Guinea-pig Neurons Research Articles

Expression of peripherin in the pig spiral ganglion – aspects of nerve injury and regeneration

Conclusion. Peripherin protein may be important not only for developing neurons but also for the maintenance and regeneration of axonal processes in the mature cochlea. More knowledge about its expression and function could improve our understanding with reference to axonal regrowth and nerve restoration in the damaged cochlea. Objective. To investigate the existence of peripherin protein in adult pig spiral ganglion and cultured spiral ganglion neurons of the guinea pig. Materials and methods. Immunohistochemistry with anti-peripherin antibodies was performed on sections of adult pig spiral ganglion and guinea pig spiral ganglion cell (SGC) culture. Results. In pig auditory neurons, both type I and type II SGCs showed expression of the protein peripherin. These cells were not preferentially located near the intraganglionic spiral bundle (IGSB). The IGSB consisted of thin calibre fibres showing intense peripherin and thicker fibres that were TUJ-1 positive. Only a few fibres within the IGSB co-expressed both peripherin and TUJ-1. Cultured guinea pig neurons displayed a rich expression of peripherin, including the nuclei. This protein was expressed in regions such as the perikaryon and axons but there was also a segmental expression of peripherin in some regions. Peripherin was more expressed in areas of axon branching and in the centre of the active growth cones and lammelipodia.

P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus

The lungs and esophagus are innervated by sensory neurons with somata in the nodose, jugular, and dorsal root ganglion. These sensory ganglia are derived from embryonic placode (nodose) and neural crest tissues (jugular and dorsal root ganglia; DRG). We addressed the hypothesis that the neuron's embryonic origin (e.g., placode vs. neural crest) plays a greater role in determining particular aspects of its phenotype than the environment in which it innervates (e.g., lungs vs. esophagus). This hypothesis was tested using a combination of extracellular and patch-clamp electrophysiology and single-cell RT-PCR from guinea pig neurons. Nodose, but not jugular C-fibers innervating the lungs and esophagus, responded to alpha,beta-methylene ATP with action potential discharge that was sensitive to the P2X3 (P2X2/3) selective receptor antagonist A-317491. The somata of lung- and esophagus-specific sensory fibers were identified using retrograde tracing with a fluorescent dye. Esophageal- and lung-traced neurons from placodal tissue (nodose neurons) responded similarly to alpha,beta-methylene ATP (30 microM) with a large sustained inward current, whereas in neurons derived from neural crest tissue (jugular and DRG neurons), the same dose of alpha,beta-methylene ATP resulted in only a transient rapidly inactivating current or no detectable current. It has been shown previously that only activation of P2X2/3 heteromeric receptors produce sustained currents, whereas homomeric P2X3 receptor activation produces a rapidly inactivating current. Consistent with this, single-cell RT-PCR analysis revealed that the nodose ganglion neurons innervating the lungs and esophagus expressed mRNA for P2X2 and P2X3 subunits, whereas the vast majority of jugular and dorsal root ganglia innervating these tissues expressed only P2X3 mRNA with little to no P2X2 mRNA expression. We conclude that the responsiveness of C-fibers innervating the lungs and esophagus to ATP and other purinergic agonists is determined more by their embryonic origin than by the environment of the tissue they ultimately innervate.

Local inhibition shapes duration tuning in the inferior colliculus of guinea pigs

Neural tuning to sound durations is a useful filter for the identification of a variety of sounds. Previous studies have shown that the interaction between excitatory and inhibitory inputs plays a role in duration selectivity in echolocating bats. However, this has not been investigated in non-echolocating mammals. In the inferior colliculus (IC) of these mammals, it is recognized that the excitatory responses to sounds are mediated through AMPA and NMDA receptors while the inhibitory input is mediated through γ-aminobutyric acid (GABA) and glycine receptors. The present study explores the potential interplay between inhibitory and excitatory inputs and its role in the duration selectivity of IC neurons in guinea pigs. It was found that the application of bicuculline (BIC, a GABA A blocker) and/or strychnine (STRY, a glycine blocker) eliminated or reduced duration tuning in most units that were duration tuned (32 out of 39 for BIC, 50 out of 64 for STRY, respectively). The inhibitory input (either by GABA or by glycine) appeared to have a stronger regulating effect on the early excitation mediated by AMPA than on later excitation by NMDA. This is more distinguishable in neurons that show duration selectivity. In conclusion, the inhibitory effect on the early responses appears to be the main contributor for the duration selectivity of the IC in guinea pigs; potential mechanisms for this duration selectivity are also discussed.

