Roles of suprachiasmatic nuclei and intergeniculate leaflets in mediating the phase-shifting effects of a serotonergic agonist and their photic modulation during subjective day

Serotonin (5-HT) has been implicated in the phase adjustment of the circadian system during the subjective day in response to nonphotic stimuli. Two components of the circadian system, the suprachiasmatic nucleus (SCN) (site of the circadian clock) and the intergeniculate leaflet (IGL), receive serotonergic projections from the median raphe nucleus and the dorsal raphe nucleus, respectively. Experiment 1, performed in golden hamsters housed in constant darkness, compared the effects of bilateral microinjections of the 5-HT1A/7 receptor agonist, 8-hydroxydipropylaminotetralin (8-OH-DPAT; 0.5 microgram in 0.2 microliter saline per side), into the IGL or the SCN during the mid-subjective day. Bilateral 8-OH-DPAT injections into either the SCN or the IGL led to significant phase advances of the circadian rhythm of wheel-running activity (p < .001). The phase advances following 8-OH-DPAT injections in the IGL were dose department (p < .001). Because a light pulse administered during the middle of the subjective day can attenuate the phase-resetting effect of a systemic injection of 8-OH-DPAT, Experiment 2 was designed to determine whether light could modulate 5-HT agonist activity at the level of the SCN and/or the IGL. Serotonergic receptor activation within the SCN, followed by a pulse of light (300 lux of white light lasting 30 min), still induced phase advances. In contrast, the effect of serotonergic stimulation within the IGL was blocked by a light pulse. These results indicate that the respective 5-HT projections to the SCN and IGL subserve different functions in the circadian responses to photic and nonphotic stimuli.     

Origin of projections from the midbrain raphe nuclei to the hypothalamic paraventricular nucleus in the rat: a combined retrograde and anterograde tracing study

A number of neuronal functions governed by the hypothalamic paraventricular nucleus are influenced by serotonin, and it is generally believed that the moderate density of serotonin-immunoreactive fibres and terminals within the paraventricular nucleus originates from the midbrain dorsal and median raphe nuclei. To further evaluate the intricate anatomy of projections from brain stem raphe nuclei of the rat, a combination of retrograde and anterograde tracing experiments were conducted to determine the medullary raphe nuclei projection to the paraventricular nucleus. Rhodamine-labelled latex microspheres, Cholera toxin subunit B and FluoroGold we used as retrograde tracers. Intracerebroventricular injections into the third ventricle of all retrograde tracers labelled a distinct population of neurons in the dorsal raphe situated in the subependymal stratum adjacent to the cerebral aqueduct indicating that these cells take up the tracer from the cerebrospinal fluid. Very few retrogradely labelled neurons were seen in the median raphe after i.c.v. administration of the tracers. Retrograde tracers delivered into the medial part of the paraventricular nucleus labelled no further cells in the midbrain dorsal and median raphe nuclei, whereas a substantial number of retrogradely labelled cells emerged in the pontine raphe magnus. However, when the retrograde tracers were delivered into the lateral part of the paraventricular nucleus, avoiding leakage of the tracer into the ventricle, very few labelled neurons were seen in the dorsal and median raphe, whereas the prominent labelling of raphe magnus neurons persisted. The anatomical organization of nerve fibres terminating in the area of the paraventricular nucleus originating from midbrain raphe nuclei was studied in a series of anterograde tracing experiments using the plant lectin Phaseolus vulgaris leucoagglutinin. Injections delivered into the dorsal raphe or median raphe labelled but a few fibres in the paraventricular nucleus proper. A high number of fine calibered nerve fibres overlying the ependyma adjacent to the paraventricular nucleus was, however, seen after the injections into the subependymal rostral part of the dorsal raphe. Injections delivered into the raphe magnus gave rise to a dense plexus of terminating fibres in the parvicellular parts of the paraventricular nucleus and moderately innervated the posterior magnocellular part of the paraventricular nucleus as well as the magnocellular supraoptic nucleus. Concomitant visualization of serotonin-immunoreactive neurons and retrograde FluoroGold-tracing from the paraventricular nucleus revealed that none of the serotonergic neurons of the raphe magnus projects to this nucleus, while a few of the neurons putatively projecting to the paraventricular nucleus from the median raphe are serotonergic. The current observations suggest that the raphe magnus constitute by far the largest raphe input to the paraventricular nucleus and strongly questions the earlier held view that most raphe fibres innervating the paraventricular nucleus are derived from the midbrain dorsal and median raphe. However, the source of serotonergic innervation of the paraventricular nucleus remains elusive.     

