Effects of 5,7-dihydroxytryptamine depletion of tissue serotonin levels on extracellular serotonin in the striatum assessed with in vivo microdialysis: relationship to behavior.

Effects of i.c.v. administration of 5,7-dihydroxytryptamine (5,7-DHT) on biochemistry and behavior were studied in awake Sprague-Dawley rats. It was found that 5,7-DHT depletion of striatal tissue levels of serotonin (5-HT) does not diminish extracellular levels until substantial depletions occur. This finding is similar to those observed after 6-hydroxydopamine lesions of the brain dopamine systems. Although varying amounts of 5,7-DHT produced serotonin depletions in striatal tissue, decreases in extracellular levels were only observed at tissue depletions greater than 60% compared to saline-injected control subjects. Thus, the effects of serotonin lesions which produce only moderate depletions may not be the result of decreased extracellular serotonin, but instead may be the result of compensatory changes in remaining neurons which maintain normal extracellular serotonin concentrations. Different degrees of striatal serotonin depletion were associated with opposite behavioral effects. Moderate levels of serotonin depletion (50-75%) produced evidence of increased anxiety, while these effects were no longer seen in rats with more severe 5-HT depletions (>75%).     

Preprotachykinin and preproenkephalin mRNA expression within striatal subregions in response to altered serotonin transmission

The effects of lowered serotonin (5-hydroxytryptamine; 5-HT) neurotransmission on preprotachykinin (PPT) and preproenkephalin (PPE) mRNA levels were examined in subregions of the striatum. Adult male rats were treated systemically with para-chlorophenylalanine (pCPA; 350 mg/kg single i.p. injection) which reduced forebrain 5-HT amounts to approximately 20% of saline-injected controls at 24 and 48 h. As measured by Northern analysis, PPT and PPE mRNA levels were elevated 50% and 160% respectively in the anterior ventromedial striatum (region included nucleus accumbens). PPT mRNA levels were raised 90% in posterior striatum (at the level of the globus pallidus) by 48 h post-pCPA injection. To determine if increased PPT and PPE mRNA levels represented a transient response to brief 5-HT inhibition, additional experiments were performed to provide continual suppression of 5-HT within the striatum. First, rats received daily intraperitoneal injections of saline or the 5-HT_1A receptor agonist, 8-OH-DPAT (1 mg/kg), for 7 days to reduce 5-HT release from raphestriatal terminals. In a parallel experiment, the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT, 5 μg), was stereotaxically injected into the striatum as a means to permanently remove 5-HT terminals. Although levels of each mRNA species were differentially sensitive to 5,7-DHT or 8-OH-DPAT, PPT and PPE mRNAs were lowered between 30–55% within the anterior dorsolateral and ventromedial striatum. Although these results support previous studies suggesting an overall positive regulatory role of serotonin on striatal tachykinin biosynthesis, PPT and PPE gene regulation in certain striatal subregions may be differentially sensitive to lowered 5-HT neurotransmission. This suggestion is supported by observations that acute systemic stimulation of 5-HT_2A/C receptors with DOI (7 mg/kg single i.p. injection) raised PPT and PPE mRNA levels within anterior dorsolateral (30–60%) and posterior (100–200%) striata, but not within the anterior ventromedial striatum.     

Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation.     

3,4-methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein

Previous experiments conducted in this laboratory showed that administration of high-dose D-fenfluramine (D-FEN) and p-chloroamphetamine (PCA) decreased 5-HT transporter (SERT) binding and tissue 5-HT by 30-60% in caudate and whole brain tissue 2 days and 2 weeks after drug administration. However, protein expression as determined by Western blot analysis did not change in either tissue or time point, except for a 30% decrease in the caudate 2 days after PCA administration. In the present study, we studied the effect of MDMA and 5,7-dihydroxytryptamine (5,7-DHT) on tissue 5-HT levels and the protein expression level of SERT and glial fibrillary acidic protein (GFAP), a validated neurotoxicity marker. HYPOTHESIS: MDMA administration decreases SERT expression. METHODS: Two weeks after MDMA administration (7.5 mg/kg i.p., q 2 h x 3 doses) or 2 weeks after i.c.v. administration of 5,7,-DHT (150 microg/rat), male Sprague-Dawley rats were sacrificed and the caudate, cortex, and hippocampal tissue collected. Western blots for SERT and GFAP were generated using published methods. Tissue 5-HT levels were determined by HPLC coupled to electrochemical detection. RESULTS: MDMA treatment decreased tissue 5-HT in cortex, hippocampus, and caudate by about 50%. However, MDMA treatment had no significant effect on expression level of SERT and GFAP in any brain region. In contrast, 5,7-DHT reduced tissue 5-HT by more than 90%, decreased SERT protein expression by 20-35%, and increased GFAP by 30-39%. CONCLUSION: These data suggest the MDMA treatment regimen used here does not cause degeneration of 5-HT nerve terminals. Viewed collectively with our previous results and other published data, these data indicate that MDMA-induced persistent 5-HT depletion may occur in the absence of axotomy.     