Electrically Evoked Responses in Onset Chopper Neurons in Guinea Pig Cochlear Nucleus

Extracellular recordings were obtained from single cochlear nucleus neurons in guinea pigs anesthetized with Nembutal and Hypnorm. Neurons were classified by their spontaneous firing rates and responses to acoustic stimuli. In addition, electrical shocks were applied to the midline at the level of the IVth ventricle and spike responses were recorded. Spikes were evoked by shocks only in neurons that were classified as onset choppers (O(c)). The shock-evoked spikes could be extinguished by acoustically evoked action potentials in the same neurons. In roughly 30% of the sample of O(c) neurons, quantitative aspects of the timing of this extinction were not compatible with the shock-evoked spike being antidromically conducted from O(c) output axons. Together with the presence of temporal jitter at high shock rates, the data suggest the possibility that at least some of the shock-evoked spikes may be generated by excitatory synaptic input to the O(c) neurons, most likely from the collaterals of the medial olivocochlear system (MOCS), whose axons pass close to the floor of the IVth ventricle. This excitatory synaptic input may operate to modulate the activity of O(c) neurons in addition to MOCS actions in the auditory periphery.

Ligand-Induced 5-HT3 Receptor Internalization in Enteric Neurons in Rat Ileum

Release of 5-hydroxytryptamine (5-HT) from mucosal enterochromaffin cells and activation of 5-HT(3) receptors (5-HT(3)Rs) on neurons in the gut wall is important in the response of the gut to the luminal environment. Intestinal inflammation is associated with increased levels of mucosal 5-HT. The aims of the study were to determine the following: (1) if 5-HT(3)R undergoes ligand-induced internalization in myenteric neurons, and (2) the effect of long-term increase of mucosal 5-HT on 5-HT(3)Rs. Acute effects of exogenous 5-HT or endogenous release of 5-HT by luminal glucose on cellular localization of 5-HT(3)Rs was determined by immunohistochemistry and confocal microscopy. Treatment with the serotonin re-uptake inhibitor, fluoxetine, for 6 days (20 mg/kg daily orally) was used to increase mucosal 5-HT chronically in rats. Net ileal fluid movement was measured in anesthetized rats by the weight change of a 2.5% agarose cylinder. Acute increases in 5-HT induced by exogenous or endogenous 5-HT decreased 5-HT(3)R immunoreactivity at the neuronal cell membrane by 70% and 60%, respectively. Chronic fluoxetine treatment increased mucosal levels of 5-HT and decreased membrane 5-HT(3)R immunoreactivity by 27%. Net fluid absorption was decreased by a 5-HT(3)R agonist or by luminal glucose; this was attenuated 88% and 99%, respectively, by fluoxetine treatment. Long-term increase in 5-HT in the intestinal mucosa results in increased 5-HT(3)R internalization in myenteric neurons. Chronic changes in mucosal 5-HT may alter gastrointestinal secretory and motor function via ongoing loss of receptor from neuronal membrane, causing a mismatch between luminal content and absorption.

Auditory thalamus responses to guinea-pig vocalizations: A comparison between rat and guinea-pig

Although neuronal responses to species-specific vocalizations have long been described, very few between-species comparisons have been made. In a previous study, a differential representation of species-specific vocalizations was found in the auditory cortex (ACx): marmoset ACx neurons responded more, and more selectively, to marmoset calls than did cat ACx neurons [Wang, X., Kadia, S.C., 2001. Differential representation of species-specific primate vocalizations in the auditory cortices of marmoset and cat. J. Neurophysiol. 86, 2616–2620]. The present study analyzed responses of guinea-pig and rat auditory thalamus neurons to four well-defined guinea-pig vocalizations. Neurons of guinea-pigs ( n = 96) and rats ( n = 87) displayed similar response strength to guinea-pig vocalizations, and did not exhibit a preference for the natural over the time-reversed version of the calls in both species. This difference with the study by Wang and Kadia might suggest that, in mammals, the selectivity for the natural version of species-specific vocalizations is prominent only at the cortical level.

