Lesions Of Raphe Nuclei Research Articles

Depressive disorder may be associated with raphe nuclei lesions in patients with brainstem infarction

BackgroundDepression is a common symptom after stroke, but its neural substrates remain unclear. The ascending serotonergic system originates from the raphe nuclei in the brainstem. We hypothesized that depressive disorder due to brainstem infarction is associated with damage to the raphe nuclei. MethodsWe prospectively enrolled 19 patients who had the first-ever acute isolated brainstem infarction in an observational cross-sectional study. All patients were evaluated by using the Montgomery Åsberg Depression Rating Scale (MADRS), the clinician-rated version of Apathy Evaluation Scale (AES-C) and Mini-Mental State Examination (MMSE). Depressive disorder was diagnosed according to DSM-5 and MADRS score of 12 or greater. Diffusion tensor imaging and proton density-weighted images were used to identify damage in the raphe nuclei. Accordingly, patients were classified into either the raphe-nuclei–damaged or intact group. Prevalence of depressive disorder and the MADRS, AES-C, and MMSE scores were compared between the two groups. ResultsDepressive disorder was more frequent in the damaged group (n=6) than in the intact group (n=13) (83% vs. 15%; P=0.01). MADRS scores were higher in the damaged group than in the intact group (mean±1 SD, 17.5±7.9 vs. 7.0±4.4; P=0.002), whereas the AES-C and MMSE scores did not differ between groups. LimitationsWe did not assess the damage to the ascending projection fibers from the raphe nuclei. ConclusionsOur results suggest that damage to the raphe nuclei underlies depressive disorder due to brainstem infarction, possibly via serotonergic denervation.

The effect of lesion of brain raphe nuclei on the activity of cytochrome P450 in the liver

The effect of lesion of brain raphe nuclei on the activity of cytochrome P450 in the liver

5,7-Dihydroxytryptamine lesion of the dorsal raphe nucleus alters neuronal activity of the subthalamic nucleus in normal and 6-hydroxydopamine-lesioned rats

The subthalamic nucleus receives serotonergic projections from the dorsal raphe nucleus. However, the role of serotonergic innervation in the activity of subthalamic neurons in vivo is unknown. The aim of the present work is to study the changes in the firing of subthalamic neurons in rats with 5,7-dihydroxytryptamine lesions of the dorsal raphe nucleus and rats with combined 5,7-dihydroxytryptamine lesions in the dorsal raphe nucleus and 6-hydroxydopamine lesions in the substantia nigra pars compacta by using single-unit extracellular recordings. In rats with 5,7-dihydroxytryptamine lesions of the dorsal raphe nucleus, the firing rate of subthalamic neurons increased significantly compared with normal rats and the firing pattern changed significantly towards a more bursting firing in the majority of the neurons observed. In rats with combined dorsal raphe nucleus and substantia nigra pars compacta lesions, the firing rate and firing pattern of subthalamic neurons did not show a significant difference compared to rats with lesions of the substantia nigra pars compacta. However, dorsal raphe nucleus and substantia nigra pars compacta lesions combined increased significantly the percentage of subthalamic neurons with burst-firing pattern compared to normal rats, while having no effect on their firing rate. These results show that the serotonergic efferent projections of the dorsal raphe nucleus significantly influence on the activity of subthalamic neurons and that the loss of dopaminergic projection by substantia nigra pars compacta lesion decreases the effect of the lesions of the dorsal raphe nucleus on subthalamic nucleus neuronal activity, suggesting that the role of the dorsal raphe nucleus may be exerted by the dorsal raphe nucleus-substantia nigra pars compacta-subthalamic nucleus pathway.

Decrease of serotonin and metabolite in the forebrain and facilitation of lordosis by dorsal raphe nucleus lesions in male rats.

