Peptidergic Interneurons Research Articles

Belly roll, a GPI-anchored Ly6 protein, regulates Drosophila melanogaster escape behaviors by modulating the excitability of nociceptive peptidergic interneurons.

Appropriate modulation of escape behaviors in response to potentially damaging stimuli is essential for survival. Although nociceptive circuitry has been studied, it is poorly understood how genetic contexts affect relevant escape responses. Using an unbiased genome-wide association analysis, we identified an Ly6/α-neurotoxin family protein, Belly roll (Bero), which negatively regulates Drosophila nociceptive escape behavior. We show that Bero is expressed in abdominal leucokinin-producing neurons (ABLK neurons) and bero knockdown in ABLK neurons resulted in enhanced escape behavior. Furthermore, we demonstrated that ABLK neurons responded to activation of nociceptors and initiated the behavior. Notably, bero knockdown reduced persistent neuronal activity and increased evoked nociceptive responses in ABLK neurons. Our findings reveal that Bero modulates an escape response by regulating distinct neuronal activities in ABLK neurons.

Local olfactory interneurons provide the basis for neurochemical regionalization of olfactory glomeruli in crustaceans.

The primary olfactory centers of metazoans as diverse as arthropods and mammals consist of an array of fields of dense synaptic neuropil, the olfactory glomeruli. However, the neurochemical structure of crustacean olfactory glomeruli is largely understudied when compared to the insects. We analyzed the glomerular architecture in selected species of hermit crabs using immunohistochemistry against presynaptic proteins, the neuropeptides orcokinin, RFamide and allatostatin, and the biogenic amine serotonin. Our study reveals an unexpected level of structural complexity, unmatched by what is found in the insect olfactory glomeruli. Peptidergic and aminergic interneurons provide the structural basis for a regionalization of the crustacean glomeruli into longitudinal and concentric compartments. Our data suggest that local olfactory interneurons take a central computational role in modulating the information transfer from olfactory sensory neurons to projection neurons within the glomeruli. Furthermore, we found yet unknown neuronal elements mediating lateral inhibitory interactions across the glomerular array that may play a central role in modulating the transfer of sensory input to the output neurons through presynaptic inhibition. Our study is another step in understanding the function of crustacean olfactory glomeruli as highly complex units of local olfactory processing.

The Drosophila Transcription Factor Dimmed Affects Neuronal Growth and Differentiation in Multiple Ways Depending on Neuron Type and Developmental Stage.

Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in Drosophila could be regulated by insulin/IGF signaling and the insulin receptor (dInR). Dimm is also known to confer a secretory phenotype to neuroendocrine cells and can be part of a combinatorial code specifying terminal differentiation in peptidergic neurons. To further understand the mechanisms of Dimm function we ectopically expressed Dimm or Dimm together with dInR in a wide range of Dimm positive and Dimm negative peptidergic neurons, sensory neurons, interneurons, motor neurons, and gut endocrine cells. We provide further evidence that dInR mediated cell growth occurs in a Dimm dependent manner and that one source of insulin-like peptide (DILP) for dInR mediated cell growth in the CNS is DILP6 from glial cells. Expressing both Dimm and dInR in Dimm negative neurons induced growth of cell bodies, whereas dInR alone did not. We also found that Dimm alone can regulate cell growth depending on specific cell type. This may be explained by the finding that the dInR is a direct target of Dimm. Conditional gene targeting experiments showed that Dimm alone could affect cell growth in certain neuron types during metamorphosis or in the adult stage. Another important finding was that ectopic Dimm inhibits apoptosis of several types of neurons normally destined for programmed cell death (PCD). Taken together our results suggest that Dimm plays multiple transcriptional roles at different developmental stages in a cell type-specific manner. In some cell types ectopic Dimm may act together with resident combinatorial code transcription factors and affect terminal differentiation, as well as act in transcriptional networks that participate in long term maintenance of neurons which might lead to blocked apoptosis.

Central relay of bitter taste to the protocerebrum by peptidergic interneurons in the Drosophila brain.

