Raphe Lesions Research Articles

ORAL LESIONS AS A DIAGNOSTIC FACTOR OF SYSTEMIC ERYTHEMATOSUS LUPUS

Lupus erythematosus is a rare autoimmune disease involving both the innate and humoral immune response. It usually occurs in the age group between 15 and 44 years, reaching mainly women; however, men, children, and adolescents can also present the disease. Patient V.S.A., 27 years old, female, brown, native of the state of Paraiba, was referred to the stomatology clinic because of intraoral lesions. The clinical examination revealed lesions on the hard/soft palate mucosa near the palatine raphe and erythematous erosive lesion in the gingiva inserted in the region of the teeth 16 and 26 with an evolution of 4 months. During anamnesis the patient did not report any systemic alterations. An excisional biopsy of one of the palatine lesions was performed, and the report confirmed lupus erythematosus. The patient was referred to the dermatology service for systemic screening and continued treatment.

The dorsal raphe nucleus is integral to negative prediction errors in Pavlovian fear

Prediction errors are central to modern learning theories. While brain regions contributing to reward prediction errors have been uncovered, the sources of aversive prediction errors remain largely unknown. Here we used probabilistic and deterministic reinforcement procedures, followed by extinction, to examine the contribution of the dorsal raphe nucleus to negative, aversive prediction errors in Pavlovian fear. Rats with dorsal raphe lesions were able to acquire fear and reduce fear to a non-reinforced deterministic cue. However, dorsal raphe lesions impaired the reduction of fear to a probabilistic cue and fear extinction to a deterministic cue, both of which involve the use of negative prediction errors. The results point to an integral role for the dorsal raphe nucleus in negative prediction error signaling in Pavlovian fear.

P.1.i.006 Brain sonography as a novel method for detection of nuclei raphe lesion in suicidal patients and MDMA users

P.1.i.006 Brain sonography as a novel method for detection of nuclei raphe lesion in suicidal patients and MDMA users

Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Role of Serotonin and Brain Derived Neurotrophic Factor

Deep brain stimulation (DBS) is being investigated as a treatment for major depression, but its mechanisms of action are still unknown. We have studied the effects of ventromedial prefrontal cortex (vmPFC) stimulation in a chronic model of depression and assessed the involvement of the serotonergic system and brain derived neurotrophic factor (BDNF) in a DBS response. Rats were subjected to chronic unpredictable mild stress during 4 weeks. Decline in preference for sucrose solutions over water, an index suggested to reflect anhedonic-like behavior, was monitored on a weekly basis. The outcome of chronic vmPFC stimulation alone (8 hours/day for 2 weeks) or combined with serotonin-depleting lesions was characterized. BDNF levels were measured in the hippocampus. Stress induced a significant decrease in sucrose preference as well as hippocampal BDNF levels as compared with those recorded in control subjects. vmPFC stimulation completely reversed this behavioral deficit and partially increased BDNF levels. In contrast, DBS did not improve stress-induced anhedonic-like behavior in animals bearing serotonin-depleting raphe lesions with associated normal hippocampal BDNF levels. vmPFC stimulation was effective in a chronic model of depression. Our results suggest that the integrity of the serotonergic system is important for the anti-anhedonic-like effects of DBS but question a direct role of hippocampal BDNF.

Nuclei Raphe Lesion in Depressed and Suicidal Patients Recorded on Transcranial Sonography

Nuclei Raphe Lesion in Depressed and Suicidal Patients Recorded on Transcranial Sonography

Abolition of the morphine effect on body temperature in midbrain raphe lesioned rats.

Abstract The hyperthermia and the hypothermia elicited by 5 mg/kg, i.p. or 30 mg/kg i.p. of morphine in rats are abolished by a previous lesion of the midbrain raphe resulting in a lowering of forebrain 5-HT and 5-hydroxyindolacetic acid. Lesions lateral to the midbrain raphe which do not modify brain 5-HT are without effect on body temperature changes induced by morphine. Animals lesioned in the midbrain raphe are still able to respond with a hyperthermia or with a hypothermia when they are treated respectively with 2,4-dinitrophenol or phentolamine.