Release of cerebral 5-hydroxytryptamine evoked by electrical stimulation of the dorsal and median raphe nuclei: effect of a neurotoxic amphetamine

Recent neuroanatomical data suggest that the axons and terminals of serotonergic neurons of the dorsal and median raphe nuclei are morphologically and pharmacologically distinct. Here we attempted to establish a functional in vivo model of serotonergic terminals derived from these nuclei, and then carry out a preliminary comparison of their physiological and pharmacological properties. Brain microdialysis was used to monitor extracellular 5-hydroxytryptamine in the hippocampus (dorsal and median raphe innervation) and frontal cortex (preferential dorsal raphe innervation) of the anaesthetized rat. To distinguish 5-hydroxytryptamine released by terminals of dorsal raphe neurons from that released by median raphe neurons, one or other of these nuclei was stimulated electrically. Electrical stimulation of either the dorsal or median raphe nucleus evoked a release of 5-hydroxytryptamine in the hippocampus. Whereas stimulation of the dorsal raphe nucleus also released 5-hydroxytryptamine in the frontal cortex, stimulation of the median raphe nucleus did not. No release of 5-hydroxytryptamine was evoked when electrodes were located in regions bordering the dorsal raphe nucleus and the median raphe nucleus. The amounts of hippocampal 5-HT released by stimulation of the dorsal or median raphe nucleus were found to be similarly altered by a 5-hydroxytryptamine uptake inhibitor (citalopram) and calcium-free perfusion medium, and also by increasing stimulation frequency (2-10 Hz). Furthermore, the amount of 5-hydroxytryptamine released by electrical stimulation of either the dorsal raphe nucleus or median raphe nucleus was markedly reduced in rats pretreated with p-chloroamphetamine. In summary, our data show that electrical stimulation of the dorsal or median raphe nucleus releases 5-hydroxytryptamine in a regionally specific manner (hippocampus versus frontal cortex), suggesting that serotonergic nerve terminals of the dorsal and median raphe pathways were being activated selectively. Using this model, we found no differences in the responsiveness of dorsal and median raphe pathways to a specific set of physiological and pharmacological manipulations. In particular, our data suggest that the neurotoxic action of p-chloroamphetamine may not be targeted solely on serotonergic axons and terminals of the dorsal raphe nucleus but includes those of the median raphe nucleus.     

Neuronal projections from the mesencephalic raphe nuclear complex to the suprachiasmatic nucleus and the deep pineal gland of the golden hamster (Mesocricetus auratus)

Neuronal projections from the mesencephalic raphe system to the suprachiasmatic nucleus and the pineal complex were mapped in this study of the golden hamster, by use of the anterograde tracer Phaseolus vulgaris-leucoagglutinin and the retrograde tracer cholera toxin subunit B. From the median raphe nucleus, a rostral projection ascended in the ventral part of the mesencephalon to continue in the medial forebrain bundle of the forebrain. Nerve fibres from this bundle innervated the ventral and medial parts of the suprachiasmatic nucleus. At the level of the interpeduncular nucleus of the mesencephalon, fibres of the ventral bundle bent dorsally to reach the epithalamic area and to continue in the forebrain in a periventricular position. Some of these fibres innervated the dorsal tip of the suprachiasmatic nucleus. The dorsal raphe nucleus was the origin of a nerve fibre bundle, located in the periaqueductal gray of the mesencephalon, innervating the deep pineal gland and pineal stalk. Injection of cholera toxin B into the suprachiasmatic nucleus labelled cells in the median raphe. Combination of the retrograde tracing from the suprachiasmatic nucleus and serotonin transmitter immunohistochemistry showed that some of the cholera toxin B-immunoreactive nerve cells also contained serotonin. Thus, this study of the golden hamster shows a serotonergic projection from the median raphe nucleus to the suprachiasmatic nucleus and a projection from the dorsal raphe nucleus to the deep pineal gland supporting physiological indications of an influence of serotonin on the photoreceptive circadian system of the brain.     