Bitter is a taste modality associated with toxic substances evoking aversive behaviour in most animals, and the valence of different taste modalities is conserved between mammals and Drosophila. Despite knowledge gathered in the past on the peripheral perception of taste, little is known about the identity of taste interneurons in the brain. Here we show that hugin neuropeptide-containing neurons in the Drosophila larval brain are necessary for avoidance behaviour to caffeine, and when activated, result in cessation of feeding and mediates a bitter taste signal within the brain. Hugin neuropeptide-containing neurons project to the neurosecretory region of the protocerebrum and functional imaging demonstrates that these neurons are activated by bitter stimuli and by activation of bitter sensory receptor neurons. We propose that hugin neurons projecting to the protocerebrum act as gustatory interneurons relaying bitter taste information to higher brain centres in Drosophila larvae.

Diverse in- and output polarities and high complexity of local synaptic and non-synaptic signaling within a chemically defined class of peptidergic Drosophila neurons

Peptidergic neurons are not easily integrated into current connectomics concepts, since their peptide messages can be distributed via non-synaptic paracrine signaling or volume transmission. Moreover, the polarity of peptidergic interneurons in terms of in- and out-put sites can be hard to predict and is very little explored. We describe in detail the morphology and the subcellular distribution of fluorescent vesicle/dendrite markers in CCAP neurons (NCCAP), a well defined set of peptidergic neurons in the Drosophila larva. NCCAP can be divided into five morphologically distinct subsets. In contrast to other subsets, serial homologous interneurons in the ventral ganglion show a mixed localization of in- and output markers along ventral neurites that defy a classification as dendritic or axonal compartments. Ultrastructurally, these neurites contain both pre- and postsynaptic sites preferably at varicosities. A significant portion of the synaptic events are due to reciprocal synapses. Peptides are mostly non-synaptically or parasynaptically released, and dense-core vesicles and synaptic vesicle pools are typically well separated. The responsiveness of the NCCAP to ecdysis-triggering hormone may be at least partly dependent on a tonic synaptic inhibition, and is independent of ecdysteroids. Our results reveal a remarkable variety and complexity of local synaptic circuitry within a chemically defined set of peptidergic neurons. Synaptic transmitter signaling as well as peptidergic paracrine signaling and volume transmission from varicosities can be main signaling modes of peptidergic interneurons depending on the subcellular region. The possibility of region-specific variable signaling modes should be taken into account in connectomic studies that aim to dissect the circuitry underlying insect behavior and physiology, in which peptidergic neurons act as important regulators.

Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans.

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with α(2)-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three α-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by Gα(o). In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of 'inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory α(2)-adrenoreceptors on afferent nociceptors and stimulatory α(1)-receptors on inhibitory peptidergic interneurons.

Neuropeptide signaling near and far: how localized and timed is the action of neuropeptides in brain circuits?

Neuropeptide signaling is functionally very diverse and one and the same neuropeptide may act as a circulating neurohormone, as a locally released neuromodulator or even as a cotransmitter of classical fast-acting neurotransmitters. Thus, neuropeptides are produced by a huge variety of neuron types in different parts of the nervous system. Within the central nervous system (CNS) there are numerous types of peptidergic interneurons, some with strictly localized and patterned branching morphologies, others with widespread and diffuse arborizations. From morphology alone it is often difficult to predict the sphere of influence of a peptidergic interneuron, especially since it has been shown that neuropeptides can diffuse over tens of micrometers within neuropils, and that peptides probably are released exclusively in perisynaptic (or non-synaptic) regions. This review addresses some questions related to peptidergic signaling in the insect CNS. How diverse are the spatial relations between peptidergic neurons and their target neurons and what determines the sphere of functional influence? At one extreme there is volume transmission and at the other targeted cotransmission at synapses. Also temporal aspects of peptidergic signaling are of interest: how transient are peptidergic messages? Factors important for these spatial and temporal aspects of peptidergic signaling are proximity between release sites and cognate receptors, distribution of peptidase activity that can terminate peptide action and colocalization of other neuroactive compounds in the presynaptic peptidergic neuron (and corresponding receptors in target neurons). Other factors such as expression of different channel types, receptor inactivation mechanisms and second messenger systems probably also contribute to the diversity in temporal properties of peptide signaling.

Multiple identified peptidergic interneurons express a novel pigment-dispersing hormone in the Daphnia brain and visual ganglia, some showing evidence for clock-neuron functions

Postgenomic, precursor, expressed sequence tag, and mass spectrometric peptidomic analyses allowed us to identify a single gene leading to a novel 18mer-isoform of a bety-type pigment-dispersing ho ...