Acceleration of irregular estrous cycle in forced running by midbrain raphe lesions in female rats

It is known that over-exercise or forced running interrupts the regular ovulatory (estrous) cycle in female mammals, including women. The serotonin content of the brain changes under stress conditions. In this experiment, radiofrequency lesions were made in the dorsal (DRL) or median (MRL) raphe nuclei of the midbrain, in which serotonergic neurons are abundant, and changes in the estrous cycle with forced running using an electric-motor running wheel were examined in female rats. Through the tests, the estrous cycle was checked by taking vaginal smears. Female rats with a regular 4-day estrous cycle were forced to run in the wheel for 30min daily over 15 days. As a result, 27.3% of the control and 30.0% of the sham-operated rats showed an irregular estrous cycle. In contrast, 100% of the DRL and 87.5% of the MRL rats showed an irregular cycle (P<0.05 vs. control and sham). Statistical analysis revealed that the median onset day of an irregular cycle was in excess of 15 days in both the control and sham groups. In the DRL and MRL groups, the median onset days of the irregular cycle were day 5 and 3, respectively, being shorter than those in control and sham groups (P<0.01). These results indicate that the dorsal and median raphe nuclei play an important role in preventing the effect of stress conditions in the ovulatory system in female rats.

In Vitro Interaction of 5-Hydroxytrptamine with Cytosolic Molybdenum Hydroxylases as a Potential Inhibitor for Initial Rates Activities

Problem statement: The role of 5-HT has been investigated in many behavioral activities. Thus, studies using raphe lesion showed that 5-HT is involved in sleep, general activity levels, habituation, aggression, pain sensitivity and morphine analgesia, avoidance behavior, self-stimulation and water consumption. Approach: The metabolic interaction between serotonin (5- hydroxytrptamine) and indole-3-aldehyde and xanthine via aldehyde oxidase (EC 1.2.3.1) and xanthine oxidase (EC 1.1.3.22), respectively, were studied in liver tissue homogenate of Dunkin-Hartley guinea pigs by following the decrease in substrate concentration using spectrophotometer. Homogenates of liver were incubated with indole-3-aldehyde in the presence and absence of serotonin or (chlorpromazine and allopurinol a potent and selective inhibitors for aldehyde oxidase and xanthine oxidase, respectively). Oxidation of indole-3-aldehyde to indole-3-acetic acid was reduced up to 63.2% in the presence of serotonin (100 µM), while oxidation of xanthine to uric acid was reduced up to 51.6% under the same conditions. Results: In comparison, incubation of the substrates with their specific inhibitors (100 µM of chlorpromazine and 100 µM allopurinol) give almost complete inhibition. These results demonstrate that in the guinea pig liver a metabolic interaction between serotonin and indole-3-aldehyde or xanthine via molybdenum hydroxylases system may take place in liver, which is the main tissue for xenobiotics detoxification. Conclusion: The overall conclusion from this research is that serotonin could be a protector for neurons and other tissue from the insult of oxidation of aldehydes and xanthines by molybdenum hydroxylases.

Erratum to: Brainstem raphe lesion in patients with major depressive disorder and in patients with suicidal ideation recorded on transcranial sonography

Erratum to: Brainstem raphe lesion in patients with major depressive disorder and in patients with suicidal ideation recorded on transcranial sonography

Brainstem raphe lesion in patients with major depressive disorder and in patients with suicidal ideation recorded on transcranial sonography

