Effects of excitatory and inhibitory amino acids on neuronal discharges in the cultured suprachiasmatic nucleus

The influence of amino acids on neuronal activity was studied microiontophoretically in the cultured Suprachiasmatic nucleus (SCN). Three types of SCN neurons could be characterized: silent (glutamate responsive), irregular, and regular neurons. Glutamate excited about 70% of the regular and 60% of the irregular cells. GABA inhibited both the spontaneous and the glutamate-evoked activity of more than 90% of all three types of SCN neurons. MK-801 partially blocked glutamate responses. N-acetyl-aspartyl-glutamate (NAAG), a new neurotransmitter found in the retinohypothalamic fibers, directly increased firing rate and potentiated glutamate responses in the SCN neurons that were studied. These results indicate the potential significance of the amino acids in neuronal transmission within the biological clock.     

Neuronal responses to 5-hydroxytryptamine and dorsal raphe stimulation within the globus pallidus of the rat

The projection from the dorsal raphe nucleus (DRN) to the globus pallidus (GP) was investigated electrophysiologically, in the urethane-anesthetized rat together with the responsiveness of cells in the GP to 5-hydroxytryptamine (5-HT) and noradrenaline (NA). The majority of spontaneously active cells in the GP had high regular firing rates. They were unaffected by both DRN stimulation (69/83 cells) and iontophoretically applied 5-HT (38/63 units) or NA (30/42 units) but were inhibited by GABA. A few cells (N = 10) were recorded from, that were spontaneously active but with a much lower and less regular firing rate, which, however, seemed to be much more responsive to 5-HT. In addition, DL-homocysteic acid (DLH) was used to activate silent cells and all seven cells activated in this manner were inhibited by 5-HT. In addition 5/6 cells that had their firings maintained by DLH were inhibited by stimulation of the dorsal raphe. The results show a lack of responsiveness to both 5-HT and DRN stimulation of the typically regular spontaneously active pallidal neurons. There seems to be a small population of normally quiescent cells, however, that is sensitive to 5-HT and receives an input from the DRN.     

Identification of serotonergic and sympathetic neurons in medullary raphe nuclei

The purpose of the present study was to identify midline medullary serotonin (5-HT) neurons and to determine if these neurons were distinct from previously identified sympathoinhibitory and sympathoexcitatory neurons. Identification of medullary 5-HT neurons was based on electrophysiological and pharmacological similarities to dorsal raphe 5-HT neurons. Sympathoinhibitory and sympathoexcitatory neurons were characterized by an irregular discharge pattern which was temporally related to inferior cardiac sympathetic nerve discharge (SND) and to the cardiac cycle. Sympathoinhibitory neurons increased their discharge rate and the discharge of sympathoexcitatory neurons decreased during baroreceptor reflex activation. A third type of neuron fired in an extremely regular fashion (as judged by interspike interval analysis), fired at a rate of 1.1 spikes/s and had spike durations of approximately 2 ms. The discharges of regularly firing neurons were not temporally related to SND and were not affected during baroreceptor reflex activation. Regularly firing neurons and sympathoinhibitory neurons could be antidromically activated by electrical stimulation of the intermediolateral cell column of the spinal cord. Axonal conduction velocity of sympathoinhibitory neurons (2.4 m/s) was significantly greater than that for regularly firing neurons (1.3 m/s). Regularly firing neurons were completely inhibited by low doses of the 5-HT1A agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) (i.e. 2 micrograms/kg, i.v.) while much higher doses of the drug failed to affect the discharges of sympathoinhibitory and sympathoexcitatory neurons. Microiontophoretic application of 5-HT and 8-OH-DPAT profoundly depressed the firing of regularly discharging neurons. Based on the striking similarities between regularly firing medullary neurons and dorsal raphe 5-HT neurons it is concluded that the regularly firing neurons were 5-HT-containing neurons. Furthermore, these medullary 5-HT neurons are distinct from sympathoinhibitory and sympathoexcitatory neurons.     