Hippocampal serotonin re-uptake and nocturnal locomotor activity after microinjections of 5,7-DHT in the fornix-fimbria

The role of the hippocampal 5-hydroxytryptamine (5-HT) terminals in the control of locomotor activity was investigated by lesioning 5-HT axons in the fimbria with 5,7-dihydroxytryptamine (5,7-DHT). Rats pretreated with desimipramine (10 mg/kg, i.p.) received microinjections of 5,7-DHT (0, 1, 3, 5 or 10 μg in 0.4 μl ascorbic Ringer's solution) into the fornix-fimbria. On the fourteenth to twenty-first nights after operation, nocturnal locomotor activity was measured in photocell cages. Twenty-eight to thirty days after operation degeneration of 5-HT terminals was assessed by measuring in vitro [³H]5-HT re-uptake in slices of dorsal hippocampus, ventral hippocampus and the septum.Groups injected with 5,7-DHT showed hyperactivity in the night period and increased decrements of activity between tests, both of which were related to the dose of neurotoxin. A reduction of [³H]5-HT re-uptake was found in dorsal hippocampus which was related to the dose of 5,7-DHT, but ventral hippocampal and septal [³H]5-HT re-uptake were not systematically reduced. For each rat, levels of dorsal and ventral hippocampal [³H]5-HT re-uptake were negatively correlated with the mean nocturnal activity from the 7 nights of testing. Levels of dorsal, but not ventral hippocampal [³H]5-HT re-uptake were negatively correlated with the mean nightly decrement of activity. No correlations were found between septal [³H]5-HT and these activity measures. These results, indicate that the increase in nocturnal locomotor activity caused by generalized depletion of 5-HT in the brain may be due to disruption of hippocampal 5-HT terminals supplied by the fornix-fimbria.     

Opposite changes in striatal neuropeptide Y immunoreactivity after partial and complete serotonergic depletion in the rat

The aim of this study was to investigate the consequences of partial vs. complete serotonergic (5-HT) depletions on the immunoreactivity of striatal interneurons containing neuropeptide Y (NPY). Taking into account the plasticity of the monoaminergic neurons, the effects of various doses of 5,7-dihydroxytryptamine (5,7-DHT) injected into the anterior raphe nuclei and P-chlorophenylalanine (PCPA) administration were compared in the dorsal (caudate-putamen) and the ventral (nucleus accumbens) striatum. Twenty days after administering 5,7-DHT injections inducing a substantial but partial decrease in the striatal 5-HT concentrations (about 80%), we detected a significant decrease in the number of NPY immunoreactive cells. In contrast, the PCPA inhibition of serotonin synthesis in the neurons spared by the partial lesion or the near-complete neurotoxic lesion induced an increase in the number of striatal NPY neurons. These results suggest that complex adaptive mechanisms are probably responsible for the changes in striatal NPY reactivity observed after a partial lesion and that these neurons can adapt according to the extent of 5-HT depletion. Upon comparing the NPY responses in the dorsal and ventral components of the striatal complex, no main differences were observed; while in the caudate-putamen, the changes were primarily found to occur in the medial zone. This finding is discussed here with reference to the topographical effects of dopaminergic or glutamatergic deafferentation. Finally, these results suggest that a complete interruption of the 5-HT transmission may lead to an increase in the intracellular NPY level, which may be associated with a decrease in the release of the peptide. It can therefore be postulated that serotonergic neurons normally exert a positive influence on NPY striatal neurons. © 1996 Wiley-Liss, Inc.     

Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum

Degeneration of serotonergic fibers in the rat striatum was produced by local administration of the serotonergic neurotoxin 5, 7-dihydroxytryptamine (5,7-DHT) or the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which is also toxic to serotonergic neurons. One week before neurotoxin administration, fibroblasts engineered to express the human BDNF gene were grafted into the mesencephalon, dorsal to the substantia nigra. Rats implanted with fibroblasts expressing the LacZ gene were used as controls, as well as sham-operated animals (not injected with any neurotoxin). After a survival period of 1 week, the serotonergic innervation of the striatum was assessed by measuring serotonin (5-HT) content and by immunohistochemical detection of 5-HT positive fibers. BDNF-producing cells prevented the striatal 5-HT loss induced by local administration of either 5,7-DHT or MPP(+), as well as the striatal dopamine (DA) loss induced by the latter neurotoxin. Grafting of fibroblasts carrying the BDNF or the Lac-Z gene did not modify striatal 5-HT or DA content in sham-operated animals. In 5, 7-DHT-lesioned rats, implanted or not with control Lac-Z fibroblasts, a striking reduction in the density of 5-HT immunoreactive fibers was observed. By contrast, the density of 5-HT fibers was similar in rats implanted with BDNF-producing fibroblasts as compared to sham-operated controls. The protective effect of BDNF on the damage to serotonergic terminals induced by the two neurotoxins suggests the interest of this neurotrophin in the treatment of behavioral disorders associated to neurodegenerative diseases.     

Endogenous levels of serotonin and 5-hydroxyindoleacetic acid in specific areas of the pigeon CNS: effects of serotonin neurotoxins

Endogenous levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined by high-performance liquid chromatography (HPLC) in specific regions of the pigeon central nervous system (CNS). High endogenous 5-HT levels in the visual wulst and brainstem and medium 5-HT content in the optic lobes were found. The cerebellum and retina showed low endogenous 5-HT levels. Similar endogenous 5-HIAA levels were measured in the visual wulst, optic lobes and brainstem, whereas the 5-HIAA content of the cerebellum and retina was significantly lower. The effects of para-chloroamphetamine (p-CA) and 5,7-dihydroxytryptamine (5,7-DHT) on the 5-HT and 5-HIAA content of the same regions were studied. Six days after p-CA treatment, the 5-HT content of the visual wulst, optic lobes, brainstem and the 5-HIAA content of the optic lobes and cerebellum markedly decreased. Nine days after 5,7-DHT administration, the 5-HT and 5-HIAA content of the visual wulst and optic lobes was significantly reduced. At longer survival times, serotonergic systems were differentially affected depending on both the neurotoxin treatment and the specific brain regions examined. The 5-HT content of the pigeon retina was not modified by p-CA treatment, whereas 5,7-DHT intravitreally injected caused a pronounced 5-HT depletion. Our results demonstrate that selective neurotoxins for serotonergic systems can provide a useful denervation tool for the study of serotonergic function in the pigeon CNS.     

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [3H]serotonin binding

The relationship between serotonin (5-HT) levels and [3H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [3H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [3H]5-HT binding. Fifty days postlesion, no significant differences in [3H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [3H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.     

Biochemical and behavioral effects of serotonin neurotoxins on the nigrostriatal dopamine system: Comparison of injection sites

Unilateral injections of the serotonin neurotoxin, 5,7-dihydroxytryptamine (DHT), at various points along the 5-HT pathway to the forebrain produce a turning syndrome associated with alterations of dopamine synthesis in the ipsilateral striatum. Unilateral injections of DHT into the SN produced an ipsilateral increase in striatal dopamine (DA) turnover and contralateral rotation in response to amphetamine or apomorphine. Injection of DHT into the MFB produced an ipsilateral decrease in striatal DA turnover and tyrosine hydroxylase (TOH) activity, and ipsilateral rotation in response to amphetamine or apomorphine. After the injection of DHT into the SN or MFB, there was a significant correlation between the rates of drug-induced rotation, the decrease in cortical 5-HT turnover, and the change in striatal DA turnover, suggesting that the unilateral change in DA turnover (and, presumably, the increased stimulation of DA receptors) is causally linked to turning. Injection of DHT into the zones of the striatum and GP richest in 5-HT terminals produced the same responses as the MFB-lesioned rats: ipsilateral rotation and a decrease in striatal TOH activity. Injection of DHT into the area of the striatum richest in DA terminals failed to produce rotation or a significant change in TOH activity. We suggest that 5-HT neurons from the raphe nuclei exert a tonic inhibition on the nigrostriatal pathway at the level of the SN through direct synapses on DA neurons, whereas their neostriatal terminals have an indirect effect on DA terminals, perhaps via interaction with cholinergic and GABA-ergic neurons.     

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [H]serotonin binding

The relationship between serotonin (5-HT) levels and [³H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [³H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [³H]5-HT binding. Fifty days postlesion, no significant differences in [³H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [³H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.     