Recent transcranial sonography (TCS) studies showed that disruption of echogenic midbrain line, corresponding to basal limbic system and raphe nuclei (RN) within, might represent functional marker for the development of depression. Major depressive disorder (MDD) is one of the most common psychiatric disorders associated with suicidal ideation. We initiated this study to assess the usefulness of TCS recording in a group of MDD patients and in MDD patients who also reported suicidal ideation, on the assumption that TCS might serve as a screening method for differentiating patients at risk of suicide. Altogether 71 subjects: 17 patients with MDD, 14 patients with MDD who also reported suicidal ideation and 40 healthy controls, were studied using TCS by two independent physicians. Reduced raphe echogenicity was found in 8 of 17 (47%) of the patients with MDD but only in 6 of 40 (15%) controls. In patients with suicidal ideations that finding was even more pronounced (12 of 14, 86%) with the highest frequency of completely not visible TCS RN finding (10 of 14, 72%). Data showed that altered echogenicity of the RN is frequent in patients with suicidal ideation. Normal RN echogenicity in MDD patients was associated with less severe depressive symptoms and rarely with the presence of suicidal ideations. As far as we know, these are the first ever obtained results which show that TCS might help differentiating MDD patients with suicidal risk or eventually predict good disease recovery based on the findings of RN hypo- or normoechogenicity.

Acceleration of anovulatoy condition in over exercise by midbrain raphe lesions in female rats

Acceleration of anovulatoy condition in over exercise by midbrain raphe lesions in female rats

Hindbrain serotonergic neurons facilitate recovery from hypotensive hemorrhage

Central serotonin is thought to contribute to sympatholytic responses to severe hemorrhage. In preliminary attempts to identify serotonergic nuclei that mediate this effect, we noted that lesion of hindbrain serotonergic neurons had no effect on sympatholytic responses to hemorrhage in conscious rats. Here, we tested whether more global serotonergic lesions delayed the hypotensive response. Hemodynamic effects of hemorrhage (3.2 ml/kg/min for 6 min) were measured in rats injected with vehicle (n=7) or the serotonergic neurotoxin, 5,7-dihydroxytryptamine, targeted to hindbrain raphe nuclei (n=7) or to the lateral cerebral ventricle and cisterna magna (n=5) 2-weeks earlier. Caudal raphe lesions reduced tryptophan hydroxylase positive (TPOH+) cell numbers by 76% in the hindbrain, but did not alter midbrain TPOH+ cell numbers. Global lesion reduced TPOH+ cells by 71% and 90% in the hindbrain and midbrain respectively. Tyrosine hydroxylase positive cells were not affected. The hypotensive response was not delayed by either lesion type. However, recovery of blood pressure and heart rate were slower in rats with hindbrain lesions compared to controls (42 ± 4**, 62 ± 6** and 82 ± 7 vs. 60 ± 5, 85 ± 6 and 91 ± 5 mm Hg; 216 ± 23**, 251 ± 20**, 288 ± 20* vs. 268 ± 22, 320 ± 21 and 345 ± 18 bpm, 10, 15 and 20 min after start of blood withdrawal, *,**P<0.05, 0.01). A similar trend was seen after global lesion. We conclude that hindbrain serotonin neurons facilitate compensatory re-establishment of blood pressure following volume depletion. Supported by HL 0722354 and 076162.

Brain serotonin depletion by lesions of the median raphe nucleus enhances the psychotomimetic action of phencyclidine, but not dizocilpine (MK-801), in rats

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [34] [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138–2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague–Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine—but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.

5,7-Dihydroxytryptamine Lesions of the Dorsal and Median Raphe Nuclei Interfere With Lithium-Induced Conditioned Gaping, but Not Conditioned Taste Avoidance, in Rats.

Both the dorsal and median raphe nuclei of the midline brainstem region in rats were lesioned with the neurotoxin 5,7-dihydroxytryptamine. Rats were then surgically implanted with intraoral cannulas for fluid delivery and received a single conditioning trial in which 2-min saccharin infusion was followed by either lithium or saline administration. The conditioned gaping seen in the lithium-conditioned rats was significantly attenuated by raphe lesions, indicating that reduction of forebrain serotonin levels interferes with conditioned gaping. However, lesioned rats still expressed comparable conditioned taste avoidance as measured by both the 1- and 2-bottle consumption tests. These results parallel previous pharmacological findings indicating that reduction of serotonin activity interferes with conditioned gaping, but not conditioned taste avoidance.