Multilevel inhibition of feeding by a peptidergic pleural interneuron in the mollusc Lymnaea stagnalis.

The pleural interneuron PlB is a white neuron in the pleural ganglion of the snail Lymnaea. We test the hypothesis that it inhibits neurons at all levels of the feeding system, using a combination of anatomy, physiology and pharmacology. There is just one PlB in each pleural ganglion. Its axon traverses the pedal and cerebral ganglia, running into the buccal ganglia. It has neuropilar branches in the regions of the cerebral and buccal ganglia where neurons that are active during feeding also branch. Activation of the PlB blocks fictive feeding, whether the feeding rhythm occurs spontaneously or is driven by a modulatory interneuron. The PlB inhibits all the neurons in the feeding network, including protraction and retraction motoneurons, central pattern generator interneurons, buccal modulatory interneurons (SO, OC), and cerebral modulatory interneurons (CV1, CGC). Only the CV1 interneuron shows discrete 1:1 IPSPs; all other effects are slow, smooth hyperpolarizations. All connections persist in Ca(2+)/Mg(2+)-rich saline, which reduces polysynaptic effects. The inhibitory effects are mimicked by 0.5 to 100 micromol l(-1) FMRFamide, which the PlB soma contains. We conclude that the PlB inhibits neurons in the feeding system at all levels, probably acting though the peptide transmitter FMRFamide.

Targeted expression of tetanus toxin reveals sets of neurons involved in larval locomotion in Drosophila

The Drosophila larva is widely used for studies of neuronal development and function, yet little is known about the neuronal basis of locomotion in this model organism. Drosophila larvae crawl over a plain substrate by performing repetitive waves of forward peristalsis alternated by brief episodes of head swinging and turning. To identify sets of central and peripheral neurons required for the spatial or temporal pattern of larval locomotion, we blocked neurotransmitter release from defined populations of neurons by targeted expression of tetanus toxin light chain (TeTxLC) with the GAL4/UAS system. One hundred fifty GAL4 lines were crossed to a UAS-TeTxLC strain and a motion-analysis system was used to identify larvae with abnormal movement patterns. Five lines were selected that show discrete locomotor defects (i.e., increased turning and pausing) and these defects are correlated with diverse sets of central neurons. One line, 4C-GAL4, caused an unusual circling behavior that is correlated with approximately 200 neurons, including dopaminergic and peptidergic interneurons. Expression of TeTxLC in all dopaminergic and serotonergic but not in peptidergic neurons, caused turning deficits that are similar to those of 4C-GAL4/TeTxLC larvae. The results presented here provide a basis for future genetic studies of motor control in the Drosophila larva.

Serotoninergic afferents preferentially innervate distinct subclasses of peptidergic interneurons in the rat visual cortex

Although it is well documented that the non-pyramidal neurons of the cerebral cortex are under the influence of the vast serotoninergic input, the ultrastructural substrate for such functional interactions appears largely obscure. We sought to address this issue by dual immunoelectron microscopy, combining antibodies against serotonin (5-HT) and three neurochemical markers for peptidergic interneurons, namely somatostatin (SRIF), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). The gold-substituted silver–peroxidase method was employed to intensify and differentiate the end-product of the peptide-immunoreaction from the non-intensified 5-HT fibers. Mainly the SRIF but also the NPY neurons were encountered among the postsynaptic targets of the 5-HT boutons. Recipients of synapses were perikarya and proximal dendrites of SRIF and NPY cells but also distal dendrites of the SRIF neurons. Neither synaptic relationships nor close appositions were ever identified between 5-HT boutons and VIP-immunoreactive elements. This remarkable synaptic preference/avoidance of 5-HT afferents for specific peptidergic subpopulations reveals a ‘wired’ component of cortical serotonin neurotransmission, which should be carefully interpreted within the frame of the available literature for extrasynaptic serotonin release.

Ciliary neurotrophic factor, unlike nerve growth factor, supports neurite outgrowth but not synapse formation by adult Lymnaea neurons.

