopore) are innervated by both peptidergic and serotonergic neurons. These neurons form a complex series of hoops around the musculature of the male atrium that houses prostate stylet type II. It is hypothesized that 5HT is the primary myoexcitatory neurotransmitter, and that it acts either synergistically with SCPb to trigger muscle contractions of the male atrium and protract the copulatory stylet, or that SCPb plays an inhibitory role during contraction of the male atrium. A comparison of the distribution of peptidergic and serotonergic neurons in G. hermaphroditus with other free-living species and parasitic rhabdocoels (Neodermata) reveals similarities in innervation of comparable (though probably not homologous) reproductive organs. These results suggest that the atrial systems of phylogenetically diverse species may share a common neuronal physiology despite their structural differences and potential independent evolutionary origins within the Platyhelminthes.

Sex-specific 24-h profile of extracellular serotonin levels in the medial prefrontal cortex

The medial prefrontal cortex (mPFC) controls emotional responses in many species, receiving serotonergic innervation from the dorsal and median raphe nucleus (DRN and MRN). To examine the sex difference in 24-h profiles of extracellular serotonin (5HT) levels in the mPFC, an in vivo microdialysis study was performed using intact male, diestrous female, and proestrous female rats. Dialysates were automatically collected by a microdialysis probe from the mPFC every 30 min for more than 24 h under freely moving conditions. The levels of 5HT in dialysates were quantified by high performance liquid chromatography. Extracellular 5HT levels exhibited episodic changes in the mPFC of both sexes of rats, with both diestrous and proestrous females exhibiting a clear diurnal change; the 5HT levels were high during the dark phase, but low during the light phase. In contrast, male rats exhibited relatively high 5HT levels throughout the day without significant diurnal changes. At mathematically analyzed trough, males showed higher 5HT levels than diestrous or proestrous females. The overall 24-h 5HT levels in males were significantly greater than proestrous females, but were not different from diestrous females. Further, stereological methods were used to examine the number of tryptophan hydroxylase (TrpH), but no sex differences in the number of TrpH immunoreactive cells in the DRN and MRN were observed. These results suggest that sex and/or the gonadal steroid environment may affect the 24-h profile of extracellular 5HT in the mPFC of rats without changes in the number of 5HT neurons in the DRN and MRN.

High resolution confocal microscopy of serotonergic innervation of the feeding system in developing Lymnaea stagnalis

High resolution confocal microscopy of serotonergic innervation of the feeding system in developing Lymnaea stagnalis

Sexual dimorphic stages affect both proliferation and serotonergic innervation in the adult rostral migratory stream

One of the sexual dimorphic differences in adult rodents is neural proliferation. Here we demonstrate that physiological hormone stages can modulate this proliferation in the adult forebrain. Female mice, both pregnant and synchronized in oestrus, exhibited higher proliferating cell percentages than males in both the rostral migratory stream (RMS) and the olfactory bulb (OB). Moreover, although the hormonal component also influenced the subventricular zone (SVZ), no differences in proliferation were observed in this region. In addition, both groups of females had higher numbers of serotonergic fibres in these regions. Serotonin may therefore be related to the mechanism of action by which hormones can affect cell proliferation of this brain region. We also evaluated cell death in the SVZ in males and females, finding that this was higher in the former. Taken together, our results support the idea that in female rodents more neuroblasts are able to reach the RMS and then proliferate, apoptosis being an additional mechanism affecting the low proliferation of cells in the RMS and OB in males. Thus, proliferation in the RMS is influenced by sexual dimorphism.

Consequences of different housing conditions on brain morphology in laying hens

The aim of this study was to analyze the impact of physical and social stress on the avian forebrain morphology. Therefore, we used laying hens kept in different housing systems from puberty (approximately 16 weeks old) until the age of 48 weeks: battery cages, small littered ground pen, and free range system. Cell body sizes and catecholaminergic and serotonergic innervation patterns were investigated in brain areas expected to be sensitive to differences in environmental stimulation: hippocampal substructures and the nidopallium caudolaterale (NCL), a functional analogue of the prefrontal cortex. Our analysis shows both structures differing in the affected morphological parameters. Compared to battery cage hens, hens in the free range system developed larger cells in the dorsomedial hippocampus. Only these animals exhibited an asymmetry in the tyrosine hydroxylase density with more fibres in the left dorsomedial hippocampus. We assume that the higher spatial complexity of the free range system is the driving force of these changes. In contrast, in the NCL the housing systems affected only the serotonergic innervation pattern with highest fibre densities in free range hens. Moreover hens of the free range system displayed the worst plumage condition, which most likely is caused by feather pecking causing an altered serotonergic innervation pattern. Considering the remarkable differences between the three housing conditions, their effects on hippocampal structures and the NCL were surprisingly mild. This observation suggests that the adult brain of laying hens displays limited sensitivity to differences in social and physical environment induced post-puberty, which warrants further studies.

