Reduction in excessive muscle tone by selective depletion of serotonin in intercollicularly decerebrated rats

Intercollicular decerebration in animals induces sustained facilitation of muscle tone of the limbs and this animal model has been used to assess centrally acting muscle relaxants. We have examined the involvement of central and spinal cord serotonergic pathways in the onset of excessive muscle tone in an intercollicularly decerebrated rat. Descending serotonergic pathways are known to modulate, directly or indirectly, the excitability of spinal cord motoneurons and it is inferred that serotonin (5-HT) plays an important role in locomotion. Alteration of muscle tone has been investigated in 5-HT-depleted rats with a neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) after pretreatment with desipramine. Intracerebroventricular (i.c.v.) administration of 5,7-DHT reduced 5-HT content in the forebrain to 50.5% and that in the spinal cord to 10.5%, while intrathecal (i.t.) administration of 5,7-DHT decreased 5-HT content in the spinal cord to 8.9% without causing any change in the forebrain. In contrast, noradrenaline or dopamine content was not affected by the neurotoxin in both tissues. These treatments significantly attenuated the muscle tone in the animal models. Moreover, the measurement of 5-HT and 5-hydroxyindoleacetic acid content in intact rats after decerebration showed that facilitation of the 5-HT turnover in the spinal cord, but not in the forebrain, was enhanced compared with sham-operated rats. These findings suggest that the descending serotonergic pathways are essential to induce excessive muscle tone in the intercollicular decerebrated rats and that 5-HT antagonists might be candidates for centrally acting muscle relaxants.     

Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats

The effect of L-dihydroxyphenylalanine (L-DOPA) on extracellular dopamine (DA) in the striatum was determined by microdialysis in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with and without the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At the same time the intensity of L-DOPA-induced rotational behavior was assessed. In 6-OHDA-lesioned rats treated with 5,7-DHT, L-DOPA (50 mg/kg, i.p.) increased extracellular DA only to 20% of that measured in animals not treated with 5,7-DHT. Likewise, 6-OHDA-lesioned rats treated with 5,7-DHT exhibited a significantly lower number of L-DOPA-induced rotations. These results suggest that serotonergic terminals in the striatum can convert exogenously administered L-DOPA into DA that can be released into the extracellular space.     

Effect of destruction of serotonin neurons on basal and fenfluramine-induced serotonin release in striatum

This study examined the relationship between the magnitude of tissue serotonin (5-HT)depletion produced by treatment with the neurotoxin 5,7-dihydroxytryptamine (5,7) and basal and fenfluramine-induced 5-HT release in the striatum. Separate groups of rats were treated with either vehicle or 5,7-DHT (100μ 76% striatal 5-HT depletion; or 200μ 93% styriatal 5-HT depletion). four weeks after treatment 5-HT release was measured in the ventral striatum using in vivo microdialysis in animals anesthetized with chloral hydrate. Basal 5-HT levels were not significantly altered in any lesion group, whereas basal 5-hydroxyindoleacetic acid levels were dosedependently reduced by 5,7-DHT. In contrast, the increase of 5-HT release produced by fenfluramine treatement (10 mg/kg) wa diminished significantly after 5-HT neuronal destruction in correlation with the reduction of striatal tissue 5-HT content. Fractional 5-HT efflux, a measure of the 5-HT release from surviving striatal nerve terminals, was also significantly elevated when tissue depletion of 5-HT exceeded 95%. This study suggests that compensatory mechanisms may enable surviving 5-HT terminals to maintain basal 5-HT levels in th striatum with as little as 5% of the terminals remaining, but those mechanisms are not sufficient to allow the damaged system to respond to a pharmacological challenge. © 1995 Wiley-Liss, Inc.     

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.     

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.     

Effect of serotonergic, corticostriatal and kainic acid lesions on the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6- tetrahydropyridine (MPTP) in mice

In mice, prior destruction of striatal 5-hydroxytryptamine (5-HT) neurons by intrastriatal or intraventricular injections of 5,7-dihydroxytryptamine did not abolish or attenuate DA depletions produced in striatum by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). This suggests that although they contain monoamine oxidase type B, the oxidative conversion of MPTP to 1-methyl-4-phenyl-pyridinium ion (MPP+) does not take place in 5-HT neurons. Likewise, decortication and kainic acid lesions did not prevent or enhance striatal MPTP-induced DA decrements suggesting that corticostriatal projections and striatal neurons are not involved in the mechanisms of MPTP neurotoxicity.     