Excitatory actions of motilin on myenteric neurons of the guinea-pig small intestine

Motilin is considered as a key factor in controlling interdigestive migrating contractions. The present electrophysiological experiments were performed in vitro to examine actions of motilin on myenteric neurons of guinea-pigs after 18-h fasting period. Superfusion of motilin depolarized both S and AH neurons; the lowest effective concentration was 10 nM, and motilin depolarization was observed in 9 of 23 S neurons and in 5 of 25 AH neurons. The motilin depolarizations were associated with an increase in neuronal input resistance. The motilin responses were preserved in Ca 2+ free/high Mg 2+ solution in which no Ca 2+ dependent synaptic transmission occurred. The reversal potential of the motilin responses was estimated about −95 mV, close to the equilibrium potential for K +. Furthermore, muscarinic depolarizations were blocked during the motilin responses. All of these indicated that motilin directly excited myenteric neurons mainly by inactivating K + channels. It is concluded that motilin might modulate neuronal excitability of the myenteric plexus, leading to the control of interdigestive migrating contractions.

Most peptide‐containing sensory neurons lack proteins for exocytotic release and vesicular transport of glutamate

We used multiple-labeling immunohistochemistry and confocal microscopy to examine co-expression of immunoreactivity for vesicular glutamate transporters (VGluTs), synaptic vesicle proteins, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in peptide-containing sensory neurons of guinea pigs, mice, and toads. Axon terminals in the superficial layers of the dorsal horn of the spinal cord with immunoreactivity (IR) for both substance P (SP) and calcitonin gene-related peptide (CGRP) lacked IR for synaptosome-associated protein of 25 kDa (SNAP-25), syntaxin, synaptotagmin, synaptophysin, and synapsin, although adjacent varicosities without neuropeptides had IR for these synaptic proteins. Similarly, peptide-containing axon terminals in the superficial dorsal horn lacked IR for VGluT1 and VGluT2, despite the presence of VGluT2-IR in nearby nonpeptide varicosities. VGluT3-IR was sparse in the dorsal horn of the mouse spinal cord and was not present in peptide-containing axons. Most peripheral terminals of sensory neurons with both SP-IR and CGRP-IR in the skin, viscera, and autonomic ganglia of guinea pigs and mice also lacked IR for synaptic vesicle proteins, SNARE proteins, VGluT1, and VGluT2. In dorsal root ganglia from guinea pigs and mice, most small neurons with IR for both SP and CGRP lacked IR for SNAP-25, VGluT1, and VGluT2. Thus, proteins considered essential for vesicular uptake and exocytotic release of glutamate are not expressed at detectable levels by most sensory neurons containing SP and CGRP in rodents and toads. These data raise the possibility that most peptide-containing sensory neurons may not normally release glutamate as a transmitter.

Reduction of human neocortical and guinea pig CA1-neuron A-type currents by organic calcium channel blockers

In epilepsy models, organic calcium antagonists regularly induce a transient activity increase before suppression of epileptiform discharges. This action was speculated to be mediated by a modulation of potassium currents. Since A-type currents potently regulate neuronal excitability, their modulation by calcium channel blockers was investigated in acutely isolated human neocortical temporal lobe neurons and CA1 neurons of guinea pigs using the whole-cell voltage-clamp technique. In human neurons, 40 μM nifedipine caused an amplitude reduction by 28% at a command potential of −6 mV and produced a biexponential, markedly accelerated current inactivation with time constants of 8.4 ± 1.1 ms ( n = 6) and 62.9 ± 6.4 ms ( n = 5). The time constant under control conditions was 50.1 ± 8.5 ms ( n = 6). Verapamil (40 μM) did not affect the current amplitude, but accelerated the monoexponential current inactivation from 40.2 ± 7.1 ms to 13.3 ± 0.8 ms ( n = 9). Accordingly, verapamil accelerated the inactivation from 42.3 ± 5.9 ms to 15.0 ± 1.3 ms ( n = 11) in guinea pig CA1 neurons, without affecting the current amplitude. In this preparation, it was shown that the two enantiomers of verapamil do not differ in their actions. The results show that the A-type current in human neocortical and in guinea pig hippocampal neurons is reduced by organic calcium channel blockers.

Effects of temperature on the spike activity of cortical neurons in guinea pigs.

Studies on parietal cortex slices from guinea pigs showed that a decrease in temperature from 37 degrees C to 24 degrees C significantly decreased the level of spontaneous neuron activity, while activatory reactions to iontophoretic administration of glutamate showed no significant change.