Excitotoxic median raphe lesions aggravate working memory storage performance deficits caused by scopolamine infusion into the dentate gyrus of the hippocampus in the inhibitory avoidance task in rats.

The interactions between the median raphe nucleus (MRN) serotonergic system and the septohippocampal muscarinic cholinergic system in the modulation of immediate working memory storage performance were investigated. Rats with sham or ibotenic acid lesions of the MRN were bilaterally implanted with cannulae in the dentate gyrus of the hippocampus and tested in a light/dark step-through inhibitory avoidance task in which response latency to enter the dark compartment immediately after the shock served as a measure of immediate working memory storage. MRN lesion per se did not alter response latency. Post-training intrahippocampal scopolamine infusion (2 and 4 microg/side) produced a more marked reduction in response latencies in the lesioned animals compared to the sham-lesioned rats. Results suggest that the immediate working memory storage performance is modulated by synergistic interactions between serotonergic projections of the MRN and the muscarinic cholinergic system of the hippocampus.

Effects of excitotoxic median raphe lesion on working memory deficits produced by the dorsal hippocampal muscarinic receptor blockade in the inhibitory avoidance in rats

The experiments investigated the interactions between median raphe nucleus (MRN) serotonergic and septo-hippocampal muscarinic cholinergic systems in the modulation of forming and storing performances of working memory. Rats with ibotenic acid-induced MRN-lesion bilaterally received scopolamine (2–4 μg/each side) infusion into the dentate gyrus of the dorsal hippocampus and were tested in a single trial step-through inhibitory avoidance. Initial preference to the dark compartment (escape latency) was taken as the measure of non-mnemonic behaviours and response latency to enter the dark compartment immediately after the foot-shock was used to measure working memory. The high-dose scopolamine infusion 10 min before the training decreased escape latencies in the sham-lesioned rats, whereas had no effect in the MRN-lesioned rats. Although MRN lesion per se did not alter response latency, it alleviated pre-training scopolamine-induced decrease, but aggravated post-training scopolamine-induced reduction in this parameter. These results suggest that the antagonistic interactive processes between MRN-serotonergic and hippocampal cholinergic systems modulate non-mnemonic component of working memory formation, whereas the storing performance of working memory is modulated by the synergistic interactions between these systems in the hippocampus, mainly in the dentate gyrus.

GABA B receptors in the median raphe nucleus: distribution and role in the serotonergic control of hippocampal activity

Previous studies have shown that serotonergic neurons of the median raphe nucleus have a suppressive effect on theta synchronization in the hippocampus. Median raphe lesion, suppression of 5-HT neuronal activity by administration of GABA A receptor antagonist or by glutamate blockade or depletion produced long-lasting non-interrupted hippocampal theta in freely behaving rats independent of behavior and in rats anesthetized with urethane. Serotonergic neurons show a characteristic sleep–wake pattern of activity and there is evidence that GABAergic mechanisms play an important role in their regulation. In this study we analyzed the distribution and subcellular localization of GABA B receptors in the midbrain raphe complex using combined 5-HT/GABA B receptor immunohistochemistry at the light and electron microscopic levels and studied the effects of their pharmacological manipulation on hippocampal electroencephalographic activity in urethane-anesthetized rats. We found that sustained infusion of the GABA B receptor agonist baclofen into the median raphe nucleus, using the microdialysis technique, elicited lasting theta activity in the hippocampus. The effect was antagonized by selective GABA B receptor antagonists. The predominant localization of GABA B receptors in the median, as well as in dorsal raphe was found on serotonergic neurons which strongly indicates that the increase in theta occurrence after baclofen injection resulted from suppression of the serotonergic output originating from the median raphe. On the electron microscopic level, we found GABA B receptors located extrasynaptically indicating that these receptors are preferentially activated by strong inputs, i.e. when GABA released from the synaptic terminals is sufficient to spill over from the synaptic cleft. Such conditions might be satisfied during rapid eye movement sleep when GABAergic neurons in the raphe are firing at their highest rate and in rhythmic synchronized bursts. Our data indicate that midbrain raphe GABA B mechanisms play an important role in behavioral state control and in hippocampal activity, in particular.

