Lesions Of Median Raphe Nucleus Research Articles

Differential role of serotonin projections from the dorsal and median raphe nuclei in phencyclidine‐induced hyperlocomotion and fos‐like immunoreactivity in rats

Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine-induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine-induced hyperlocomotion by parallel assessment of Fos-like immunoreactivity (FLI), a marker of neuronal activation in the brain. Male Sprague-Dawley rats were anesthetized with pentobarbitone and stereotaxically microinjected with 5 μg of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into either the dorsal raphe (DRN) or median raphe nucleus (MRN). Two weeks after the surgery, rats with lesions of the MRN, but not those with lesions of the DRN, showed significant enhancement of the hyperlocomotion induced by injection of 2.5 mg/kg of phencyclidine. Rats with MRN lesions also showed significantly higher levels of FLI in the polymorphic layer of the dentate gyrus in the dorsal hippocampus (PoDG) when compared with sham-operated controls. Rats with lesions of the DRN showed significantly higher levels of FLI in the nucleus accumbens (NAcc). These results indicate that FLI in the PoDG, but not the NAcc, correlates with enhanced phencyclidine-induced locomotor hyperactivity in MRN-lesioned rats. These results support our previous studies suggesting a role of serotonergic projections from the MRN to the dorsal hippocampus in some of the symptoms of schizophrenia.

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.

Anxiolytic-like effects of median raphe nucleus lesion in the elevated T-maze

The cell bodies of 5-HT containing neurons that innervate the limbic forebrain are mainly found in the dorsal raphe nucleus and in the median raphe nucleus (MRN). To assess the role of the median raphe nucleus in anxiety, rats bearing either electrolytic or 5-HT-selective neurotoxic lesion of the MRN were tested in the elevated T-maze. This apparatus consists of two opposed open arms perpendicular to one enclosed arm. Two tasks are performed in succession by the same rat in one experimental session, namely inhibitory avoidance of the open arm, taken as a measure of conditioned anxiety and one-way escape from the open arm, considered as a measure of unconditioned fear. The test was performed 7 days after the electrolytic lesion (3 mA, 10 s) or 14 days after the neurotoxic lesion (5,7-DHT, 8 μg/1 μl). The results showed that while the electrolytic lesion impaired both inhibitory avoidance and one-way escape, the neurotoxic lesion impaired only inhibitory avoidance. Therefore, serotonergic pathways originating in the MRN seem to participate in the modulation of conditioned anxiety but not unconditioned fear. Other neurotransmitter systems that either originate in or pass through the MRN may regulate unconditioned fear.

Anxiogenic effect of median raphe nucleus lesion in stressed rats

Serotonin (5-HT) neurons located in the median raphe nucleus (MRN) may have a role in the development of behavioral changes to stress. The objective of the present work was to investigate the effects of a selective lesion of 5-HT neurons located in the MRN in previously stressed male Wistar rats submitted to the elevated plus maze (EPM). In an initial experiment, the animals ( n=20–22) were submitted to one (acute) or seven (chronic) daily restraint stress periods (2 h) and tested in the EPM 24 h later. Results showed that acute restraint caused a significant decrease in the number of entries into the open arms, as compared to nonstressed controls. This effect disappeared when the animals were submitted to chronic restraint. In the next set of experiments, animals ( n=6–8) received, 1 week before the behavioral studies, intra-MRN injection of 5,7-dihydroxytryptamine (5,7-DHT; 8 μg/1 μl). Neurochemical analysis showed that this treatment significantly decreases 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) levels in the hippocampus, but not in the striatum. No difference between lesioned and sham-operated animals in EPM performance was found in nonstressed animals or in those submitted to acute restraint. In chronically restrained animals, however, lesioned rats showed a significant decrease in the number of entries and time spent in the open arms. These results suggest that lesions of 5-HT neurons located in the MRN cause anxiogenic-like behavior in animals that have been chronically restrained.

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.