Spare receptors and intrinsic activity: studies with D1 dopamine receptor agonists

Anti-nitric oxide synthase antibody was used to study the distribution, cytoarchitecture, and synaptic relations of nitric oxide synthase-like immunoreactive neurons in the whole rostral-caudal length of the dorsal raphe nucleus of the rat and compared them with serotonergic neurons. Results showed that the distribution of the nitric oxide synthase in the dorsal raphe nucleus was similar to that of the serotonergic neurons at the rostral part of the dorsal raphe nucleus, including the mediodorsal and the medioventral cell groups, and changed at the middle and caudal parts of the dorsal raphe nucleus. The cytoarchitecture of the nitric oxide synthase-like immunoreactive neurons in the medioventral cell group of the dorsal raphe nucleus was similar to that of the serotonergic neurons. Similar to the serotonergic neurons there, nitric oxide synthase-like immunoreactive neurons also received synapses from axon terminals that contained round, or flattened vesicles, or both kinds. Different to the serotonergic neurons, the few nitric oxide synthase-like immunoreactive axon terminals that were in this area formed synapses.     

Interconnections among nuclei of the subcortical visual shell: the intergeniculate leaflet is a major constituent of the hamster subcortical visual system

The intergeniculate leaflet (IGL), a major constituent of the circadian visual system, is one of 12 retinorecipient nuclei forming a "subcortical visual shell" overlying the diencephalic-mesencephalic border. The present investigation evaluated IGL connections with nuclei of the subcortical visual shell and determined the extent of interconnectivity between these nuclei. Male hamsters received stereotaxic, iontophoretic injections of the retrograde tracer, cholera toxin beta fragment, or the anterograde tracer, Phaseolus vulgaris-leucoagglutin, into nuclei of the pretectum (medial, commissural, posterior, olivary, anterior, nucleus of the optic tract, posterior limitans), into the superior colliculus, or into the visual thalamic nuclei (lateral posterior, dorsal lateral geniculate, intergeniculate leaflet, ventral lateral geniculate). Retrogradely labeled cell bodies identified nuclei with afferents projecting to the site of injection, whereas the presence of anterogradely labeled fibers with terminals revealed brain nuclei targeted by neurons at the site of injection. The IGL projects bilaterally to all nuclei of the visual shell except the lateral posterior and dorsal lateral geniculate nuclei. The IGL also has afferents from the same set of nuclei, except the nucleus of the optic tract. The extensive bilateral efferent projections distinguish IGL from the ventral lateral geniculate nucleus. The superior colliculus, commissural pretectal, olivary pretectal, and posterior pretectal nuclei also project bilaterally to the majority of subcortical visual nuclei. The IGL has a well-established role in circadian rhythm regulation, but there is as yet no known function for it in the larger context of the subcortical visual system, much of which is involved in oculomotor control.     

Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor

A variety of observations from several rodent species suggest that a serotonin (5-HT) input to the suprachiasmatic nucleus (SCN) circadian pacemaker may play a role in resetting or entrainment of circadian rhythms by non-photic stimuli such as scheduled wheel running. If 5-HT activity within the SCN is necessary for activity-induced phase shifting, then it should be possible to block or attenuate these phase shifts by reducing 5-HT release or by blocking post-synaptic 5-HT receptors. Animals received one of four serotonergic drugs and were then locked in a novel wheel for 3 h during the mid-rest phase, when novelty-induced activity produces maximal phase advance shifts. Drugs tested at several doses were metergoline (5-HT1/2 antagonist; i.p.), (+)-WAY100135 (5-HT1A postsynaptic antagonist, which may also reduce 5-HT release by an agonist effect at 5-HT1A raphe autoreceptors; i.p.), NAN-190 (5-HT1A postsynaptic antagonist, which also reduces 5-HT release via an agonist effect at 5-HT1A raphe autoreceptors; i.p.) and ritanserin (5-HT2/7 antagonist; i.p. and i.c.v.). Mean and maximal phase shifts to running in novel wheels were not significantly affected by any drug at any dose. These results do not support a hypothesis that 5-HT release or activity at 5HT1, 2 and 7 receptors in the SCN is necessary for the production of activity-induced phase shifts in hamsters.     