Axonal projections originating from raphe serotonergic neurons in the developing and adult zebrafish,Danio rerio, using transgenics to visualize raphe‐specificpet1expression

Serotonin is a major central nervous modulator of physiology and behavior and plays fundamental roles during development and plasticity of the vertebrate central nervous system (CNS). Understanding the developmental control and functions of serotonergic neurons is therefore an important task. In all vertebrates, prominent serotonergic neurons are found in the superior and inferior raphe nuclei in the hindbrain innervating most CNS regions. In addition, all vertebrates except for mammals harbor other serotonergic centers, including several populations in the diencephalon. This, in combination with the intricate and wide distribution of serotonergic fibers, makes it difficult to sort out serotonergic innervation originating from the raphe from that of other serotonergic cell populations. To resolve this issue, we isolated the regulatory elements of the zebrafish raphe-specific gene pet1 and used them to drive expression of an eGFP transgene in the raphe population of serotonergic neurons. With this approach together with retrograde tracing we 1) describe in detail the development, anatomical organization, and projection pattern of zebrafish pet1-positive neurons compared with their mammalian counterparts, 2) identify a new serotonergic population in the ventrolateral zebrafish hindbrain, and 3) reveal some extent of functional subdivisions within the zebrafish superior raphe complex. Together, our results reveal for the first time the specific innervation pattern of the zebrafish raphe and, thus, provide a new model and various tools to investigate further the role of raphe serotonergic neurons in vertebrates.

Functional interrelations between nucleus raphé dorsalis and nucleus raphé medianus: A dual probe microdialysis study of glutamate-stimulated serotonin release

Dual-probe in vivo microdialysis was used to explore the relationships between the two midbrain raphé nuclei, raphé dorsalis (DRN) and raphé medianus (MRN). Infusion of the excitatory neurotransmitter glutamate (10 mM) into the dorsal raphé nucleus produced a large increase in the extracellular 5-HT (5-HT ext) in the dorsal raphé (1400% of control values) that was limited to the time of infusion. This was followed by a significant decrease in extracellular 5-HT below baseline levels that continued for the duration of the experiment (3 h). Extracellular 5-HT (5-HT ext) was also increased to 500% of control values in the median raphé nucleus following infusion of 10 mM glutamate (GLU) into the dorsal raphé nucleus. Infusion of the competitive NMDA receptor antagonist AP5 prior to and during infusion of GLU into the DRN resulted in a decrease in the response to GLU in the DRN and an antagonism of the increase of 5-HT ext in the MRN. Infusion of 10 mM GLU into the lateral midbrain tegmentum, an area of the brain just lateral to the DRN, also increased 5-HT ext in the probe in the lateral midbrain tegmentum (900% of control) but did not alter 5-HT ext in the MRN. When glutamate was infused into the MRN, 5-HT ext was also increased to 1400% of control in a time course similar to that seen with infusion of GLU into the DRN. Infusion of glutamate into the MRN, however, did not alter the 5-HT ext in the DRN. These data suggest a serotonergic innervation of the median raphé nucleus by the dorsal raphé nucleus. A reciprocal innervation from the median raphé to the dorsal raphé is not mediated by glutamate, does not appear to be serotonergic, and does not regulate extracellular serotonin in the dorsal raphé.

Intact serotonergic and dopaminergic systems in two cases of orthostatic tremor

JO N 3 02 3 A previous single-photon emission computed tomography (SPECT) study demonstrated striatal dopamine transporter (DAT) deficits in OT [2] but also patients with normal presynaptic nigrostriatal pathway have been reported [3]. OT has been suggested to arise from a central oscillator involving the brainstem or cerebellum [4–7]. Interestingly, neuropathological changes in essential tremor have also been found in brainstem and cerebellar structures [8]. An association between the severity of parkinsonian rest tremor and the reduction of serotonin receptor (5-HT1A) binding potential in the midbrain raphe has been shown in a positron emission tomography (PET) study which might indicate a role of the serotonergic system in the generation of tremor [9, 10]. Although imaging of presynaptic pathways by measuring the serotonin transporter (SERT) availability has been performed in different neuropsychiatric disorders including Parkinson’s disease [11, 12] where in advanced patients a regionally widespread loss of brain serotonergic innervation was found [13], studies of the serotonergic system in OT do not exist. Here, we report for the first time two cases of OT with normal SERT availability and intact nigrostriatal dopaminergic pathways suggesting a normal function of these monaminergic neurotransmitter systems. Two patients (A: 61 years, male, B: 61 years, female) presented to our neurologic department with a 5 (A) and 10 (B) year history of progressive instability when standing. Their past medical histories were unremarkable except hypertension that was treated adequately. The family history of patient A remained uninformative, the father of patient B had suffered from Parkinson’s disease. On neurological examination both patients disFlorian Wegner Karl Strecker David Boeckler Armin Wagner Christoph Preul Donald Lobsien Osama Sabri Swen Hesse