EFFECTS OF EXCITOTOXIC MEDIAN RAPHE LESIONS ON SCOPOLAMINE-INDUCED WORKING MEMORY DEFICITS IN INHIBITORY AVOIDANCE

The aim of the present study was to investigate the effects of excitotoxic damage of the serotonergic cell bodies in the median raphe nucleus (MRN) on the scopolamine-induced working memory deficits in a single-trial light/dark inhibitory avoidance task. Rats were given 1 mg/kg of scopolamine hydrobromide (intraperitonal, IP) or saline before the inhibitory avoidance training, in which initial preference to the dark compartment (escape latency) was used to measure nonmnemonic behaviors, and response latency to enter the dark compartment immediately after the shock was used to measure working memory. It was found that scopolamine significantly reduced escape latencies in sham-lesioned rats, whereas it had no effect in the rats with MRN lesions. Although MRN lesion per se did not alter response latency, it prevented scopolamine-induced decrease in this parameter. These results suggest that the antagonistic interactive processes between serotonergic projections of the MRN and the muscarinic cholinergic system modulate nonmnemonic attentional component of working memory formation in the inhibitory avoidance.

Distinct contributions of median raphe nucleus to contextual fear conditioning and fear-potentiated startle.

Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also reduced the amount of freezing and the fear-potentiated startle. Freezing is a prominent response of contextual fear conditioning, but does not seem to be crucial for the enhancement of the startle reflex by explicit aversive cues. As fear-potentiated startle may be produced in posttraining lesioned rats that are unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, contextual fear and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN.

Serotonergic lesion of median raphe nucleus alters nerve growth factor content and vulnerability of cholinergic septohippocampal neurons in rat

About 45% of the serotonergic raphe neurons are reported to express nerve growth factor (NGF) receptors. We therefore investigated whether selective serotonergic lesions of the median or dorsal raphe nuclei are associated with changes in NGF protein levels of the brain and whether the loss of serotonergic function alters the vulnerability of cholinergic septohippocampal neurons. In adult rats the hippocampal NGF content changed in a biphasic way after lesion of the median raphe nucleus by 5,7-dihydroxytryptamine (5,7-DHT), with a significant increase after 2–3 weeks of up to 35%, followed by a significant reduction of 22% below control levels after 7 weeks, and a return to control levels within the following 4 weeks. By contrast, the decrease in hippocampal serotonin and 5-hydroxyindoleacetic acid remained throughout the observation period of 11 weeks, being still reduced to 15 and 30% of the control levels, respectively. In the frontal cortex the partial loss of the serotonergic innervation projecting from the median raphe was associated 5 weeks after 5,7-DHT injection with an increase in NGF protein of 39.7±9.6% ( P<0.05), which remained elevated up to 11 weeks. At 9 weeks after 5,7-DHT, the lesion of the septohippocampal cholinergic neurons induced by the cholinotoxin ethylcholine aziridinium (AF64A) was exaggerated ( P<0.05) as compared to AF64A-treated rats with intact serotonergic innervation. The present data indicate that a serotonergic lesion of the median raphe nucleus results in biphasic changes of NGF protein content and in a delayed increase in the vulnerability of septohippocampal cholinergic neurons.

Median raphe nucleus mediates forming long-term but not short-term contextual fear conditioning in rats

The brain serotonin is involved in mediation of emotional behaviour including anxiety and related fear conditioning. It is known that the median raphe nucleus (MRN) is the origin of a serotonergic pathway and mainly innervates septo-hippocampal formation which plays an important role in emotional cognition. However, its regulatory role in different types of fear conditioning is still unclear. In the present study, the animals underwent ibotenic acid or sham lesions of the median raphe nucleus and the effects of MRN lesions on immediate and delayed fear conditioning to multiple contextual cues were studied. Freezing behaviour served as a measure of contextual fear. Sham-lesioned animals showed reliable conditional freezing when observed immediately following foot-shock (1.0 mA) for 3-min test and 48 h after the shock for 12-min test. Rats with MRN lesions displayed robust freezing behaviour immediately after the shock, even though they showed a marked deficit in freezing 48 h following the shock. These findings indicate that the MRN-serotonergic septo-hippocampal pathway is involved in the regulation of anxiety related to fear conditioning triggered by contextual cues, suggesting that short-term contextual fear is independent on the MRN while long-term contextual fear depends on the MRN.