Colocalization of substance P or enkephalin in serotonergic neuronal afferents to the hypoglossal nucleus in the rat

The serotonergic innervation of the hypoglossal nucleus originates from the caudal raphe nuclei. Non-serotonergic neurons in the caudal raphe nuclei also project to the hypoglossal nucleus. We employed a triple-fluorescence technique to determine whether the substance P- or the enkephalin-containing neurons in the caudal raphe nuclei that projected to the hypoglossal nucleus also contained serotonin. Rhodamine latex microspheres were injected into the hypoglossal nucleus, and then serotonin and peptide dual-immunofluorescence was performed to colocalize perikarya containing serotonin, substance P, and rhodamine microspheres; or perikarya containing serotonin, enkephalin, and rhodamine microspheres. Our results demonstrate that most substance P-containing neuronal afferents to the hypoglossal nucleus colocalize serotonin. In contrast, few enkephalin-containing neuronal afferents to the hypoglossal nucleus also contain serotonin. These data suggest that substance P projections to the hypoglossal nucleus are a subset of serotonergic projections and that limited overlap exists between the populations of enkephalinergic and serotonergic neuronal afferents to the hypoglossal nucleus. Either substance P- or enkephalin-containing somata account for a very small proportion of non-serotonergic caudal raphe projections to the hypoglossal nucleus. Finally, these data demonstrate the medial tegmental field origins of the substance P projections and the enkephalin projections to the hypoglossal nucleus.     

Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors

5-HT1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HT(ext)) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HT(ext) during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 micromol/L citalopram in the dorsal or median raphe nucleus reduced 5-HT(ext) in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HT(ext) induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.     

Nitric oxide synthase immunoreactivity in rat pontine medullary neurons

Nitric oxide synthase immunoreactivity was detected in neurons and fibers of the rat pontine medulla. In the medulla, nitric oxide synthase-positive neurons and processes were observed in the gracile nucleus, spinal trigeminal nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus, nucleus ambiguus, medial longitudinal fasciculus, reticular nuclei and lateral to the pyramidal tract. In the pons, intensely labeled neurons were observed in the pedunculopontine tegmental nucleus, paralemniscal nucleus, ventral tegmental nucleus, laterodorsal tegmental nucleus, and lateral and medial parabrachial nuclei. Labeled neurons and fibers were seen in the interpeduncular nuclei, dorsal and median raphe nuclei, central gray and dorsal central gray, and superior and inferior colliculi. Double-labeling techniques showed that a small population (< 5%) of nitric oxide synthase-positive neurons in the medulla also contained immunoreactivity to the aminergic neuron marker tyrosine hydroxylase. The majority of nitric oxide synthase-immunoreactive neurons in the dorsal and median raphe nuclei were 5-hydroxytryptamine-positive, whereas very few 5-hydroxytryptamine-positive cells in the caudal raphe nuclei were nitric oxide synthase-positive. Virtually all nitric oxide synthase-positive neurons in the pedunculopontine and laterodorsal tegmental nuclei were also choline acetyltransferase-positive, whereas nitric oxide synthase immunoreactivity was either low or not detected in choline acetyltransferase-positive neurons in the medulla. The results indicate a rostrocaudal gradient in the intensity of nitric oxide synthase immunoreactivity, i.e. it is highest in neurons of the tegmentum nuclei and neurons in the medulla are less intensely labeled. The majority of cholinergic and serotonergic neurons in the pons are nitric oxide synthase-positive, whereas the immunoreactivity was either too low to be detected or absent in the large majority of serotonergic, aminergic and cholinergic neurons in the medulla.     

Does licensing of drugs in industrialized countries guarantee drug quality and safety for Third World countries? The case of norplant licensing in Finland

A knowledge of the anatomy of medullary serotonergic cells is critical to understanding local and brainstem circuits in which these cells participate. Serotonergic neurons (n = 16) were identified, as previously described (Mason [1997] J. Neurophysiol. 77:1087-1098) by their slow and steady background discharge in halothane anesthetized rats. Neurons were then intracellularly labeled with Neurobiotin and visualized with 3,3'diaminobenzidine. The validity of the physiological identification of serotonergic cells was confirmed by processing two neurons that were physiologically characterized as serotonergic for serotonin immunoreactivity; both tested cells contained immunoreactive serotonin. The dendrites and axon of each labeled cell were reconstructed by using a three-dimensional computerized system. Somata were small or medium in size and had fusiform, triangular, or multipolar shapes. The dendritic arbor was constricted with most dendrites extending for less than 500 microm from the soma. All labeled axons projected caudally and travelled in the ventrolateral medulla, either dorsal or ventral to the lateral reticular nucleus. Most cells had collaterals and/or dense axonal swellings in the nucleus reticularis gigantocellularis, nucleus reticularis magnocellularis, raphe magnus, and the ventrolateral medulla. Non-local collaterals and swellings were also observed in the nucleus reticularis gigantocellularis and in the ventrolateral medulla at all medullary levels. The results demonstrate that 1) the dendrites of serotonergic cells are restricted to raphe magnus and the ventral part of nucleus reticularis magnocellularis; and 2) serotonergic cells project to medullary nuclei that contain bulbospinal cells which project to dorsal, intermediate, and ventral horns. Serotonergic cell projections to brainstem sites may mediate the integration of sensory, autonomic, and motor modulation at the brainstem level.     