The nerve growth factor (NGF) family and ciliary neurotrophic factor (CNTF) support survival and/or neurite outgrowth of many cell types. However, it is not known whether the neurite outgrowth induced by neurotrophic factors results in the formation of synapses. We tested NGF and CNTF for their ability to induce neurite outgrowth and synapse formation in vitro by interneurons from the mollusc Lymnaea. Dopaminergic and peptidergic interneurons survived in the absence of neurotrophic factors but exhibited robust outgrowth in response to both NGF and CNTF. Chemical synapses formed between these interneurons and their target neurons cultured in NGF, but synapses were absent in CNTF. Survival, neurite outgrowth, and synaptogenesis are therefore differentially regulated in these neurons.

Dissection of a model for membrane potential oscillations in bursting neuron of snail, Helix pomatia

A slow-wave model for bursting activity based on the hyperpolarization-activated outward current has been analysed by simulation of the well-known experimental data. It is shown that the slow-wave model demonstrates an increase of membrane input resistance during the development of the depolarizing phase; responds adequately to stationary de- or hyperpolarizing current; demonstrates a phenomenon of induced hyperpolarization and contingency. Change of definite model parameters selectively affects burst or interburst interval, and the period of slow-wave oscillation. It is found that the investigated model, when using the slowest process (1.5 sec) can generate persistent oscillations with a period of more than 100 sec. Introduction of variable parameters in the model simulates an initiation of slow-wave oscillation in Helix bursting neuron evoked by stimulation of identified peptidergic interneuron. The limitation of the presented model of slow-wave oscillation is discussed.

Mechanisms of membrane potential oscillation in bursting neurons on the snail, Helix pomatia

1. 1. The mechanism of generation of membrane potential (MP) oscillations was studied in identified bursting neurons from the snail Helix pomatia. 2. 2. Long-lasting stimulation of an identified peptidergic interneuron produced a persistent bursting activity in a non-active burster. 3. 3. External application of calcium channel blockers (1 mM Cd 2+ or 5 mM La 2+) resulted in a transient increase in the slow-wave amplitude and subsequent prevention of pacemaker activity generation in bursting neurons. Application of these blockers together with endogenous neuropeptide initiating bursting activity generation, increased MP wave amplitude without prevention of bursting activity generation. 4. 4. Replacement of all NaCl in normal Ringer's solution with isoosmotic CaCl 2, glucose or Tris-HCl produced a reversible block of bursting activity generation. Stationary current-voltage relation (CVR) of bursting neuron membrane has a region of negative resistance (NRR) and does not intersect the potential axis in threshold region for action potential (AP) generation in normal Ringer's solution. In Na-free solution stationary CVR is linear and intersects the potential axis near — 52 mV. 5. 5. Novel potential- and time-dependent outward ( E rev = − 58 mV) current, I B , activated by hyperpolarization was found in the bursting neuron membrane. Having achieved a maximal value, this current decayed with a time constant of about 1 sec. Hyperpolarization inactivated maximal conductance, g B , responsible for I B , and depolarization abolished inactivation of g B . 6. 6. Short-lasting (0.01 sec) hyperpolarization of the bursting neuron membrane by inward current pulse induced the development of prolonged hyperpolarization wave lasting up to 10 sec. 7. 7. These results suggest that: (a) persistent bursting activity of RPal neuron in the snail Helix pomatia is not endogenous but is due to a constant activation of peptidergic synaptic inputs of these neurons; (b) Ca 2+ ions do not play a pivotal role in the ionic mechanism of MP oscillations but play a determining role in the process of secretion of a peptide initiating bursting activity by the interneuron presynaptic terminal; (c) depolarizing phase of the MP wave is due to specific properties of stationary CVR and hyperpolarization phase is due to regenerative properties of hyperpolarization-activated outward current I B . The minimal mathematical version of MP oscillations based on the experimental data is presented.