Serotonergic sprouting is induced by dopamine-lesion in substantia nigra of adult rat brain

We have previously extracted a serotonin (5-HT) neurotrophic supernatant from the 5,7-DHT lesioned hippocampus. The current study shows that a new 5-HT neurotrophic signal was monitored in the striatum and nigra after DA-denervation. Such a signal may be involved in the heterotypic sprouting. Dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA), was injected directly into the substantia nigra of adult rats. Two months after surgery, immunocytochemical staining showed that tyrosine hydroxylase (TH)-positive cell bodies had mostly disappeared in the substantia nigra, and TH-positive terminals in the striatum were almost completely depleted. Meanwhile, the 5-HT fibers, which exist in the same areas with low density, sprouted in the nigra as well as in the striatum and became dense. Normally 5-HT fibers innervate the striatum sparsely and the globus pallidus densely with sharp delineation (in the control side), and become dense across both areas with no appreciable delineation (in the lesion side). The increase of 5-HT fibers was more prominent in the posterior than in the anterior striatum. A significant increase in 5-HT and 5-HIAA levels was also evident in the posterior striatum when the decrease in DA level exceeded 90% in the nigra and striatum. In addition, we found that induction of 5-HT sprouting requires a greater than 90% decrease of DA level. Current data support that 6-OHDA injection in the substantia nigra of adult rats triggered a trophic signal or removed an inhibition for the growth of 5-HT neurons which responded with sprouting in the nigra as well as in the 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.     

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.     

Intratesticular Serotonin Affects Steroidogenesis in the Rat Testis

The effect of intratesticular administration of serotonin (5-HT), ketanserin (5-HT2 receptor antagonist), and 5,7-dihydroxytryptamine (5,7-DHT) (the neurotoxin that destroys serotoninergic neural elements) on steroidogenesis was studied in immature and adult rats. In adults, bilateral intratesticular injection of 5-HT resulted in a significant decrease in basal but not in hCG-stimulated testosterone secretion and in serum testosterone concentration, whereas ketanserin induced a significant rise in steroidogenesis 1  h post-treatment. There was no effect 1 day after administration of 5-HT or ketanserin, and 7 days after the injection of 5,7-DHT. In immature rats 1 day after bilateral testicular administration of ketanserin, basal testosterone secretion in vitro was significantly suppressed. In immature hemicastrates, local injection of 5-HT resulted (1 day post-treatment) in a significant rise in steroidogenesis while administration of 5,7-DHT decreased testosterone secretion 7 days after the injection of the neurotoxin. The results indicate that in adult rats 5-HT exerts a suppressive, whereas in immature rats, a stimulatory action on steroidogenesis occurs. Data also suggest that, in both age groups, the effect of 5-HT is mediated through 5-HT2 receptors. The observation that in immatures administration of the neurotoxin resulted in an effect similar to that found following the treatment with the receptor antagonist suggests that, in this age group, 5-HT derived from local neural elements might also be involved in the control of 5-HT on Leydig cell steroidogenesis.     

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.     

Evidence for a mutual interaction between noradrenergic and serotonergic agonists in stimulation of ACTH and corticosterone secretion in the rat

We investigated the mutual interactions between hypothalamic norepinephrine (NE) and serotonin (5-HT) in mediating the ACTH and corticosterone responses to direct stimulation of the paraventricular nucleus (PVN) with adrenergic and serotonergic agonists. The hormone responses to the intrahypothalamic injection of the alpha1-adrenergic agonist phenylephrine (20 nmol/2 microl) were significantly reduced by prior depletion of hypothalamic 5-HT with intra-PVN injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), but not after depletion of hypothalamic NE by intra-PVN injection of the noradrenergic neurotoxin 6-hydroxydopamine (6-OHDA). The ACTH and corticosterone responses to intrahypothalamic injection of the 5-HT(1A) receptor agonist 8-OH-DPAT (20 n mol/2 microl) were significantly reduced by depletion of hypothalamic NE with 6-OHDA, but not after depletion of hypothalamic 5-HT with 5,7-DHT. These mutual interactions between the NE and 5-HT neuronal systems, which innervate the PVN, may explain previous findings of equivalent reductions in the hypothalamic-pituitary-adrenal axis responses to neural stimulation after neurotoxic lesioning of either the NE or 5-HT systems.     

Ultrastructural, biochemical and electrophysiological changes induced by 5,6-dihydroxytryptamine in the CNS of the snail Helix pomatia L.