Serotonergic, sensory modifications in the apical ganglion during development to metamorphic competence in larvae of the dendronotid nudibranchs Melibe leonina and Tritonia diomedea

The following investigation examines changes in the distance between the right and left dendritic termini arising from the serotonergic sensory neurons found in the apical ganglion of the larval dendronotid nudibranchs, Melibe leonina and Tritonia diomedea. A significant increase in separation, that is different in extent, occurs in both species as they grow from hatching to metamorphic competence. Competent M. leonina larvae exhibit a separation that is about 4.5 times that at hatching, whereas competent larvae of T. diomedea show an increase that is only 1.6 times that at hatching. The increase in separation of the lateral, serotonergic, dendritic termini (particularly in M. leonina) may allow the larva to more effectively assess left versus right differences in an as yet unknown sensory stimulus. The serotonergic innervation that arises from the apical ganglion is known to be associated with the muscles and large ciliated cells of the velum. Better right versus left discrimination of sensory stimuli experienced during the pelagic or settling larval phases may allow the larva to more precisely control swimming activities such that the likelihood of successful feeding or settlement behavior is increased.

P.8.a.025 Therapeutic contact through Internet. Discussion of the theoretical and technical possibilities of realization therapy

Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS). Yet, under certain circumstances the neurotransmitter contributes to the increase in sleep propensity. Most of the serotonergic innervation of the cerebral cortex, amygdala, basal forebrain (BFB), thalamus, preoptic and hypothalamic areas, raphe nuclei, locus coeruleus and pontine reticular formation comes from the dorsal raphe nucleus (DRN). The 5-HT receptors can be classified into at least seven classes, designated 5-HT1–7. The 5-HT1A and 5-HT1B receptor subtypes are linked to the inhibition of adenylate cyclase, and their activation evokes a membrane hyperpolarization. The actions of the 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes are mediated by the activation of phospholipase C, with a resulting depolarization of the host cell. The 5-HT3 receptor directly activates a 5-HT-gated cation channel which leads to the depolarization of monoaminergic, aminoacidergic and cholinergic cells. The primary signal transduction pathway of 5-HT6 and 5-HT7 receptors is the stimulation of adenylate cyclase which results in the depolarization of the follower neurons. Mutant mice that do not express 5-HT1A or 5-HT1B receptor exhibit greater amounts of REMS than their wild-type counterparts, which could be related to the absence of a postsynaptic inhibitory effect on REM-on neurons of the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT). 5-HT2A and 5-HT2C receptor knock-out mice show a significant increase of W and a reduction of slow wave sleep (SWS) which has been ascribed to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems. Sleep variables have been characterized, in addition, in 5-HT7 receptor knock-out mice; the mutants spend less time in REMS that their wild-type counterparts. Direct infusion of the 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan into the DRN significantly enhances REMS in the rat. In contrast, microinjection of the 5-HT1B (CP-94253), 5-HT2A/2C (DOI), 5-HT3 (m-chlorophenylbiguanide) and 5-HT7 (LP-44) receptor agonists into the DRN induces a significant reduction of REMS. Systemic injection of full agonists at postsynaptic 5-HT1A (8-OH-DPAT, flesinoxan), 5-HT1B (CGS 12066B, CP-94235), 5-HT2C (RO 60-0175), 5-HT2A/2C (DOI, DOM), 5-HT3 (m-chlorophenylbiguanide) and 5-HT7 (LP-211) receptors increases W and reduces SWS and REMS. Of note, systemic administration of the 5-HT2A/2C receptor antagonists ritanserin, ketanserin, ICI-170,809 or sertindole at the beginning of the light period has been shown to induce a significant increase of SWS and a reduction of REMS in the rat. Wakefulness was also diminished in most of these studies. Similar effects have been described following the injection of the selective 5-HT2A receptor antagonists volinanserin and pruvanserin and of the 5-HT2A receptor inverse agonist nelotanserin in rodents. In addition, the effects of these compounds have been studied on the sleep electroencephalogram of subjects with normal sleep. Their administration was followed by an increase of SWS and, in most instances, a reduction of REMS. The administration of ritanserin to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder caused a significant increase in SWS. The 5-HT2A receptor inverse agonist APD-125 induced also an increase of SWS in patients with chronic primary insomnia. It is known that during the administration of benzodiazepine (BZD) hypnotics to patients with insomnia there is a further reduction of SWS and REMS, whereas both variables tend to remain decreased during the use of non-BZD derivatives (zolpidem, zopiclone, eszopiclone, zaleplon). Thus, the association of 5-HT2A antagonists or 5-HT2A inverse agonists with BZD and non-BZD hypnotics could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.