Circadian regulation of mouse suprachiasmatic nuclei neuronal states shapes responses to orexin

Our knowledge of how circadian and homeostatic brain circuits interact to temporally organize physiology and behavior is limited. Progress has been made with the determination that lateral hypothalamic orexin (OXA) neurons control arousal and appetitive states, while suprachiasmatic nuclei (SCN) neurons function as the master circadian clock. During the day, SCN neurons exhibit heterogeneity in spontaneous resting membrane potential (RMP), with some neurons becoming severely depolarized (hyperexcited) and ceasing to fire action potentials (APs), while other neurons rest at moderate RMP and fire APs. Intriguingly, the day phase is when the SCN clock is most readily influenced by arousal, but it is unclear if and how heterogeneity in the excitability state of SCN neurons shapes their response to arousal signals, such as OXA. In whole‐cell recordings we show that during the day OXA recruits GABA‐GABA_A receptor signaling to suppress the RMP of hyperexcited silent as well as moderately hyperpolarized AP‐firing SCN neurons. In the AP‐firing neurons, OXA hyperpolarized and silenced these SCN cells, while in the hyperexcited silent neurons OXA suppressed the RMP of these cells and evoked either AP‐firing, depolarized low‐amplitude membrane oscillations, or continued silence at a reduced RMP. These results demonstrate how the resting state of SCN neurons determines their response to OXA, and illustrate that the inhibitory action of this neurochemical correlate of arousal can trigger paradoxical AP firing.     

Spontaneous and stimulated firing in cultured rat suprachiasmatic neurons.

Neurons from the suprachiasmatic nucleus (SCN) of the hypothalamus, the site of a circadian pacemaker in mammals, were isolated from embryonic rat. After mechanical dissociation neurons were brought into culture for 1-2 weeks, using a chemically defined medium. Recordings were made from 74 bipolar neurons using two different configurations of the patch-clamp technique. During cell attached patch recordings, 45% of neurons fired spontaneously. The mean firing rate was 0.7 +/- 0.6 Hz and the firing pattern was irregular. In whole cell recordings 73% of the investigated neurons showed spontaneous activity with an irregular firing pattern. The mean spontaneous firing rate with an intracellular Cl- concentration of 145 mM was 1.0 +/- 0.6 Hz. The resting membrane potential of the bipolar neurons was estimated to be -62 +/- 24 mV. An intracellular Cl- concentration of 145 mM depolarised the membrane potential. It also increased the probability of spontaneous firing. A depolarising current stimulus produced an action potential with a threshold voltage of -46 +/- 9 mV. Suprathreshold stimuli resulted in repetitive firing with a mean frequency of 12 +/- 4 Hz. The minimum interspike interval was 52 +/- 14 ms. All action potentials either occurring spontaneously or elicited by current stimuli were abolished by the Na(+)-channel blocker TTX. These results indicate that our cultured neurons have some electrophysiological properties in common with SCN neurons in brain slices and in vivo.     

Modulatory action of acetylcholine on striatal neurons: microiontophoretic study in awake,unrestrained rats

Cholinergic interneurons innervate virtually all medium spiny striatal cells, but the relevance of this input in regulating the activity and afferent responsiveness of these cells remains unclear. Studies in anaesthetized animals and slice preparations have shown that iontophoretic acetylcholine (ACh) either weakly excites or inhibits striatal neurons. These differential responses may reflect cholinergic receptor heterogeneity but may be also related to the different activity states of recorded units and different afferent inputs specific in each preparation. Single-unit recording was combined with iontophoresis in awake, unrestrained rats to examine the effects of ACh and selective muscarinic (oxotremorine M or Oxo-M) and nicotinic agonists (nicotine or NIC) on dorsal and ventral striatal neurons. These effects were tested on naturally silent, spontaneously active and glutamate-stimulated units. We found that iontophoretic ACh primarily inhibited spontaneously active and glutamate-stimulated units; the direction of the ACh response, however, was dependent on the firing rate. The effects of ACh were generally mimicked by Oxo-M and, surprisingly, by NIC, which is known to excite units in most central structures, including striatal neurons in anaesthetized preparation. Given that NIC receptors are absent on striatal cells but located primarily on dopamine terminals, we assessed the effects of NIC after complete blockade of dopamine receptors induced by systemic administration of a mixture of D1 and D2 antagonists. During dopamine receptor blockade the number of NIC-induced inhibitions dramatically decreased and NIC had mainly excitatory effects on striatal neurons. Thus, our data suggest that under physiologically relevant conditions ACh acts as a state-dependent neuromodulator, and its action involves not only postsynaptic but also presynaptic cholinoreceptors located on dopamine- and glutamate-containing terminals.     