In castrated male rats, a radiofrequency lesion was made in the dorsal raphe nucleus (DRL) and lordosis behavior was observed following treatment with estrogen. After the behavioral test, brains were removed and the contents of 5-HT and 5-HIAA in the forebrain were measured by high pressure liquid chromatography (HPLC). In the results, only 2 of 16 control males without brain surgery showed lordosis, and the mean lordosis quotient (LQ) was extremely low when compared to that in control females. In contrast, all male rats with DRL displayed lordosis and the mean LQ was higher than that of control males without brain surgery but lower than that in control females (P < 0.001). In the DRL males, 5-HT and 5-HIAA contents in the septum (SPT), the preoptic area (POA), the ventromedial hypothalamus (VMH) and the striatum (STM) were lower than those in control male and female groups (P < 0.001). These results suggest that the dorsal raphe nucleus prevents male rats from showing lordosis by serotonergic influence in the forebrain. In addition, HPLC results showed that levels of the 5-HT in the SPT, the POA and the VMH in the female group were higher than those in the control male group (P < 0.05). In female rats, the POA (P < 0.01) and the VMH (P < 0.05) contained larger 5-HT than those in the SPT and the STM, but there were no difference of 5-HT contents in the male rat.

Prevention of inhibitory effect of dorsal raphe nucleus lesions on ovulation and LH surge by 5-HT 2A/2C receptor agonists in female rats

In order to investigate the role of the dorsal raphe nucleus and the serotonergic system in the regulation of ovulation, the number of ova and plasma luteinizing hormone (LH) concentrations were measured in female rats after making lesions in this nucleus (DRL) and/or treatment with 5-hydroxytryptamine (5-HT) receptor agonists or antagonists. DRL or sham lesion was made on the afternoon of proestrous (12:00-14:00 h) under ether anesthesia and the number of ova in the oviduct was counted on the next estrous and diestrous morning. In some animals, blood samples were taken via the atrial cannula during the proestrous evening for the radioimmunoassay of LH. All intact control and sham-operated females ovulated and plasma LH increased between 19:00 and 21:00 h. In contrast, ovulation was seen in only 36% of DRL rats. LH surge did not occur in this group. However, 80% of DRL rats ovulated after treatment with (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride [(+/-)-DOI; a 5-HT 2A/2C receptor agonist] at 15:00 h on proestrous day. LH surge was also observed in the DRL rats with (+/-)-DOI. On the other hand, only 8% of DRL rats ovulated after treatment with buspirone (5-HT 1A receptor agonist). Furthermore, when mianserin (5-HT 2A/2C receptor antagonist) was administered at 16:00 h on proestrous day, ovulation was not seen in all rats without DRL. These results suggest that the dorsal raphe nucleus plays an important role in induction of LH surge and ovulation and the 5-HT 2A/2C receptor system is involved in this mechanism.

Differential Effects of Dorsal Raphe Nucleus Lesions on Pseudopregnancy Induced by Reserpine or Vaginal Stimulation in Female Rats.

The role of the dorsal raphe nucleus in the maintenance of pseudopregnancy induced by reserpine and/or vaginal stimulation was investigated in female rats. In order to induce pseudopregnancy, either the vagina was stimulated electrically (VS) on the day of proestrus, or 1 mg/kg b.w. reserpine (R) was injected on the day of diestrus I. In some females, both VS and R treatments (VS+R) were applied. Radiofrequency lesions were made in the dorsal raphe nucleus (DRL) 5 days after VS and 3 days after R. At the same time, the left uterine horn was traumatized in order to induce deciduoma. As a result, positive decidual responses were seen in most control and sham-control rats with VS or R-treatments. In contrast, the incidence of deciduoma in DRL females with R injection was lower than that in control and sham groups, but the incidence in DRL females with VS or VS+R was comparable to that in control and sham females. These results suggest that the dorsal raphe nucleus plays an important role in maintaining the mechanism of pseudopregnancy induced by reserpine, but not in that induced by vaginal stimulation.

Effects of p-chlorophenylalanine on male sexual behavior in female rats with mesencephalic raphe nuclei lesions.