The serotonin neurotoxin, 5,6-dihydroxytryptamine (5,6-DHT), was injected into the body cavity of snails. Changes induced in the central nervous system (CNS) by the neurotoxin were studied by morphological, electrophysiological and biochemical techniques for up to 90 days following injection. The neurotoxin induced a variety of ultrastructural alterations during the early phase (1st to 6th days) following treatment. On day 6 after treatment, membranous structures first appeared in the synaptic-like areas and apparently migrated to cell bodies where they were detected by day 14. Their number increased with time. Neurotoxin-induced structural alterations were found in neuronal processes and cell bodies of the serotonergic metacerebral giant cells injected intracellularly with horseradish peroxidase and in serotonin immunoreactive axons. These findings suggest that the toxin-induced alterations are rather selective for the serotonin-containing neuronal elements. The neurotoxin decreased the concentration of 5-HT in and [3H]5-HT uptake into cerebral and pedal ganglia, with a maximum effect between the 3rd and 5th day following drug administration. 5-HT levels and 5-HT uptake returned to normal by 19-21 days after treatment. The concentration of dopamine and of [3H]DA uptake capacity were reduced between 3-5 days after injection of 5,6-DHT by 6-7 days following treatment. The transmission from identified serotonergic synapses to targets was reduced beyond day 5 after 5,6-DHT administration. By 15 days after treatment, synaptic transmission between the metacerebral giant cell (MGC) and buccal followers was blocked. Transmission recovered by day 21 after 5,6-DHT. Comparison of the time-course of functional and structural recovery indicates that while functional recovery takes place within 21 days after treatment, certain structural alterations, e.g. the membranous structures and dense particles, remain in the nerve fibres and cell bodies. These may serve as specific intracellular markers of the serotonin-containing neuronal elements long after functional recovery from the effect of 5,6-DHT.     

Identification of and interactions between noradrenergic and serotonergic neurites in the myenteric plexus

Interactions between enteric noradrenergic and serotonergic neurites in the myenteric plexus were examined. The influence of exogenous norepinephrine (NE) and endogenously released NE on the release of 3H-serotonin (3H-5-HT) from electrically stimulated, everted segments of guinea pig small intestine were analyzed. In addition, methods were employed to permit the ultrastructural identification of enteric serotonergic and noradrenergic neurites. These included electron microscopic radioautographic localization of 3H-5-HT in gut from animals treated with 6-hydroxydopamine (6-HD; 100 mg/kg) and examination of NaMnO4-fixed tissue from animals given desmethylimipramine and the indolic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Exogenous NE antagonized the stimulated release of 3H-5-HT; this action was mediated through alpha adrenoceptors. Evidence was obtained, however, that endogenous NE liberated from sympathetic postganglionic nerve terminals had a different action on the stimulated release of 3H-5-HT from that of exogenous NE. Endogenous NE appeared to facilitate 3H-5-HT release through an action on beta adrenoceptors. Terminals identified as probably serotonergic by radioautographic labeling with 3H-5-HT or by loading with 5,7-DHT were most often found to end on neuronal somata or proximal dendrites. Synaptic specializations were found by radioautography in these locations. Terminals, dendrites, and cell bodies that took up 5,7-DHT could be identified in NaMnO4-fixed material that also permitted the simultaneous recognition of noradrenergic varicosities. Apparent noradrenergic-serotonergic axoaxonic contacts were found by means of this double-labeling technique. Together with the results of the experiments on the release of 3H-5-HT, these anatomical observations suggest that noradrenergic axons form facilitatory axoaxonic synapses with enteric serotonergic neurons.     

Prefrontal cortex serotonin, stress, and morphine-induced nucleus accumbens dopamine

Uncontrollable, but not controllable, stress produces a persistent potentiation of morphine-induced nucleus accumbens dopamine (DA) efflux and morphine-induced medial prefrontal cortex serotonin (5-HT) efflux. Here we investigate medial prefrontal cortex 5-HT mediation of this potentiation. Male Sprague-Dawley rats received bilateral medial prefrontal cortex microinjections of the neurotoxin 5,7-dihydroxytriptamine (5,7-DHT, 8 microg/microl/side), which selectively depleted medial prefrontal cortex 5-HT, or vehicle (Sham), and cannula implantation in the nucleus accumbens shell. After 2 weeks, rats received either uncontrollable stress or no stress. Microdialysis and morphine (3 mg/kg) treatment were performed the following day. Morphine produced an enhanced increase in DA in the Stress-Sham group that was completely blocked by 5,7-DHT lesions, suggesting that 5-HT in the medial prefrontal cortex mediates this potentiation.     