Single unit recording in hypothalamus and preoptic area of estrogen-treated and untreated ovariectomized female rats.

Single unit activity was recorded with micropipettes in the medial hypothalamus and preoptic area of urethane-anesthetized ovariectomized female rats. Some females had received long-term estradiol treatment, while others had been left untreated. In the medial preoptic region and bed nucleus of the stria terminalis, estrogen-treated rats had fewer cells (compared to untreated rats) with recordable spontaneous activity, due primarily to a loss of cells with very slow firing rates. In the basomedial hypothalamus, estrogen-treated rats had more cells (than untreated rats) with recordable spontaneous activity, due primarily to an increase in the number of cells with slow firing rates. Responsiveness of neurons to somatosensory stimulation was generally low. If present it was depressed by estrogen treatment in medial preoptic area and bed nucleus of stria terminalis, while it tended to be elevated by estrogen treatment in medial anterior hypothalamus and basomedial hypothalamus. Differences in the effects of long-term systemic estrogen treatment on medial preoptic neurons compared to basomedial hypothalamus are paralledled by differences in the control of lordosis by these neurons in female rats.     

Modulatory role for biogenic amines in the cerebral cortex. Microiontophoretic studies

In order to investigate the mode of action of biogenic amines in rat cerebral cortex, the unitary activity of spontaneously firing neurons and their excitatory response to acetylcholine (ACh) were examined using microiontophoretic administration of dopamine (DA), noradrenaline (NA) and serotonin (5-HT). The predominant effect of these biogenic amines on the spontaneous activity was a profound and prolonged inhibition of firing (2–4 min), which attained its maximum within 15–120 sec. This response was generally more abrupt in onset and of greater magnitude with NA and 5-HT than with DA. Most units inhibited by DA, NA and 5-HT also showed marked depression of their excitatory response to ACh when pretreated with these biogenic amines. With repetitive administration of ACh, it could be shown that the total duration of inhibition of ACh responses by DA and NA was not as prolonged as the inhibition of the spontaneous firing of the same cells. With 5-HT, the initial ACh responses of many neurons could be completely blocked, and this inhibitory effect lasted as long as the inhibition of spontaneous firing.In view of the anatomical data demonstrating a relative sparsity of monoamine nerve terminals in cerebral cortex, the strong inhibition induced by DA, NA or 5-HT may have reflected slow inactivation of the biogenic amines. However, it could also be indicative of underlying mechanisms of action dependent on metabolic changes. Indeed, the interaction between biogenic amines and ACh might imply a balance between the intracellular pools of cAMP and cGMP is directly or indirectly influenced by the biogenic amines and ACh, respectively. This hypothesis would not exclude other modes of local interaction between DA, NA, 5-HT and ACh, and appears compatible with the modulatory role of biogenic amines in cerebral cortex.     

Neurochemical identification of stereotypic burst-firing neurons in the rat dorsal raphe nucleus using juxtacellular labelling methods

Recent electrophysiological studies have discovered evidence of heterogeneity of 5-hydroxytryptamine (5-HT) neurons in the mesencephalic raphe nuclei. Of particular interest is a subpopulation of putative 5-HT neurons that display many of the electrophysiological properties of presumed 5-HT-containing neurons (regular and slow firing of single spikes with a broad waveform) but fire spikes in short, stereotyped bursts. In the present study we investigated the chemical identity of these neurons in rats utilizing in vivo juxtacellular labelling methods. Of ten dorsal raphe nucleus (DRN) neurons firing short stereotyped bursts within an otherwise regular firing pattern, all exhibited immunoreactivity for either 5-HT (n = 6) or the 5-HT synthesizing enzyme, tryptophan hydroxylase (TRH; n = 2) or both (n = 2). Supporting pharmacological experiments demonstrated that the burst firing DRN neurons demonstrated equal sensitivity to 5-HT(1A) agonism and alpha(1)-adrenoceptor antagonism to single spiking DRN neurons that we have previously identified as 5-HT-containing. Collectively these data provide direct evidence that DRN neurons that exhibit stereotyped burst firing activity are 5-HT containing. The presence of multiple types of electrophysiologically distinct midbrain 5-HT neurons is discussed.     