The role of serotonergic neurons in the mesencephalic raphe nuclei in regulating male sexual behavior in female rats was examined. The median or dorsal raphe nucleus lesions (MRL or DRL) were made in ovariectomized rats and behavioral tests were performed after implantation of Silastic tubes containing testosterone and treatment with serotonin synthesis inhibitor p-chlorophenylalanine (pCPA). Half of the animals in each group received 4 100 mg/kg pCPA injections before the behavioral test. As a result, the incidences and frequencies of mounts and intromissive patterns in the MRL and DRL groups were comparable to those in control females without brain surgery. Mount latency in the MRL females was shorter than that in the control females. When pCPA was given, most females with or without brain surgery showed mounts and intromissive patterns, and frequencies were higher than those in females without pCPA. These results suggest that the median raphe nucleus plays an inhibitory role in the onset mechanism for mounting. On the other hand, a stronger inhibitory influence in regulating male sexual behavior exists in other serotonergic neurons than those in the median and dorsal raphe nuclei in female rats.

Potentiation of ejaculatory activity by median raphe nucleus lesions in male rats: effect of p-chlorophenylalanine.

The effect of radiofrequency lesions in the median or dorsal raphe nucleus (MRL or DRL) on copulatory behavior was examined in sexually inexperienced male rats. Three weeks after castration and the brain surgery, all males were subcutaneously implanted with Silastic capsules containing testosterone. In the first behavioral test, the frequency of ejaculation in the MRL group was significantly higher than that in sham and DRL males, but mount and intromission were not. Seven days after the first test, the second test was carried out after treatments with 100 mg/kg p-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, or saline daily for 4 days in MRL and DRL males. The frequencies of male sexual behavior in PCPA treated DRL males were higher than those in saline treated DRL males. In contrast, even after treatments with PCPA, male sexual activity in MRL males was comparable to those in saline treated MRL males. These results suggest that serotonergic neurons in the median raphe nucleus play an inhibitory role in the regulation of male sexual activity, especially ejaculation. Furthermore, it can be thought that PCPA acts on the median raphe neurons and facilitates ejaculatory behavior.

In vivo tryptophan hydroxylase activity in rat major cerebral arteries is decreased by dorsal raphe nucleus lesions.

The in vivo presence of tryptophan hydroxylase activity in rat major cerebral arteries as well as the possible origin of the structure containing it were explored. Enzyme activity was appraised by accumulation of 5-hydroxytryptophan after inhibition of aromatic L-amino acid decarboxylase. Decarboxylase inhibition evoked a significant increase in 5-hydroxytryptophan levels in rat cerebral arteries, striatum, hippocampus, hypothalamus, and plasma but had no effect on aorta. p-Chlorophenylalanine reduced 5-hydroxytryptophan accumulation in the cerebral vessels and brain nuclei, whereas alpha-methyltyrosine did not modify it except in hypothalamus, where it was enhanced. alpha-Methyltyrosine significantly reduced noradrenaline levels in cerebral arteries and L-dopa accumulation after inhibition of the decarboxylase in striatum. Dorsal raphe nucleus lesioning significantly diminished 5-hydroxytryptophan formation in cerebral arteries, striatum, and hypothalamus, without affecting it in hippocampus. Lesion of median raphe nucleus reduced 5-hydroxytryptophan accumulation in hippocampus and in hypothalamus but not in cerebral blood vessels or striatum. Superior cervical ganglia removal decreased noradrenaline levels in cerebral blood vessels without affecting 5-hydroxytryptophan accumulation. These results indicate the presence of a functionally active tryptophan hydroxylase in rat cerebral arteries associated with fibers originating from dorsal raphe nucleus. This supports that rat major cerebral arteries receive serotonergic innervation from central origin.

2414 Inhibitory effect of dorsal raphe nucleus lesions on ovulation in female rats: Recovery by treatment with a serotonin 2A/2C receptor agonist

2414 Inhibitory effect of dorsal raphe nucleus lesions on ovulation in female rats: Recovery by treatment with a serotonin 2A/2C receptor agonist

Effects of chronic lesions in mesencephalic raphe nuclei on induction of pseudopregnancy.