Regulation of contextual conditioning by the median raphe nucleus

The median raphe nucleus (MRN) has been suggested as the origin of a behavioral inhibition system that projects to the septum and hippocampus. Electrical stimulation of this mesencephalic area causes behavioral and autonomic manifestations characteristic of fear such as, freezing, defecation and micturition. In this study we extend these observations by analyzing the behavioral and autonomic responses of rats with lesions in the MRN submitted to a contextual conditioning paradigm. The animals underwent electrolytic or sham lesions of the median raphe nucleus. One day (acute) or 7 days (chronic) later they were tested in an experimental chamber where they received 10 foot-shocks (0.7 mA, 1 s with 20-s interval). The next day, sham and MRN-lesioned animals were tested again either in the same or in a different experimental chamber. During this, the duration of freezing, rearings, bouts of micturition and number of fecal boli were recorded. Sham-operated rats placed in the same chamber showed more freezing than rats exposed to a different context. This freezing behavior was clearly suppressed in rats with acute or chronic lesions in the MRN. MRN lesions also reduced the bouts of micturition and number of fecal boli. These rats showed a reduced number of rearings than sham-lesioned rats. This effect is probably the result of the displacement effect provoked by freezing since no significant differences in the number of rearings could be observed between these animals and the NMR-lesioned rats tested in an open field. This lesion produced higher horizontal locomotor activity in this test than the controls (sham-lesioned rats). These results point to the importance of the median raphe nucleus in the processing of fear conditioning with freezing being the most salient feature of it. Behavioral inhibition is also under control of MRN but its neural substrate seems to be dissociated from that of contextual fear.

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.

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.

Selective destruction of midbrain raphe nuclei by 5,7-DHT: is brain 5-HT involved in alcohol drinking in Sprague-Dawley rats?

Since serotonin (5-HT) reportedly is involved in aberrant drinking of ethyl alcohol, the present study examined a possible role of the concentration of 5-HT in systems originating in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN) or both nuclei. The preference for alcohol offered in concentrations increased over 10 days from, 3% to 30% was determined for each Sprague-Dawley rat. After the rats were anesthetized with sodium pentobarbital, either 10 μg 5,7-DHT or artificial cerebrospinal fluid (CSF) was micro-injected stereotaxically into the DRN, MRN or both nuclei. After 10 days, a second alcohol preference test was offered to the animals. Then the rats were decapitated, each brain removed and the block of tissue containing injection sites was saved for histological analysis. The remaining portion was dissected into separate regions for analysis by HPLC of 5-HT, 5-hydroxyindoleacetic-acid (5-HIAA), norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The 5,7-DHT lesion of the DRN depleted the levels of 5-HT and 5-HIAA by 50–55% in the midbrain and pons and by 70–80% in the frontal cortex, whereas, the 5,7-DHT lesion of MRN reduced 5-HT in all regions except the corpus striatum. The depletion of 5-HT was lower in MRN-lesioned than in DRN-lesioned rats in the frontal cortex and nucleus accumbens. The combined lesion of both DRN and MRN produced a massive decline of > 90% of 5-HT and 5-HIAA in all structures except the pons where 5-HT was reduced by 70%. Whereas the level of NE was reduced mainly in the frontal cortex, the levels of DA and its metabolites were essentially unaffected by the 5,7-DHT lesions. Although single or combined lesions of the DRN and MRN failed to alter the intake of alcohol of the rats, the combined serotonergic lesions increased significantly the ingestion of water but not food. Correlational analyses in the sham groups showed a negative association between the intake of alcohol and cortical dopamine and possibly hippocampal 5-HT and NE as well as between the ingestion of food and 5-HT in the frontal cortex. Taken together, these observations in the Sprague-Dawley rat suggest that lower levels of these monoamines in certain regions of the brain may play a role in the maintenance of the basal intake of alcohol but not in the drinking after the injection of 5,7-DHT. Explanations of our findings include: (1) a compensatory neurochemical change in pre- or postsynaptic 5-HT receptors subsequent to the dysfunction of serotonergic neurons in the forebrain; (2) a unique characteristic of the Sprague-Dawley strain of rat; and (3) residual quanta of 5-HT which sustains the pattern of alcohol drinking.

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.

Reduction of ECS-induced retrograde amnesia of passive avoidance conditioning after 5,7-dihydroxytryptamine median raphe nucleus lesion in the rat.