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.     

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.     

Ontogenetic Serotoninergic Lesioning Alters Histaminergic Activity in Rats in Adulthood

The aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats lesioned as neonates with the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At 3 days after birth Wistar rats were pretreated with desipramine (20 mg/kg ip) before bilateral icv administration of 5,7-DHT (37.5 μg base on each side) or saline—ascorbic (0.1%) vehicle (control). At 10 week levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were determined in frontal cortex, striatum, and hippocampus by an HPLC/ED technique. In the hypothalamus, frontal cortex, hippocampus and medulla oblongata, the level of histamine was analyzed by an immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped activity) were performed, and effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists S(+)chlorpheniramine (H₁), cimetidine (H₂), and thioperamide (H₃) were determined. We confirmed that 5,7-DHT profoundly reduced contents of 5-HT and 5-HIAA in the brain in adulthood. Histamine content was also reduced in all examined brain regions. Moreover, in 5,7-DHT-lesioned rats the locomotor and oral activity responses to thioperamide were altered, and apomorphine-induced stereotype was intensified. From the above, we conclude that an intact central serotoninergic system modulates histamine H₃ receptor antagonist effects on the dopaminergic neurons in rats.     

Serotonergic function of aging hippocampal CA3 pyramidal neurons: Electrophysiological assessment following administration of 5,7-dihydroxytryptamine in the fimbria-fornix and cingulum bundle

Serotonergic (5-hydroxytryptamine; 5-HT) neuro-transmission has been implicated in the regulation of cognitive function and this neurotransmitter system may underlie selective neuronal degeneration found in the aging hippocampus. Age-dependent changes in 5-HT function of hippocampal CA3 subfield pyramidal neurons were evaluated in female Fischer 344 rats (2 and 17 months) following denervation of the serotonergic afferents to the dorsal hippocampus using the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Vehicle (ascorbic saline) or 5,7-DHT was administered bilaterally in the fimbria-fornix/cingulum bundle and dorsal pyramidal cell responses to microiontophoretic application of 5-HT, the 5-HT_1A agonist (±)-8-hydroxy-2-(di-N-propylamino) tetralin, the 5-HT_1A antagonist WAY 100,135 and N-methyl-D-aspartate were recorded at 3 weeks post-lesion. Independent of changes in sensitivity to the inhibitory effects of 5-HT with aging, the time to recovery of cell firing following application of 5-HT was significantly increased in the 18 month 5,7-DHT group compared to the 18 month Vehicle and 3 month 5,7-DHT groups (3.3- and 2.6-fold, respectively). These results demonstrate that serotonergic neurotransmission is altered with aging following a selective neurotoxic insult to the hippocampus. J. Neurosci. Res. 47:58–67, 1997. © 1997 Wiley-Liss, Inc.     

Possible role of central serotoninergic neurons in the development of dental pain and aspirin-induced analgesia in the monkey

The effects of aspirin or 5-hydroxytryptamine (5-HT)-related drugs on the dental pain induced by electrical stimulation of tooth pulp afferent fibers were assessed in conscious monkeys. The electrical current required for producing jaw opening is referred to as the pain threshold. Both systemic (25 to 75 mg/kg, i.p.) or central (0.5 to 1.5 mg, third cerebral ventricle) administration of aspirin produced analgesia in monkeys. In addition, activation of central 5-HT receptors with central injection of either 5-HT or its precursor, 5-hydroxytryptophan, also produced analgesia. On the other hand, inhibition of central 5-HT receptors with central administration of either cyproheptadine (a blocking agent of 5-HT receptors), p-chlorophenylalanine (PCPA, an inhibitor of 5-HT synthesis) or 5,7-dihydroxytryptamine (5,7-DHT, a depletor of central 5-HT nerve fibers) produced an enhancement in pain sensitivity (or a decrease in pain threshold). Furthermore, the analgesia induced by aspirin was antagonized by pretreatment of monkeys with either cyproheptadine, PCPA, or 5,7-DHT. The results indicate that increases in the activity of central 5-HT neurons are associated with reduced dental pain and enhanced aspirin-induced analgesia, whereas decreases in the activity of those neurons correlate with dental hyperalgesia and diminished aspirin-induced analgesia in monkeys.