The role of mesencephalic raphe nuclei in the induction of pseudopregnancy was investigated in female rats. The dorsal or median raphe nucleus lesions (DRL or MRL, respectively) were made by means of a radiofrequency lesion generator. Two or 3 weeks after the operation, in order to induce pseudopregnancy, the vagina was stimulated electrically on the day of proestrus or 1 mg/kg b.w. reserpine was injected on the day of diestrus I. Traumatization by passing thread to one uterine horn was performed to induce deciduoma 5 days after vaginal stimulation or 3 days after reserpine injection. As the results, decidual response was seen in most control and sham females in both vaginal stimulation and reserpine-treated groups. In contrast, incidences of deciduoma in DRL females with vaginal stimulation or reserpine-injection were significantly lower than those in control and sham groups. In the MRL females with either vaginal stimulation or reserpine-treatment, incidences of deciduoma were comparable to those of the control and sham operated groups. These results suggest that the dorsal raphe nucleus plays an important role in pseudopregnancy-inducing mechanisms in female rats.

Inhibitory effect of baclofen on lordosis in female and male rats with dorsal raphe nucleus lesion or septal cut.

The inhibitory effect of baclofen, a GABAB receptor agonist, on lordosis was examined in female and male rats with dorsal raphe nucleus lesions (DRL) or cut of the septal fibers (ARD). Both female and male DRL and ARD rats showed higher lordosis quotients (LQ) than corresponding controls without brain surgery. This indicates that the dorsal raphe nucleus and the septum exert lordosis-inhibiting influences in female and male rats. After treatment with 10 mg/kg baclofen, the mean LQs in female control and female ARD groups were significantly lower than those of vehicle-treated control and ARD females. In DRL females, however, LQs did not decrease, even after the injection of baclofen. In males, baclofen also diminished lordosis in ARD rats, but not in DRL rats. These results suggest that the GABAB receptor system plays an inhibitory role in regulating lordosis behavior not only in female but also in male rats. Furthermore, the function of the GABA neurons depends on the inhibitory mechanism of the dorsal raphe nucleus in the regulation of female sexual behavior.

Excessive serotonin release, not depletion, leads to memory impairments in rats

Eight experiments compared and contrasted the effects of serotonin release and depletion on performance by rats in two tests of memory. Most experiments (Experiments 1–5) examined the effects of the serotonergic releasing/depleting agent p-chloroamphetamine on passive avoidance performance. Additional experiments explored p-chloroamphetamine's effects on retention performance by animals trained in an 8-arm radial maze (Experiment 6), and the effects of dorsal raphe nucleus lesions on passive avoidance in animals treated with (Experiment 8) or not treated with (Experiment 7) p-chloroamphetamine. In general, acute increases in serotonin release produced consistent and extensive retention performance deficits in both passive avoidance and radial arm maze. Results from an ancillary control experiment indicated that the p-chloroamphetamine-induced passive avoidance impairment was not related to drug-induced alterations in pain sensitivity. Other experiments ruled out the possibility that p-chloroamphetamine was disrupting passive avoidance retention performance by affecting post-trial consolidation processes, producing state-dependent retention, having direct effects at postsynaptic receptors, or indirectly by affecting non-serotonergic neurotransmitter systems. Depletion of serotonin resulting from either the long-term residual effects of p-chloroamphetamine or lesions of the dorsal raphe nucleus failed to alter passive avoidance retention scores although it produced extensive depletion (45–85%) of serotonin and 5-hydroxyindoleacetic acid in the cortex and hippocampus. These data contribute to the growing body of literature indicating an important role of serotonin in cognitive processes by demonstrating that excessive release, but not depletion, of serotonin produces profound retention performance impairment.