Effects of ketamine on different types of anxiety/fear and related memory in rats with lesions of the median raphe nucleus

The aim of the present study was to determine the involvement of the median raphe serotonergic system in the effects of ketamine on anxiety behaviours and related memory. The effects of ketamine pretreatment (3 and 10 mg/kg, i.p.) on three types of fear-motivated behaviours, unconditioned one-way escape, conditioned avoidance and freezing were tested. Experiments were performed with the inhibitory avoidance apparatus in rats with ibotenic acid lesions of the median raphe nucleus. It was found that 10 mg/kg ketamine had an anxiogenic-like effect on one-way escape type of fear and anxiolytic-like effect on conditioned freezing-related fear; these effects were unaffected by median raphe lesions. Both ketamine doses impaired freezing-related fear memory. Ketamine (10 mg/kg) also produced an anxiolytic-like effect on avoidance type of fear and impaired avoidance memory. The median raphe lesions attenuated the anxiolytic action of the drug on the avoidance type of fear and prevented ketamine-induced avoidance memory impairment. These results suggest that the anxiolytic-like effect of ketamine on avoidance-type fear is mediated through the median raphe serotonergic system.

The prognostic significance of abnormalities seen on magnetic resonance imaging in late life depression: clinical outcome, mortality and progression to dementia at three years.

To study the course of depressive symptoms over 3 years, rate of dementia and mortality in relation to baseline neuroradiological abnormalities. Retrospective casenote analysis of 38 patients (of 44) who had a Magnetic Resonance Imaging (MRI) scan 3 years earlier. Twenty-two patients also received a detailed interview. Overall outcome was good for around two-thirds of the sample. Poorer clinical course was associated with lesions in pons and more than five Virchow Robins spaces in the corona radiata. Pontine raphe lesions and confluent periventricular lesions were associated with later dementia and with reduced survival from cardiovascular death. Males had more recurrences and a reduced survival. MRI lesions influence outcome, mortality and the onset of dementia. However, because they are quite common in elderly depressed patients they have limited utility on their own as predictors of outcome. The association of periventricular lesions with dementia is a new finding, and suggests that the site and type of lesions may be as important than the quality of them.

When injected into the fimbria-fornix/cingular bundle, not in the raphe, 5,7-dihydroxytryptamine prevents amphetamine-induced hyperlocomotion

The locomotor effects of acute amphetamine treatment (1 mg/kg, i.p.) were assessed in Long–Evans rats after 5,7-dihydroxytryptamine (5,7-DHT) injections into the fimbria-fornix/cingular bundle (FiFx/CB; 4 μg/side), or the dorsal and median raphe (Raphe; 10 μg). In control rats, amphetamine induced a significant increase of home-cage activity for about 2 h. This effect was similar in Raphe rats, but was absent in FiFx/CB rats. The raphe lesions reduced serotonin concentrations by 50% in the dorsal hippocampus, 75% in the ventral hippocampus and 58% in the fronto-parietal cortex. After FiFx/CB lesions, the reduction amounted 50, 61 and only 25%, in each of these regions, respectively. In the fronto-partietal cortex, dopamine concentration was significantly decreased in Raphe (−27%) and FiFx/CB rats (−65%). The results suggest that a serotonergic denervation of the hippocampus by injections of 5,7-DHT into the FiFx/CB pathways hampers the stimulating effects of amphetamine on locomotor activity. This effect might be related to the reduced dopaminergic tone in the fronto-parietal cortex.