5,7-Dihydroxytryptamine (5,7-DHT), median raphe nucleus (MRN)-lesioned and sham-lesioned rats were submitted to one-trial passive avoidance conditioning followed by electroconvulsive shock (ECS) or sham-ECS. On test session (24 h later) MRN-lesioned rats presented a longer conditioned response and, chiefly, a remarkable reduction of ECS-induced retrograde amnesia in comparison to sham-lesioned animals. This effect appeared unrelated to major changes in spontaneous behavior: on training session MRN-lesioned rats exhibited a faster stepping-down from the platform; their exploratory activity into a novel cage was characterized by a slightly higher initial response; moreover MRN lesion did not significantly effect pain threshold. A reduced brain 5-HT functional activity following MRN lesion was suggested by the study of the hyperactivity syndrome induced by tranylcypromine plus L-tryptophan. Lastly, MRN-lesioned rats showed a significantly lower brain 5-HT steady level without differing from the sham-lesioned ones with respect to turnover rate. The reduction of ECS-induced retrograde amnesia observed in 5,7-DHT, MRN-lesioned rats was considered as due to a lower synaptic availability of 5-HT at the time of ECS administration.

Behavioral effect of selective and non-selective lesions of median raphe nucleus in the rat.

The role of the serotonergic (5-HT) system in the regulation of locomotor activity and consummatory behaviors was studied. Electrolytic and chemical (5,7-dihydroxytryptamine: 5,7-DHT) lesions were made in the median raphe nucleus (MR). The effects of these lesions on spontaneous locomotor activity, food and water intake and body weight were then studied. In these experiments, rats on an ad libitum feeding-drinking regimen were housed individually in cages with activity wheels located in a room kept at a temperature of 22 + 1 degrees C. For each rat, records were kept of its spontaneous locomotor activity, food and water intake, and body weight for 8 weeks before and after the placement of lesion in MR. It was observed that: (1) electrolytic destruction of the MR produced a permanent decrease in locomotor activity, and (2) there were a reduced food intake and a decreased spontaneous activity after intra-MR injection of 5,7-DHT.

Effects of median raphe nucleus lesions on hippocampal EEG in the freely moving rat

The effects of median raphe lesions on the hippocampal EEG were examined in freely moving rats. First, median raphe lesions, including those restricted to the median raphe nucleus, unequivocally produced hippocampal low-frequency theta activity (5.8 Hz, SD= 0.47 Hz) during relaxed immobility which was not observed under normal conditions. This lesion-induced theta activity during immobility continued for at least 20 days, and was markedly suppressed by atropine sulfate (10 mg/kg, i.p.). On the other hand, reticular formation lesions had little effect on either hippocampal EEG patterns during immobility, movement or PS. Second, the mean frequency of theta activity was significantly reduced during movement and PS on the day following the median raphe lesion. These findings suggest a raphe-hippocampal pathway in which the median raphe nucleus plays a major role in hippocampal desynchronization (irregular pattern) by exerting an inhibitory influence on the hippocompal theta generating or facilitating mechanism. Thus the theta activity will be induced by the disinhibition following median raphe lesions.

Effect of P-chloroamphetamine and 5,7-dihydroxytryptamine on rotation and dopamine turnover

Injections of p-chloroamphetamine (PCA) or 5,7-dihydroxytryptamine (DHT) (after pretreatment with desmethylimipramine) into the median raphe nucleus (MRN) caused depletions of 5-HT and 5-HIAA in the cortex and striatum, and a decrease of cortical 5-HT uptake without affecting NE uptake. Unilateral injections of these neurotoxins into the MRN caused contralateral rotation, which was blocked by haloperidol. The size of the lesion correlated with the rate of rotation and the decrease in 5-HT turnover in the cortex. We also found a significant correlation between the rate of rotation and the decrease in cortical 5-HT turnover, and the increase in striatal DA turnover. Moreover, there was a significant correlation between the decrease in cortical 5-HT turnover and the increase in striatal DA turnover. It was found that injections of DHT into the SN produced similar behavioral and biochemical changes as did the MRN lesions. In this model, amphetamine and apomorphine produce turning in the same direction, whereas they have opposite effects after lesions of the nigrostriatal pathway where postsynaptic DA supersensitivity occurs. Presynaptic changes appear to determine turning in this model. An inhibitory role of the serotonergic MRN on the dopaminergic nigrostriatal pathway mediated via the substantia nigra (SN) is suggested.