Alterations in cerebral cortical galanin concentrations following neurotransmitter-specific subcortical lesions in the rat

Galanin is associated with multiple projection neurons, and its immunoreactivity in the cerebral cortex may be derived from diverse sources. We investigated the effects of subcortical lesions on cerebral cortical galanin concentrations. Lesions of the anterior noradrenergic bundle (ANB) comparably reduced cerebral cortical galanin and norepinephrine (NE) concentrations. The effects of the ANB lesions on galanin were immediate and became most pronounced 1 week later. Extensive unilateral lesions of the nucleus basalis of Meynert (NBM) decreased galanin concentrations, although not as markedly as after ANB lesions. The NBM lesions had no additional effect in the presence of an ANB lesion. Decreases in cerebral cortical galanin concentrations depended upon the extent and the duration of the NBM lesion and were not as pronounced as the decreases in markers of cholinergic activity. Acute treatments with physostigmine, which inhibit cerebral cortical AChE, had no effect on galanin concentrations. The depletion of galanin following an NBM lesion was most pronounced within hours of the insult, while the depletion of ChAT following the same lesions required several days to develop. Cortical concentrations of galanin and 5-HT increased 1 hr after dorsal raphe nucleus (DRN) lesions and then decreased 7 d later. Six weeks later, galanin concentrations recovered in the cerebral cortex despite the continued depletion of 5-HT. These studies suggest that a substantial portion of cerebral cortical galanin may derive from noradrenergic neurons and may be modulated by cortically-projecting ACh and 5-HT neurons.

Cat Cerebral Arteries Are Functionally Innervated by Serotoninergic Fibers From Central and Peripheral Origins

Tryptophan hydroxylase activity and responses to tyramine were analyzed in cat cerebral arteries to investigate serotoninergic innervation. Enzymatic activity and responses to tyramine were measured in vessels from animals subjected to cervical gangliectomy and dorsal and median raphe nuclei lesions. Tryptophan hydroxylase activity in cat cerebral arteries was reduced after ganglia removal and raphe nuclei destruction. Contractile responses of the middle cerebral artery after gangliectomy were decreased by ketanserine. Dorsal raphe nucleus destruction had a significant effect on the contractile response, whereas median raphe nucleus destruction had only a slight effect. Cat cerebral arteries receive serotoninergic innervation from central and peripheral origins.

Two types of lordosis-inhibiting systems in male rats: Dorsal raphe nucleus lesions and septal cuts

To examine the functional relationships between the dorsal raphe nucleus and the septum in the inhibitory regulation of feminine sexual behavior in male rats, castrated male rats received destruction of the dorsal raphe nucleus (DRL), interruption of the septal outputs (ARD), or both DRL and ARD (DRL + ARD). All animals were treated with estradiol by using Silastic tubes, and feminine sexual behavior was observed every other day for 10 days. Most castrated control male rats did not show lordosis throughout the tests. In contrast, all of the males with DRL alone or ARD alone displayed lordosis, but the lordosis quotients (LQ) in these groups were lower than those of the female control group. On the other hand, DRL + ARD males showed higher LQs than the DRL or the ARD males, being comparable to control females. Thus, two types of strong inhibitory influence exist in the dorsal raphe nucleus and the septum, and resist the facilitation of feminine sexual behavior by estrogen in male rats. Furthermore, these inhibitory systems operate independently, because an additive effect of DRL and ARD in facilitating lordosis was clearly observed in DRL + ARD males.

Pharmacological suppression of the median raphe nucleus with serotonin 1a agonists, 8-OH-DPAT and buspirone, produces hippocampal theta rhythm in the rat