The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems

The ventral lateral geniculate nucleus (vLGN) and the intergeniculate leaflet (IGL) are retinorecipient subcortical nuclei. This paper attempts a comprehensive summary of research on these thalamic areas, drawing on anatomical, electrophysiological, and behavioral studies. From the current perspective, the vLGN and IGL appear closely linked, in that they share many neurochemicals, projections, and physiological properties. Neurochemicals commonly reported in the vLGN and IGL are neuropeptide Y, GABA, enkephalin, and nitric oxide synthase (localized in cells) and serotonin, acetylcholine, histamine, dopamine and noradrenalin (localized in fibers). Afferent and efferent connections are also similar, with both areas commonly receiving input from the retina, locus coreuleus, and raphe, having reciprocal connections with superior colliculus, pretectum and hypothalamus, and also showing connections to zona incerta, accessory optic system, pons, the contralateral vLGN/IGL, and other thalamic nuclei. Physiological studies indicate species differences, with spectral-sensitive responses common in some species, and varying populations of motion-sensitive units or units linked to optokinetic stimulation. A high percentage of IGL neurons show light intensity-coding responses. Behavioral studies suggest that the vLGN and IGL play a major role in mediating non-photic phase shifts of circadian rhythms, largely via neuropeptide Y, but may also play a role in photic phase shifts and in photoperiodic responses. The vLGN and IGL may participate in two major functional systems, those controlling visuomotor responses and those controlling circadian rhythms. Future research should be directed toward further integration of these diverse findings.     

A direct retinal projection to the dorsal raphe nucleus in the rat

A direct projection from the retina to the dorsal raphe nucleus at the pontomesencephalic junction was demonstrated with both antero- and retrograde tracing techniques in the rat. Following intravitreous injections of choleratoxin subunit B (CTB), horseradish peroxidase (HRP) and CTB-conjugated HRP, varicose fibers were labeled in the lateral region of the dorsal raphe nucleus, predominantly contralateral to the injection. Many of these labeled fibers were intermingled with serotonin-immunoreactive neurons, but some fibers were also found further laterally, beyond the boundary of dorsal raphe nucleus but within the periaqueductal gray. Following injections of the retrograde tracers Fluoro-Gold and CTB into the dorsal raphe nucleus and adjacent periaqueductal gray (without contamination of previously known targets of retinal projections), a small population of ganglion cells was labeled in the retina. These data provide evidence for the existence of a direct retinal projection to the lateral region of the dorsal raphe nucleus and the adjacent mesopontine periaqueductal gray in the rat. This projection may have a role in sensorimotor coordination and the regulation of circadian rhythm as well as sleep and wakefulness.     

Mutual interactions among cholinergic, noradrenergic and serotonergic neurons studied by ionophoresis of these transmitters in rat brainstem nuclei