Modulation of calcium-currents by capsaicin in a subpopulation of sensory neurones of guinea pig

The action of capsaicin (CAP) on the total Ca2+ current was examined in internally perfused voltage-clamped dorsal root ganglion (DRG) neurones of guinea pigs. CAP changed the total Ca2+ current in about 50% of the investigated DRG neurones ("CAP-sensitive" neurones) in the following way: (I) a transient increase of the current amplitude at potentials between -35 mV and about -10 mV was accompanied by a shift of the current-voltage relation towards negative potentials by 5-8 mV; (II) the current inactivation was accelerated at potentials positive to about -35 mV; and (III) the current activation of Ca2+ currents (time to peak values) was also accelerated. Separated low voltage-activated (T-type) currents at potentials negative to about -35 mV were either not affected or reduced. It remains undecided whether CAP increases T-type currents in a particular potential range or activates an N-type current. External application of 50 microM Ni2+ blocks the effect of CAP, but does not affect the acceleration of the high voltage-activated (L-type) current inactivation induced by menthol. This appears to exclude a CAP effect on L-type current inactivation. "CAP sensitive" and "CAP insensitive" neurones could be discriminated by their different Ca2+ currents: the former demonstrate both fast and slow inactivating currents while the latter have only L-type currents. The observed changes of fast-inactivating Ca2+ currents may be related to the specific action of CAP on peptidergic sensory neurones.

Selective Expression of a Persistent Tetrodotoxin-Resistant Na+Current and NaV1.9 Subunit in Myenteric Sensory Neurons

Voltage-gated Na(+) currents play critical roles in shaping electrogenesis in neurons. Here, we have identified a TTX-resistant Na(+) current (TTX-R I(Na)) in duodenum myenteric neurons of guinea pig and rat and have sought evidence regarding the molecular identity of the channel producing this current from the expression of Na(+) channel alpha subunits and the biophysical and pharmacological properties of TTX-R I(Na). Whole-cell patch-clamp recording from in situ neurons revealed the presence of a voltage-gated Na(+) current that was highly resistant to TTX (IC(50), approximately 200 microm) and selectively distributed in myenteric sensory neurons but not in interneurons and motor neurons. TTX-R I(Na) activated slowly in response to depolarization and exhibited a threshold for activation at -50 mV. V(1/2) values of activation and steady-state inactivation were -32 and -31 mV in the absence of fluoride, respectively, which, as predicted from the window current, generated persistent currents. TTX-R I(Na) also had prominent ultraslow inactivation, which turns off 50% of the conductance at rest (-60 mV). Substituting CsF for CsCl in the intracellular solution shifted the voltage-dependent parameters of TTX-R I(Na) leftward by approximately 20 mV. Under these conditions, TTX-R I(Na) had voltage-dependent properties similar to those reported previously for NaN/Na(V)1.9 in dorsal root ganglion neurons. Consistent with this, reverse transcription-PCR, single-cell profiling, and immunostaining experiments indicated that Na(V)1.9 transcripts and subunits, but not Na(V)1.8, were expressed in the enteric nervous system and restricted to myenteric sensory neurons. TTX-R I(Na) may play an important role in regulating subthreshold electrogenesis and boosting synaptic stimuli, thereby conferring distinct integrative properties to myenteric sensory neurons.

Calmodulin kinase IIα in the signal transduction pathway for slow synaptic excitation in enteric neurons of guinea pig, rat and human small intestine

Calmodulin kinase IIα in the signal transduction pathway for slow synaptic excitation in enteric neurons of guinea pig, rat and human small intestine

Histamine H1 receptor mRNA is expressed in capsaicin-insensitive sensory neurons with neuropeptide Y-immunoreactivity in guinea pigs

Histamine H1 receptor mRNA-expressing sensory neurons in guinea pigs are unmyelinated and are not immunoreactive to substance P and calcitonin gene-related peptide (CGRP) [Mol. Brain Res. 66 (1999) 24], which are implicated in the nociceptive transmission of the primary sensory system. In this study, we examined whether these H1 receptor mRNA-expressing neurons are sensitive to capsaicin by using in situ hybridization histochemistry. Of lumbar dorsal root ganglion (DRG) neurons in control animals, 17% were positive for CGRP. In guinea pigs neonatally treated with capsaicin (50 mg/kg), few CGRP-immunoreactive neurons were seen in the DRGs. However, the percentages of H1 receptor mRNA-expressing neurons (15–20%) and the intensity of the mRNA signals in these neurons were not affected by neonatal capsaicin treatment. We also revealed the presence of both capsaicin-sensitive and insensitive neuropeptide Y (NPY)-immunoreactive neurons in the DRGs. These neurons were exclusively small. H1 receptor mRNA was expressed in NPY-immunoreactive neurons in naive guinea pig DRGs. These results suggest that H1 receptor mRNA is expressed in capsaicin-insensitive DRG neurons with NPY-immunoreactivity in guinea pigs.

