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The role of serotonin 5-HT5A receptors in the modulation of miniature inhibitory synaptic activity was studied using intracellular recording of miniature glycinergic inhibitory postsynaptic potentials (glymIPSPs) in the lumbar motoneurons of the isolated spinal cord of the frog Rana ridibunda. In a medium containing TTx, CNQX, D-AP5, bicuculline, application of the serotonin receptor agonist 5-CT (10 µM) with high affinity for 5-HT5A led to a suppression of frequency by 86%, as well as the disappearance of high-amplitude glymIPSPs (200–500 µV) at preservation of rare potentials with an amplitude of about 100 µV. This effect indicates the possibility of pre- and postsynaptic action of 5-CT at such a concentration, not limited to its effect only on 5-HT5A receptors. The addition of methysergide, a blocker of 5-HT1,2 receptors, to the medium reduced the average frequency of glymIPSPs by 67%, the frequency of high-amplitude events by 5 times and their average amplitude by 20%, which may indicate the participation of 5-HT5A receptors in pre- and postsynaptic modulation in glymIPSPs of motoneurons. Application of 1 µM 5-CT led to a decrease in the frequency of glymIPSPs by 49% without a noticeable change in the amplitude of glymIPSPs, and the subsequent introduction of SB-699551, a selective antagonist of 5-HT5A receptors, into the solution increased the frequency of events by 41%, which confirms the involvement of 5-HT5A receptors in presynaptic modulation of glymIPSPs. Immunofluorescence study showed that supra- and intraspinal 5-HT+ ir neurons produce abundant branching in the lumbar region with the possibility of forming axosomatic contacts with labeled motoneurons and axodendritic contacts on the proximal and distal portions of their dendrites. It is also possible to form contacts in the perimedullary plexus, penetrated by the distal dendrites of motoneurons and astrocytic processes. This represents the structural basis for post-, pre- and extrasynaptic modulation of motoneuron activity by serotonin. The possibility of postsynaptic modulation of motoneuron activity through 5-HT5A receptors is confirmed by the point-like fluorescence of the 5-HT5ARlike+ signal on the dendrites and bodies of labeled motoneurons, which is present in the neuropil but absent in the perimedullary plexus. Double labeling with antibodies to the 5-HT5A receptor and the Ca2+-binding protein, parvalbumin, revealed 5-HT5ARlike+ localization in the myelin sheath of dorsal and ventromedial funiculi fibers. In preparations after long-term stimulation of the ventral roots through suction electrodes when labeling motor neurons with biocytin, a bright 5-HT5ARlike+ signal was detected in the myelin of motor axons, dorsal root fibers entering the brain in the region of the dorsal horn and individual fibers of the ventromedial funiculus. The participation of extrasynaptic 5-HT5A receptors in the functioning of feedback circuits of lumbar motoneuron activity, with the possible participation of glial elements in these circuits, is discussed. [ABSTRACT FROM AUTHOR]

Abstract: The limbic system is composed of cortical as well as subcortical structures, which are intimately interconnected. The resulting macrostructure is responsible for the generation and expression of motivational and affective states. Especially high levels of serotonin are found in limbic forebrain structures. Serotonin projections to these structures, which arise from serotonergic cell body groups in the midbrain, form a dense plexus of axonal processes. In many areas of the limbic system, serotonergic neurotransmission can best be described as paracrine or volume transmission, and thus serotonin is believed to play a neuromodulatory role in the brain. Serotonergic projections to limbic structures, arising primarily from the dorsal and median raphe nuclei, compose two distinct serotonergic systems differing in their topographic organization, electrophysiological characteristics, morphology, as well as sensitivity to neurotoxins and perhaps psychoactive or therapeutic agents. These differences may be extremely important in understanding the role of these two serotonergic systems in normal brain function and in mental illness. Central serotonergic neurons or receptors are targets for a variety of therapeutic agents used in the treatment of disorders of the limbic system. [Copyright &y& Elsevier]

Cochlear serotonergic innervation is constituted by efferent fibers projecting both to the area below the inner and the outer hair cells. Previous detection of serotonin (5-HT) metabolites and 5-HT receptor mRNAs suggests the existence of serotonergic synaptic activity in the cochlea. The present study explores this possibility through the effect of 6-nitroquipazine (6-NQ), a 5-HT selective reuptake inhibitor, on the basal turnover of 5-HT. The concentrations of 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) were quantified by high performance liquid chromatography with electrochemical detection in blood-free cochleae of rats treated with 6-NQ or saline and kept under silent conditions. Treatment with 6-NQ induced a significant increase of the cochlear concentration of 5-HT and a significant reduction of 5-HIAA concentration with respect to saline treatment. These findings could indicate that 6-NQ induced the blockade of the 5-HT selective reuptake to the cochlear serotonergic fibers. This suggests that plasma membrane 5-HT transporters are present in cochlear serotonergic fibers. Even though the role of serotonergic innervation on cochlear physiology remains unknown, the existence of cochlear serotonergic synaptic activity is strongly supported by present contributions. [Copyright &y& Elsevier]

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra and dopamine depletion in the striatum. Non-dopaminergic systems are also affected, including the serotonergic system. Enhanced striatal serotonergic innervation is a proposed compensatory mechanism for the dopaminergic deficit. Meanwhile a serotonergic deficit has been suggested as preceding the nigrostriatal dopaminergic pathology in PD. Our aim was to assess the serotonergic innervation of the striatum in a model of progressive experimental parkinsonism in macaques, from pre-symptomatic to symptomatic stages. The neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) was administered to adult macaque monkeys using a slow intoxication protocol. The intoxicated animals were classified into asymptomatic, recovered, moderate and severe parkinsonian, based on their motor behavior. The serotonergic innervation was studied by immunohistochemistry against serotonin (5-HT). In the striatum, the density of 5-HT-immunoreactive (5-HT+) axons was estimated with stereology. Images of the striatum in the immunostained sections were taken to compare the distribution patterns of the serotonergic innervation between groups. These patterns were apparently similar among the groups. Axonal density estimations showed no differences in striatal 5-HT+ innervation between the intoxicated groups and the control group. Accordingly, this study fails to find significant changes in the striatal serotonergic axonal innervation in MPTP-treated monkeys, coinciding with previous biochemical findings in our model. However, it is possible that alterations in the serotonergic system in PD could be independent of axonal density changes. Consequently, the proposed role for striatal serotonin serving as a compensatory mechanism for dopaminergic denervation merits further study. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'. • Enhanced and reduced striatal 5-HT innervation have been purported in parkinsonism. • The length density of serotonergic axons does not change in parkinsonian monkeys. • Serotonergic alterations, if present, may be independent of axonal density changes. [ABSTRACT FROM AUTHOR]