Neurite Outgrowth and Synapse Formation By Lymnaea Neurons: Towards a Characterization of Molluscan Neurotrophic Factors

For the last several years we have endeavoured to characterize the endogenous neurotrophic factors of the pulmonate snail, Lymnaea stagnalis. When plated in brain conditioned medium, motoneurons, interneurons and neurosecretory cells of Lymnaea all exhibited neurite outgrowth. We showed earlier that the motoneurons and interneurons respond to a Nerve Growth Factor-like (NGF-like) component of conditioned medium. Neurosecretory cells, however, appear to be under the control of a factor derived from the endocrine dorsal body cells. Most recently, we were surprised to learn that motoneurons and interneurons also respond to another vertebrate neurotrophic factor, i.e., Ciliary Neurotrophic Factor (CNTF). The outgrowth in CNTF differs both in appearance and in functional outcome. Specifically, neurites in CNTF are thin, have small growth cones and elongate more quickly than their counterparts in NGF. Regarding functional consequences, both dopaminergic and peptidergic interneurons fail to form synapses on target neurons when cultured in CNTF, but do so in NGF, as expected from our previous studies in conditioned medium. These data shed new light on the functions of neurotrophic factors and provide the first evidence that outgrowth and synaptogenesis can be differentially regulated.

Dopamine inhibits transmission between the interneuron initiating pacemaker activity in a bursting neuron and the bursting neuron on the snail Helix pomatia

1. The effect of external application of dopamine on connection between a peptidergic interneuron initiating bursting pacemaker activity in non-active burster RPal and the bursting neuron itself of the snail Helix pomatia has been investigated under clamp conditions. 2. External application of dopamine in a dose-dependent manner ( K d 15μM) produces a reversible inhibition of slow inward current (SIC) in the RPal neuron evoked by stimulation of peptidergic interneuron. At the same time, an increase of duration and amplitude of interneuronal action potential was observed. 3. Stimulation of the anal nerve evokes in RPal neuron postsynaptic current consisting of at least three components: two fast ones with reversal potentials −50 and−70mV and a long-lasting one with no reversal potential between −50 and −95mV. 4. It is concluded that inhibition of SIC by dopamine is due to the processes occurring in the postsynaptic RPal neuron. 5. Based on the hypothesis that bursting activity of RPal neuron results from the activation of presynaptic unidentified peptidergic interneuron(s) with persistent activity and on data presented it is suggested that inhibition of bursting activity evoked by application of dopamine or anal nerve stimulation is a consequence of decreased efficiency of synaptic transmission between the interneuron initiating bursting activity and the burster.

Control of Central and Peripheral Targets by a Multifunctional Peptidergic Interneuron.

In the terrestrial slug, Limax maximus, feeding activity and cardiovascular function have been shown to be correlated. For example, in intact animals, both feeding responsiveness and heart activity are suppressed during dehydration (Grega and Prior, 1986). The paired peptidergic buccal ganglion neurons RB1 and LB1 have dramatic modulatory effects on both the feeding motor program (FMP) and the force of heart contraction (Welsford and Prior, 1991). The B1 neurons appear to contain the small cardioactive peptides (SCPs). Observations have a frequency dependent excitation of both the FMP and the heart demonstrated by intracellular stimulation of B1. Thus, interneuron B1 may serve to mediate the coincident modulation of multiple responses to physiological stresses.

Somatostatin selectively inhibits excitatory contractile pathways of the feline lower esophageal sphincter

Intrinsic reflexes of the feline lower esophageal sphincter (LES) have been shown to be mediated by specific arrangements of excitatory peptidergic interneurons. Inhibition of intrinsic reflexes may also be mediated by neuropeptides. The specific aims of this study were: (1) to examine the effect of somatostatin (SOM) and vasoactive intestinal peptide (VIP) on basal LES tone, and (2) to determine if these transmitters exert selective inhibitory effects on excitatory contractile pathways. Intraluminal pressures were recorded from the LES, esophagus and fundus by a fixed perfused catheter assembly in anesthetized cats. Peptides were administered via the left gastric artery. SOM had no effect on basal LES pressure with doses ranging from 10 −9 to 10 −5 g/kg. VIP induced a dose-dependent inhibition of basal LES pressure. The maximal effective dose of VIP, 10 −6 g/kg, completely inhibited basal LES pressure ( 34.7 ± 6.8 to 1.0 ± 0.6 mmHg , P < 0.001). We have previously shown that bombesin (BN) but not substance P (SP) or bethanechol contracts the LES via tetrodotoxin-sensitive pathways. BN at the D 50 (5·10 −8 g/kg) increased LES pressure by 32.1 ± 3.6 mmHg . SOM (10 −5 g/kg) decreased this BN response to 19.2 ± 5.0 mmHg , P < 0.05. In contrast, while the D 50 of SP (5·10 −8 g/kg) gave a similar increase in LES pressure, 28.8 ± 5.1 mmHg , this effect was not altered by SOM ( 23.8 ± 6.7 mmHg , P > 0.10). SOM also had no effect on bethanechol-induced LES contractions ( P > 0.10). VIP (10 −6 g/kg) totally inhibited the LES response to the D 50 of BN, SP, and bethanechol. A submaximal dose of VIP (10 −7 g/kg) partially inhibited the contractile response of all three. Conclusions: (1) VIP, but not SOM, inhibits basal LES tone. (2) SOM selectively inhibits BN but not SP- or bethanechol-induced LES contraction. (3) VIP inhibits BN, SP and bethanechol-induced LES contractions. These studies suggest that somatostatin can selectively inhibit excitatory interneurons at the LES.