In urethane-anesthetized rats, single neuronal activity was recorded in or around the central gray of the caudal mesencephalon to rostral pons with multibarrel microelectrodes for ionophoretic application of acetylcholine, noradrenaline and serotonin. Neurons were classified by spike shape into broad-spike and brief-spike neurons. In the laterodorsal tegmental nucleus, locus coeruleus or dorsal raphe, broad-spike neurons, marked by Pontamine Sky Blue and discriminated in sections processed for histochemistry of reduced nicotinamide adenine dinucleotide phosphate diaphorase or Nissl staining, were presumed to be cholinergic, noradrenergic or serotonergic, respectively. The majority of these neurons were inhibited through autoreceptors, except some laterodorsal tegmental neurons which might not be furnished by autoreceptors. Noradrenaline and serotonin inhibited more than two-thirds of the laterodorsal tegmental neurons tested, while a few neurons were excited by noradrenaline. Though effects of noradrenaline on dorsal raphe neurons and those of serotonin on locus coeruleus neurons were not clear in many neurons tested, neurons affected in these examinations (30%) were all inhibited clearly and no excitatory effect was observed. Acetylcholine exerted inhibition on about one-half of dorsal raphe neurons, while effects of acetylcholine on locus coeruleus neurons were the only case in the present study in which excitation was the major effect, though more than a half of locus coeruleus neurons were not sensitive to this drug. Thus, in this study some new data on the pharmacological properties of the cholinergic laterodorsal tegmental neurons were obtained. In addition, mutual interactions between brainstem cholinergic, noradrenergic and serotonergic neurons were assayed by comparing the pharmacological properties of these neurons tested with a uniform procedure. The interactions between these diffuse projection neurons may be involved in neural mechanisms controlling vigilance, wakefulness and/or sleep.     

Dominant host range selection of vaccinia recombinants by rescue of an essential gene

The intergeniculate leaflet (IGL) is a distinct division of the lateral geniculate complex that participates in the regulation of the circadian rhythm through its projections to the circadian pacemaker located in the suprachiasmatic nuclei of the hypothalamus. A high number of neuropeptide Y (NPY) cell bodies has been described in the IGL by immunohistochemistry and in situ hybridization. The present study investigated whether NPY in the IGL is influenced by the length of the daily photoperiod. By using in situ hybridization we show a significant increase of the number of NPY mRNA containing neurons in the mid-part of the IGL of Syrian hamsters maintained in a short photoperiod compared to those kept in a long photoperiod. On the other hand, NPY mRNA expression per cell in the IGL is similar in both photoperiods tested.     

Effects of corticotropin-releasing factor on brain serotonergic activity

The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 microgram decreasing, and 3.0 micrograms increasing 5-HT dialysate concentrations. i.c.v. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 microgram) and high (3 micrograms) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.     

Differential behavioral effects of lesions of the medial or dorsal raphe nuclei in rats: Open field and pain-elicited aggression.

Electrolytic lesions were placed in either the dorsal or median raphe nuclei of 32 male adult Sprague-Dawley rats. Both lesions produced significant reductions in forebrain serotonin levels. Lesions of the dorsal nucleus produced a long-lasting increase in pain-elicited aggression, whereas median lesions were without effect. By contrast, lesions of the median nucleus produced significant increases in open-field activity, which began immediately and lasted for at least 3 mo, whereas lesions of the dorsal nucleus had no such effect. Similarly, when 22 Ss with dorsal or sham lesions were tested in an open field and then given a brief noncontingent footshock, their open-field activity was markedly reduced on the following day. Median Ss, however, showed little or no decrease in open-field activity on the day after footshock. Results suggest that the serotonin-containing neurons of the median raphe nucleus may exert an influence over the emotional responsivity of the rat. Overall results extend previous reports that lesions specific to the dorsal nucleus produce markedly different behavioral effects than lesions confined to the median nucleus. They also challenge the utility of manipulations that fail to take this into account. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Managed care and medication compliance: implications for chronic depression

Syrian hamsters, Mesocricetus auratus, were confined to novel running wheels for a 3-h period, starting at approximately circadian time (CT) 4.5 (i.e., approaching the middle of their subjective day). It can be reliably predicted from the amount of running in this situation whether or not there will be a subsequent phase-shift. Expression of the immediate early genes c-fos and fosB was examined by immunocytochemistry in the suprachiasmatic nucleus (SCN), the intergeniculate leaflet (IGL) of the thalamus, and the medial pretectal area of hamsters that ran vigorously in the novel wheel and would have phase-shifted. c-Fos was increased, compared to levels in a control group left in their home cages, in the IGL, and the pretectum (PT), but decreased in the SCN. No significant changes in FosB were detected in any region examined. An additional experiment argued against the possibility that the changes in c-Fos could be attributed to a rapid advance of the pacemaker to a different phase in the circadian cycle. Counts of c-Fos-positive cells in the IGL were similar in animals given pulses of running starting at CT 4.5 and starting at CT 12.5-16 (i.e., in the subjective night when they would have been active anyway). Altogether the results support the view that activation of the IGL is important in nonphotic clock resetting, and raise the possibility that the PT may also be involved in nonphotic resetting. However, the results also indicate that novelty-induced running does not alter c-Fos induction in a phase-specific manner in the IGL. The inhibition of c-Fos in the SCN by nonphotic phase-shifting events contrasts with the well-known inducing effects of light pulses. These different effects might underlie some of the interactions between nonphotic and photic zeitgebers when both act together on the circadian system.     