Modulation of Neural Cell Membrane Conductance by the Herbal Anxiolytic and Antiepileptic Drug Aswal

To evaluate the effects of aswal on ionic fluxes and neuronal excitation, we performed extracellular and whole cell patch clamp recordings on CA1 pyramidal neurons of guinea pigs and Long-Evans rats. Aswal (100– 250 mg/l) was administered systemically, and its effects on the rate of synchronized extracellular field potentials (EFP), membrane parameters, action potentials and postsynaptic potentials were recorded. The extracellular results obtained are consistent with calcium antagonistic properties. Intracellular recordings suggest that a direct sodium antagonistic effect as seen in many antiepileptic drugs plays no significant role. Further effects on ligand gated ion channels are discussed controversially. In summary, the cellular action of aswal appears heterogeneous with calcium antagonism playing a prominent role in counteracting excitation which may be a common feature in epilepsy and different psychiatric conditions as mood and anxiety disorder.

Electrophysiological features of morphological Dogiel type II neurons in the myenteric plexus of pig small intestine.

By intracellular recording, 99 myenteric neurons with Dogiel type II morphology were electrophysiologically characterized in the porcine ileum and further subdivided into three groups based on their different types of afterhyperpolarization (AHP). In response to a depolarizing current injection, a fast AHP (fAHP; duration 34 +/- 11 ms; amplitude -11 +/- 6 mV; mean +/- SD) immediately followed every action potential in all neurons. In 32% of the neurons, this fAHP was the sole type of hyperpolarization recorded. Statistical analysis revealed the presence of two neuronal subpopulations that displayed either a long-lasting medium AHP (mAHP; duration after a single spike 773 +/- 753 ms; 51% of neurons) or a slow AHP (sAHP; 4, 205 +/- 1,483 ms; 17%). Slow AHP neurons also differed from mAHP neurons in the delayed onset of the AHP (mAHP 0 ms; sAHP 100-200 ms), as well as in maximum amplitude values and in the time to reach this amplitude (t(max); 148 +/- 11 ms vs. 628 +/- 108 ms). Medium AHP neurons further differed from the sAHP neurons in the occurrence of the AHP following subthreshold current injection and in their resting membrane potential (mAHP, -53 +/- 8 mV; sAHP, -62 +/- 10 mV). Medium AHP and sAHP behaved similarly in that a higher number of spikes increased their amplitude and duration, but not t(max). The majority of neurons fired multiple spikes (up to 25) in response to a 500-ms current injection (81/99) and showed a clear TTX-resistant shoulder on the repolarizing phase of the action potential (77/99), irrespective of the presence of sAHP or mAHP. These results demonstrate that the porcine Dogiel type II neurons differ in various essential electrophysiological properties from their morphological counterparts in the guinea pig ileal myenteric plexus. The most striking interspecies differences were the low occurrence of sAHP (17% vs. 80-90% in guinea pig) with relatively small amplitude (-5 vs. -20 mV), the high occurrence of mAHPs (unusual in guinea pig) and the ability to fire long spike trains (up to 25 spikes vs. 1-3 in guinea pig). In fact, Dogiel type II neurons in porcine ileum combine distinct electrophysiological features considered typical of either S-type or sAHP-type neurons in guinea pig. It can therefore be concluded that in spite of a similar morphology, Dogiel type II neurons do not behave electrophysiologically in a universal way in large and small mammals.

Electrophysiological characteristics of non-bursting, glutamate decarboxylase messenger RNA-positive neurons of the medial septum/diagonal band nuclei of guinea-pig and rat