Neural and hormonal consequences of neonatal 5,7-dihydroxytryptamine may not be associated with serotonin depletion

The neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) is often used in neonatal rats to induce specific, rapid, and permanent depletion of brain serotonin (5-HT). One assumed benefit of using this drug in neonates is that it is well-tolerated, with pups exhibiting few side effects normally attributed to 5-HT depletion. Here, we present evidence that 5,7-DHT administered neonatally induces seizure-like behavior, decreases weight gain, and increases plasma corticosterone without depletion of brain 5-HT.     

Regional central serotonin-2 receptor binding and phosphoinositide turnover in rats with 5,7-dihydroxytryptamine lesions

"Denervation supersensitivity" of serotonin (5-HT) receptors has been proposed to explain the behavioral supersensitivity to 5-hydroxytryptophan (5-HTP) which develops after lesions of indoleamine neurons with 5,7-dihydroxytryptamine (5,7-DHT). To examine the possible role of receptor recognition sites and second messenger activity in supersensitivity, we measured regional 5-HT2 receptor ligand binding and 5-HT-stimulated phosphoinositide turnover in adult rats with 5,7-DHT lesions made by intracisternal injection and their saline-treated controls. In [3H]ketanserin binding studies of fresh brain tissue two weeks after 5,7-DHT injection, there were no significant changes in frontal cortex, brainstem, or spinal cord in Bmax, Kd, or nH of 5-HT2 receptors, 5,7-DHT lesions did not affect basal levels of [3H]inositol phosphate (IP) accumulation but significantly increased 5-HT-stimulated [3H]IP accumulation in the brainstem (+27%) and cortex (+23%). Because brainstem rather than cortex is involved in 5-HTP-evoked myoclonus, increased 5-HT-stimulated phosphoinositide hydrolysis in brainstem following 5,7-DHT lesions in the rat may be relevant to serotonergic behavioral supersensitivity.     

Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography

In this study, noradrenergic (NE) terminals in the dorsal raphe were identified by [3H]NE electron microscopic (EM) autoradiography. Lesioning of NE terminals by treatment with the selective catecholamine neurotoxin, 6-hydroxydopamine produced a marked decrease in NE-labelled terminals. [3H]5-HT EM autoradiography of the dorsal raphe produced labelling of cell bodies, dendrites and axons but labelled terminals with synaptic junctions were not observed. Serotonergic (5-HT) neurons were identified at an early stage of degeneration following treatment with the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). When both [3H]NE autoradiography and 5,7-DHT lesioning were combined, a majority of NE-labelled terminals, which formed synaptic specializations, innervated degenerating dendrites. These findings suggest that NE terminals directly innervate 5-HT cells in the dorsal raphe.     

Serotonin neurons grafted to the adult rat hippocampus. II. 5-HT release as studied by intracerebral microdialysis

Extracellular levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were monitored by microdialysis in the hippocampal formation previously denervated of its serotonergic input by an intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), and in 5,7-DHT denervated hippocampi reinnervated by grafted fetal rat serotonin neurons. Two weeks after 5,7-DHT lesion, baseline 5-HT release was reduced to levels below detection, and KCl- and p-chloro-amphetamine-evoked release was reduced by 90-95%. In the chronically denervated hippocampus (3 months after lesion), baseline 5-HT release had recovered to near-normal levels, but KCl- and p-chloroamphetamine-evoked release remained severely impaired. Addition of the 5-HT re-uptake blocker indalpine to the perfusion medium induced a 5-6-fold increase in serotonin overflow in the normal hippocampus, while the serotonin overflow in the 5,7-DHT denervated hippocampus remained unaffected. The intrahippocampal fetal raphe transplants restored 5-HT release to near-normal levels, not only under baseline conditions but also in the presence of re-uptake blockade. Both KCl- and p-chloroamphetamine-induced release had recovered in the grafted hippocampus and the responses were even greater than those seen in normal animals. In both normal and grafted hippocampus addition of the sodium channel blocker tetrodotoxin reduced 5-HT overflow to the level seen in the denervated hippocampus. The new hippocampal serotonin innervation, established by the grafts, was markedly denser than normal, and the tissue 5-HT and 5-HIAA levels were 3-4-fold higher than normal in the grafted hippocampi. The 5-HIAA level in the perfusate collected from the grafted hippocampi showed a similar increase above normal, whereas 5-HT release was maintained within the normal range, both under baseline conditions and in the presence of re-uptake blockade. The results indicate that the grafted serotonergic raphe neurons are spontaneously active at the synaptic level, despite their ectopic location. The ability of the grafted neurons to maintain 5-HT release within the normal range suggests that local regulatory mechanisms at the terminal level can compensate for abnormalities in the graft-derived innervation density.     