Serotonin increases GABA release in rat entorhinal cortex by inhibiting interneuron TASK-3 K + channels

Whereas the entorhinal cortex (EC) receives profuse serotonergic innervations from the raphe nuclei in the brain stem and is critically involved in the generation of temporal lobe epilepsy, the function of serotonin (5-hydroxytryptamine, 5-HT) in the EC and particularly its roles in temporal lobe epilepsy are still elusive. Here we explored the cellular and molecular mechanisms underlying 5-HT-mediated facilitation of GABAergic transmission and depression of epileptic activity in the superficial layers of the EC. Application of 5-HT increased sIPSC frequency and amplitude recorded from the principal neurons in the EC with no effects on mIPSCs recorded in the presence of TTX. However, 5-HT reduced the amplitude of IPSCs evoked by extracellular field stimulation and in synaptically connected interneuron and pyramidal neuron pairs. Application of 5-HT generated membrane depolarization and increased action potential firing frequency but reduced the amplitude of action potentials in presynaptic interneurons suggesting that 5-HT still increases GABA release whereas the depressant effects of 5-HT on evoked IPSCs could be explained by 5-HT-induced reduction in action potential amplitude. The depolarizing effect of 5-HT was mediated by inhibition of TASK-3 K + channels in interneurons and required the functions of 5-HT 2A receptors and Gα q/11 but was independent of phospholipase C activity. Application of 5-HT inhibited low-Mg 2+-induced seizure activity in slices via 5-HT 1A and 5-HT 2A receptors suggesting that 5-HT-mediated depression of neuronal excitability and increase in GABA release contribute to its anti-epileptic effects in the EC.

Caste- and sex-specific adaptations within the olfactory pathway in the brain of the ant Camponotus floridanus

Olfaction plays a key role in mediating ant behavior, and ant societies are characterized by caste- and sex-specific division of labor. We propose that caste- and sex-specific adaptations in the olfactory pathway promote differences in olfactory behavior. This study compares olfactory centers in the brain of large (major) workers, small (minor) workers, virgin queens, and males of the carpenter ant Camponotus floridanus. The number of glomeruli in the antennal lobe was similar in the female castes, although the glomerular volumes differed. Males had ∼45% fewer glomeruli compared to females (∼258 and ∼434) and one antennal sensory tract was absent. A dual output pathway to the mushroom bodies was present in males. In contrast to females, however, the number of glomeruli connected to the medial antennocerebral tract was substantially smaller than those associated with the lateral tract. All glomeruli in the male antennal lobe contained serotonergic processes, whereas in the female castes glomeruli in the large tract six cluster lacked serotonergic innervations. We conclude that differences in general glomerular organization are subtle among the female castes, but sex-specific differences in the number, connectivity and neuromodulatory innervation of glomeruli are substantial and likely to underlie differences in olfactory processing and learning.

Methamphetamine Causes Microglial Activation in the Brains of Human Abusers

Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.

Demonstration of decreased activity of dorsal raphe nucleus neurons in depressed suicidal patients by the AgNOR staining method

Background Suicide and depression are closely related yet distinct phenomena. In both these phenomena, research has focused on central serotonergic system disturbances. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of limbic structures crucial for the regulation of emotionally influenced behaviour. Methods The study was carried out on paraffin-embedded brains from 23 depressed patients (12 suicides and 11 non-suicides) and 26 matched controls without mental disorders. The karyometric parameters of DRN neurons were evaluated by the AgNOR silver staining method. Results The significant effect of suicide on the nuclear area was found in the cumulative analysis of all DRN subnuclei (ANOVA, P = 0.032). A decreased mean value of this parameter was observed in the suicides group versus controls ( t-test, P = 0.032). This effect was especially pronounced in the violent suicide victims ( t-test, P = 0.001), who also demonstrated a decreased AgNOR area versus controls ( t-test, P = 0.007). No significant effect of depression or polarity on AgNOR parameters was found. Limitations A major limitation of this study is relatively small case number. A further limitation is given by the lack of data on drug exposure across the whole life span. Conclusion Our findings suggest that hypoactivity of DRN neurons is a distinct phenomenon in depression, specific only for suicidal subgroup of depressed patients.