Inhibition of an identified snail postsynaptic neuron evoked by stimulation of a peptidergic interneuron initiating bursting pacemaker activity in another neuron

Beating neuron V8, whose activity is abolished upon interneuronal stimulation, has been found and identified in the CNS of the snail, Helix pomatia. It was found earlier that stimulation of the same interneuron initiates bursting pacemaker activity in another neuron. Under voltage clamp conditions interneuronal stimulation evoked a slow outward current in the V8 neuron with a latency of about 2 s. Intracellular injection of tetraethylammonium or Cs + ions into the interneuron greatly increased the slow outward current amplitude. External application of CdCl 2 (1 mM), LaCl 3 (5 mM) or replacement of Ca 2+ by Mg 2+ ions reversibly abolished transmission between the interneuron and the V8 neuron. The neuronal membrane conductance increased by about three times on the maximum of the slow outward current development. Computer fitting showed that a decay of the slow outward current can be approximated by the sum of two exponentially decaying components with time constants of about l s and 16 s. Extrapolated reversal potential for a fast (1 s) component of the current was about −70 mV. A slow (16 s) component asymptotically decreased upon hyperpolarization and it was observed at even more negative potential than E k. Theophylline (1 mM) and 3-isobutyl-1-methylxanthine (0.1 mM) reversibly increased the slow outward current amplitude, whereas imidazole (5 mM) and tolbutamide (5 mM) caused its reversible decrease. It is concluded that inhibitory monosynaptic transmission exists between the interneuron and the beating V8 neuron. Interneuronal simulation evokes an increase in the membrane potassium conductance and probably a decrease in stationary potential-dependent sodium conductance of the postsynaptic V8 neuron. The cellular cyclase system seems to be involved in the postsynaptic response.

Anatomical features and physiological properties of central serotonin neurons.

The authors describe the anatomical features and physiological properties of central serotonergic neurons. The central serotonin neurons (part of which store peptides [substance P, TRF, enkephalins] in addition to 5HT) are highly collateralized reticular-type brain stem neurons receiving multi-modal afferent information from ascending sensory and descending motor pathways. They are under control by noradrenergic, peptidergic and and gaba-ergic projection neurons and interneurons. Furthermore, they establish variable synaptoid and synaptic contacts to neuronal, glial and secretory targets throughout the entire neuraxis and send terminal branches into the ventricular CSF space. Firing rate and transmission activity appear to be controlled in a complex and rather rigid manner by 5HT release-dependent dendrodendritic and dendrosomatic inhibition via autoreceptors (which also regulate release at the axon terminals) and via transsynaptic inhibitory feedback circuits which may involve gabaergic projection and interneurons. 3H-imipramine appears to bind to an "imipramine recognition site" in the vicinity of the 5HT carrier, and to a variety of other transport and (postsynaptic) receptor sites (NA uptake, H1, 5HT2- and alpha 1-binding sites). Circumstantial evidence points to an as yet undetermined role of the postsynaptic 5HT-1-binding sites in neurotransmission. 5HT-2-binding sites fulfil the criteria for receptors: binding affinity of antagonists to these sites correlates significantly with their potency to inhibit behavioral excitation in rats elicited by 5-hydroxytryptophan or 5HT agonists.(ABSTRACT TRUNCATED AT 250 WORDS)