Experimentally induced supersensitivity of neocortical neurons to microiontophoretically administered serotonin

Central serotonergic fiber systems of the rat were selectively lesioned by intraventricular injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At various times thereafter, the sensitivity of rostral cortical neurons to microiontophoretically administered serotonin (5-HT) was compared in groups of lesioned and sham-operated animals pretreated with the 5-HT uptake inhibitor CGP 6085. Twenty-four hours after the injection of 5,7-DHT, at which time the cortical 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were both reduced by 40%, there was no significant difference in the sensitivity of cortical neurons to 5-HT. However, 3 days after such treatment, when the cortical 5-HT and 5-HIAA levels were reduced by 52% and 53% respectively, pronounced supersensitivity to 5-HT was noted. The depressant action of 5-HT on neuronal firing was potentiated with regard to both maximal firing depression and duration of the firing inhibition. A similar potentiation of the 5-HT responses was observed 7 days after lesioning. Supersensitivity thus appears to develop between 1 and 3 days after the injection of 5,7-DHT. Seven days after lesioning, the sensitivity of rostral cortical neurons to gamma-aminobutyric acid was unchanged compared to that observed in sham-operated animals.     

Depletion of serotonin in the nervous system of Aplysia reduces the behavioral enhancement of gill withdrawal as well as the heterosynaptic facilitation produced by tail shock

Noxious stimuli, such as electrical shocks to the animal's tail, enhance Aplysia's gill- and siphon-withdrawal reflex. Previous experimental work has indicated that this behavioral enhancement, known as dishabituation (if the reflex has been habituated) or sensitization (if it has not been habituated), might be mediated, at least in part, by the endogenous monoaminergic transmitter serotonin (5-HT). To assess 5-HT's role in dishabituation and sensitization of Aplysia withdrawal reflex, we treated Aplysia with the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). We found that 5,7-DHT treatment significantly reduced the dishabituation of the withdrawal reflex produced by tail shock. Treatment with the neurotoxin also blocked the heterosynaptic facilitation of monosynaptic connections between siphon sensory neurons and their follower cells, which contributes to the behavioral enhancement. Analysis by high-performance liquid chromatography indicated that 5,7-DHT treatment significantly reduced 5-HT levels in the Aplysia CNS. Moreover, the neurotoxic effects of 5,7-DHT appeared to be relatively specific for serotonergic pathways. Thus, 5,7-DHT treatment did not disrupt the ability of nonserotonergic facilitatory interneurons, the L29 cells, to facilitate the connections of siphon sensory neurons. Also, 5,7-DHT reduced 5-HT-dependent, but not dopamine-dependent, histofluorescence in Aplysia central ganglia. Finally, 5,7-DHT does not reduce the levels of the facilitatory peptides SCPA and SCPB within the Aplysia CNS. Our results, together with those of Mackey et al. (1989), indicate that 5-HT plays a major role in mediating dishabituation and sensitization of Aplysia's withdrawal reflex.     

Effect of hypothalamic injections of 5,7-dihydroxytryptamine on elicitation of mouse-killing in rats

An overall and marked serotonin (5-HT) depletion of the brain was found to facilitate initiation of mouse-killing behavior in the rat, whereas more selective 5-HT depletions within forebrain structures such as the septum, hippocampus, cingular cortex and amygdala, did not have such an effect. In order to further investigate the topography of the 5-HT pathways and terminals thought to be involved in an inhibitory control over this behavior, localized lesions of the serotonergic system(s) were performed by means of bilateral 5,7-dihydroxytryptamine (5,7-DHT) injections (5 μg/μl) into the hypothalamus in naive rats. 5,7-DHT injections into the medial hypothalamus did not affect the initiation of mouse-killing behavior, whereas the reflexive startle responses to air puffs were increased. The animals' open-field behavior remained unchanged. Forebrain 5-HT content was reduced by 50% in this group. 5,7-DHT injections into the lateral hypothalamus increased the proportion of killers to 46% as compared to 10% in the control group, in spite of a reduced activity in the open-field and unchanged startle responses. Forebrain 5-HT content was reduced by 88%. As the lateral hypothalamus contains afferents from both the dorsal and the median raphe nuclei, it is likely that 5-HT terminals modulate some hypothalamic mechanism involved in the control of mouse-killing behavior.     

Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression

Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague-Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 microg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine (PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60-66% across three subregions of the A-STR and 52-59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50-62%) and P-STR (55-82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.