Predictors of medication compliance after hospital discharge in adolescent psychiatric patients

Serotonin amacrine cells have been described in the retina of vertebrates, except mouse and rat. Moreover, serotonin immunoreactive fibers have been reported in the optic nerve of rodents, frog and stingray. The purpose of this work was to study serotonin dorsal raphe nucleus projections to the retina, and to determine whether this pathway occurs in teleosts. The existence of specific connections was investigated in the rat and in the goldfish by the use of the neurotoxic substance 5,7-dihydroxytryptamine followed by monoamines determination in the retina by HPLC. The administration of 5,7-dihydroxytryptamine into the central or the lateral area of the rat dorsal raphe nucleus decreased serotonin levels in the raphe area and in the hippocampus, but only the bilateral injection into the dorsal raphe nucleus decreased it in the retina. In the goldfish, the injection of 5,7-dihydroxytryptamine into the optic tectum decreased serotonin concentration in situ and in the retina. The binding of [3H]paroxetine, a marker of serotonin transporter, was reduced in the retina of both species after the central treatment with the neurotoxic substance. In addition, the administration of the serotonin precursor 5-hydroxytryptophan into the optic tectum increased serotonin levels in the site of the injection and in the retina. The intraocular administration of 5,7-dihydroxytryptamine produced a big decrease in the content of retinal serotonin. This indoleamine and 5-hydroxyindoleacetic acid were detected in the optic nerves of rat and goldfish. The results indicate the existence of serotonergic retinopetal fibers in the rat and in the goldfish, a pathway that was not specifically demonstrated for the rat and was not previously proposed for the fish. The study of these serotonergic projections from the brain to the retina could be of interest in the understanding of the functional role of serotonin in the retina.     

Sensory responsiveness of "broad-spike" neurons in the laterodorsal tegmental nucleus, locus coeruleus and dorsal raphe of awake rats: implications for cholinergic and monoaminergic neuron-specific responses

Although cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei have been shown to have a pivotal role in neural mechanisms of paradoxical sleep, their function during wakefulness is less understood. To examine the latter, we have recorded from "broad-spike neurons", which were distinguished by their long spike duration, in the laterodorsal tegmental nucleus of undrugged, head-restrained rats, and examined their response properties to sensory stimuli such as light touch to the tail, air puff to the face, 2 kHz pure tone and flashes of light. Broad-spike neurons from the locus coeruleus and dorsal raphe nucleus were studied for comparison; these neurons have been demonstrated to be noradrenergic and serotonergic, respectively. The broad-spike neurons in the laterodorsal tegmental nucleus have also been suggested to be cholinergic. There were two kinds of responses: (1) a simple increase or decrease in firing, reflecting an elevated level of vigilance; and (2) a phasic response composed of a single spike or brief, high frequency burst, usually diminishing or disappearing upon repetition of the stimulus. When two or more types of stimuli were effective in a neuron, they evoked responses of the same quality. Most of the dorsal raphe neurons displayed only the simple increase of firing, whereas the locus coeruleus neurons gave a phasic response with rather weak attenuation upon repetition. Compared with these, the laterodorsal tegmental neurons were heterogeneous: about one-quarter showing only a simple change of firing (half increasing, half decreasing); and two-thirds displaying phasic responses. The latter response of many neurons attenuated strongly upon repetition. The laterodorsal tegmental neurons were classified into several groups according to their spontaneous firing behavior during sleep and wakefulness, but every neuron in a group did not show the same type of response. For example, some of the neurons which were most active during paradoxical sleep and essentially silent during wakefulness decreased or stopped firing upon sensory stimulation, while others in this group had strong phasic responses. These results suggest that putative cholinergic neurons in the laterodorsal tegmental nucleus have heterogenous properties not only with respect to their spontaneous activity during sleep and wakefulness but also with respect to their response to sensory stimulation. Some of these neurons may function to induce a global attentive state in response to a novel stimulus.