Nuclei of the medial septum/diagonal band region of the mammalian forebrain contain neurons that give rise to the septohippocampal pathway, which has separate cholinergic and GABAergic components. This pathway is known to influence hippocampal-dependent memory and learning processes, but the precise role of each component is unclear. In this study, we tested the hypothesis that fast-firing, non-bursting medial septum/diagonal band neurons are GABAergic. We used brain slice preparations from young adult guinea-pigs and rats, or from weanling rats, to perform current-clamp recordings from medial septum/diagonal band neurons. Recorded neurons were injected with biocytin for subsequent visualization with fluorescent avidin, and then hybridized with a 35S-labeled riboprobe for glutamate decarboxylase-67 messenger RNA. As a positive control, guinea-pig cerebellar Purkinje cells were labeled and hybridized with the riboprobe. As expected, labeled Purkinje cells were glutamate decarboxylase-67 messenger RNA positive. Slow-firing, cholinergic (choline acetyltransferase-positive) guinea-pig medial septum/diagonal band neurons were glutamate decarboxylase-67 messenger RNA negative. Contrary to our hypothesis, of the guinea-pig neurons, only three of 11 fast-firing neurons were glutamate decarboxylase-67 positive. Of the rat medial septum/diagonal band neurons, three of four were positive for glutamate decarboxylase-67 messenger RNA. These data suggest that fast-firing, non-bursting neurons of the medial septum/diagonal band, as sampled by sharp-electrode intracellular recordings in brain slices, may be a heterogeneous group of neurons, some of which are GABAergic. Together with recent data demonstrating the presence of another GABAergic marker, parvalbumin, in fast-firing septal neurons, we conclude that GABAergic septohippocampal neurons include a population of fast-firing, non-bursting neurons. The influence of these neurons on the hippocampus is likely to occur on a shorter time-scale and over a wider range of firing frequencies as compared to slowly firing cholinergic septohippocampal neurons.

Modulation of APP processing and secretion by okadaic acid in primary guinea pig neurons.

Primary cultures of guinea pig neurons were used as a model system to study the influence of the protein phosphatase inhibitor okadaic acid (OA) on the secretion, processing and phosphorylation of the amyloid precursor protein (APP). This primary cell culture system mimics more closely than other cell culture systems the human in vivo condition, as guinea pig APP is 98% homologous to human APP at the protein level, identical regarding the Abeta sequence and is processed in a similar manner as human APP. Both intracellular and secreted APP was upregulated by OA treatment (0.3 nM-10 nM) of 14 days old cultures in a concentration dependent manner while the amount of Abeta in the medium was decreased. OA treatment did not affect cell membrane integrity of primary neurons but induced DNA fragmentation. Phosphorylation of APP was unchanged by the low OA concentration used. These results show that OA treatment of guinea pig primary cultures might be used as a model to study the effects of modulation of signal transduction on secretion and processing of APP.

Blockade of neurokinin3 receptors antagonizes drug‐induced population response and depolarization block of midbrain dopamine neurons in guinea pigs

In vivo extracellular recording techniques were used to investigate the effects of neurokinin3 (NK3) receptor blockade on the pharmacological activation of midbrain dopamine (DA) neurons in the guinea pig substantia nigra (A9) and ventral tegmental area (A10). The number of spontaneously active DA cells (population response) was largely increased in A10 and A9 by acute administration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose-dependently prevented in both areas by the selective NK3 receptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectively). This compound, which was totally inactive by itself, also antagonized the increase of population response induced in A10 cells by the neurotensin receptor antagonist SR142948 (1 mg/kg i.p.) and in A9 cells by the NK2 receptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 were reproduced by SR142806, its (R)-enantiomer with 240-fold lower affinity for NK3 receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the NK1 receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol-induced response. The antagonistic effects of SR142801 (3 mg/kg i.p.) were also observed on the depolarization block-related decrease of A10 cell population response evoked by repeated administration (22 days) of haloperidol. Finally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A10 cells by acute co-administration of SR142948 and haloperidol, both on population response and on single cell firing. These results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK3 receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B. Synapse 33:71–79, 1999. © 1999 Wiley-Liss, Inc.

Blockade of neurokinin3 receptors antagonizes drug-induced population response and depolarization block of midbrain dopamine neurons in guinea pigs.

In vivo extracellular recording techniques were used to investigate the effects of neurokinin3 (NK3) receptor blockade on the pharmacological activation of midbrain dopamine (DA) neurons in the guinea pig substantia nigra (A9) and ventral tegmental area (A10). The number of spontaneously active DA cells (population response) was largely increased in A10 and A9 by acute administration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose-dependently prevented in both areas by the selective NK3 receptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectively). This compound, which was totally inactive by itself, also antagonized the increase of population response induced in A10 cells by the neurotensin receptor antagonist SR142948 (1 mg/kg i.p.) and in A9 cells by the NK2 receptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 were reproduced by SR142806, its (R)-enantiomer with 240-fold lower affinity for NK3 receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the NK1 receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol-induced response. The antagonistic effects of SR142801 (3 mg/kg i.p.) were also observed on the depolarization block-related decrease of A10 cell population response evoked by repeated administration (22 days) of haloperidol. Finally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A10 cells by acute co-administration of SR142948 and haloperidol, both on population response and on single cell firing. These results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK3 receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B.