The effects on the hippocampal electroencephalogram of microinjections of procaine hydrochloride and the serotonin 1a agonists, 8-OH-DPAT and buspirone, into the median raphe nucleus were examined in the urethane anesthetized rat. Injections of procaine, 8-OH-DPAT or buspirone into the median raphe nucleus produced a change in the hippocampal electroencephalogram from a spontaneous desynchronized pattern to a synchronized pattern (theta rhythm) within short latencies and for long durations post-injection. Procaine was shown to elicit theta at a mean latency of 52 s and for a mean duration of 21.75 min; buspirone at a mean latency of 2 min and for a mean duration of 34.5 min. A dose dependent relationship was observed between 8-OH-DPAT injections and latencies but not durations. Small doses (0.5μg) of 8-OH-DPAT produced theta at a mean latency of 1.33 min and large doses (3.0μg) at a mean latency of 1.17 min. 8-OH-DPAT injections generated theta for a mean duration of 62 min. Injections of each of these substances into structures dorsal, lateral or rostrocaudal to the median raphe (dorsal raphe nucleus, pontine reticular formation, caudal linear nucleus or raphe pontis, respectively) failed to generate theta or in a few cases produced theta at very long latencies (> 24 min). Saline injections in the median raphe nucleus or control structures were without effect. The demonstration that agents injected into the median raphe nucleus that inhibit its activity (procaine and serotonin 1a agonists) produce theta indicate that serotonin-containing median raphe neurons normally suppress theta or are involved in the control of hippocampal desynchronization. The present findings are consistent with previous work showing that median raphe nucleus stimulation desynchronizes the hippocampal electroencephalogram and that median raphe nucleus lesions produce constant theta, but are at odds with the proposal that serotonergic mechanisms may play a role in the generation of the theta rhythm.

Re-examination of the effects of raphe lesions on the sleep/wakefulness cycle states in cats.

To study the specific effects of central superior raphe nucleus (CeSR) lesions on the different sleep/wakefulness cycle states of the cat, nine animals with implanted electrodes for EOG, EMG and EEG recordings were used. Seven cats received diathermocoagulation lesions that destroyed between 13 and 100 percent of the CeSR; the remaining two cats, which suffered lesions in the paramedial region of the oral pontine reticular nucleus (RPO), were used to determine the effects on sleep/wakefulness states caused by damage to adjacent CeSR structures and/or passage fibres. Three prelesion and five postlesion weekly 24 h recordings were obtained from each cat. Recordings were scored according to the polygraphic criteria for wakefulness (W), drowsiness (D), slow wave sleep (SWS) and paradoxical sleep (PS). Results indicated that insomnia is not produced exclusively by CeSR lesions, since adjacent paramedial RPO lesions also decrease both SWS and PS; however, increased W occurred after the former while increased D occurred after the latter. Correlation coefficient analyses showed that W is the only state that correlates significantly with the volume of CeSR destroyed. The following correlations between different states of the sleep/wakefulness cycle were, however, significant: W-D, W-SWS and SWS-PS. Disinhibition of W, therefore, and not sleep loss seems to be the primary effect of CeSR lesions. Thus, the CeSR nucleus appears to be involved in arousal mechanisms rather than in direct sleep promotion.

The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock.

It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hr after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the escape learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed.

Female sexual behaviors in male rats with dorsal raphe nucleus lesions: Treatment with p-chlorophenylalanine

The effects of the serotonin-synthesis inhibitor, p-chlorophenylalanine (PCPA) on female sexual behaviors were examined in male rats with or without lesions (DRL) of the dorsal raphe nucleus, which contains a large number of serotonergic cell bodies. Estrogen-primed castrated males without brain surgery (control) showed extremely low levels of lordosis compared with females. On the other hand, DRL males displayed lordosis response more frequently than control males, but the lordosis quotient (LQ) in this group was lower than that in females. As well as DRL males, all PCPA-treated males showed lordosis, the mean LQ being comparable to the DRL group. Thus, the destruction of the dorsal raphe nucleus or the deprivation of serotonin by PCPA treatment facilitates manifestation of lordosis behavior in male rats. However, synergistic effect of DRL and PCPA treatments on female sexual behaviors have not been observed. The mean LQ in PCPA-treated male rats with DRL was almost the same as in DRL males or PCPA-treated males. These results suggest that the possible site of action of PCPA in regulating female sexual behavior in male rats is the serotonergic neurons in the dorsal raphe nucleus. Furthermore, the lordosis-facilitating effect of DRL is due to destruction of the serotonergic cell bodies in the dorsal raphe nucleus.