Subthalamic nucleus lesion regularizes firing patterns in globus pallidus and substantia nigra pars reticulata neurons in rats

Subthalamic nucleus lesion altered the statistical properties of the firing patterns of globus pallidus and substantia nigra pars reticulata neurons recorded in urethane anesthetized rats by increasing the proportion of cells in both structures that fired with a very highly regular pattern (from 25%to 50%). In all cases, the most regularly firing neurons fired at a higher mean rate than did more slowly firing neurons. In contrast, globus pallidus lesion shifted the pattern of substantia nigra neurons towards more irregular firing and induced a bursty pattern in two neurons.     

Intracellular recording from putative dopamine-containing neurons in the ventral tegmental area of Tsai in a brain slice preparation

Coronal slices of rat mesencephalon containing the ventral tegmental area of Tsai (VTA) and the substantia nigra were prepared. Stable intracellular recordings were obtained from presumed dopamine (DA)-containing neurons in the VTA. Both silent and spontaneously active cells were encountered; spontaneously active neurons fired in an extremely regular pacemaker-like fashion. These neurons had resting membrane potentials ranging from -45 to -75 mV and input resistances ranging from 80-400 M omega. DA-containing neurons in the VTA demonstrated marked anomalous rectification in response to hyperpolarizing current pulses. Application of DA or the GABAB agonist, baclofen, to the bathing medium produced suppression of spontaneous firing, sometimes accompanied by membrane hyperpolarization. Neuronal input resistance was not changed consistently by DA and was generally reduced by baclofen.     

Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons.

The effect of 5-HT on activity of noradrenergic locus coeruleus (LC) neurons was studied using microiontophoretic and micropressure drug application in anesthetized rats. 5-HT had no consistent effect on LC spontaneous discharge, eliciting a modest decrease overall. However, 5-HT reliably attenuated responses of LC neurons to excitatory amino acids (EAAs), one of the major classes of transmitters in afferents to these neurons. This effect was specific for EAA responses because it occurred for glutamate and kainate but not for ACh. In contrast, iontophoretic norepinephrine (NE) selectively attenuated spontaneous activity but not responses evoked by either glutamate or ACh. The responsiveness of LC neurons to EAAs as quantified by a response-contrast measure (evoked excitation/basal activity) was markedly reduced by 5-HT, but was increased by NE. For ACh, such responsiveness of LC cells was not changed by 5-HT, but was increased by NE. The effects of 5-HT were prevented and reversed by iontophoretically applied antagonists of 5-HT receptors, methysergide and methiothepin. Thus, 5-HT appears to selectively interact with EAA responses of LC neurons, acting as a filter to attenuate LC activity linked to its major EAA inputs while allowing other channels afferent to the LC (e.g., those utilizing ACh) to be expressed.     

Behavior of inhibitory and excitatory propriobulbar respiratory neurons during fictive vomiting.

The behavior of propriobulbar respiratory neurons was studied during fictive vomiting in decerebrate, paralyzed, artificially ventilated cats. Fictive vomiting was identified by a characteristic series of synchronous phrenic and abdominal nerve bursts, induced by electrical stimulation of abdominal vagal afferents and/or i.v. infusion of emetic drugs. Data were obtained from inspiratory neurons having decrementing (I-DEC) or constant (I-CON) discharge patterns and expiratory decrementing (E-DEC) neurons located in the B?tzinger complex and adjacent rostral ventral respiratory group. These neurons are known to make excitatory (I-CON) and inhibitory (I-DEC, E-DEC) connections with a variety of medullary respiratory neurons. During fictive vomiting: 8 of 14 I-DEC neurons fired in phase with synchronous bursts of phrenic and abdominal nerve discharge; the other 6 were silent. Of 12 I-CON neurons, 5 fired in phase with phrenic and abdominal bursts; 7 were silent. All (6) E-DEC neurons were either silent or fired weakly between bursts of phrenic and abdominal discharges. The possible roles of I-DEC and I-CON neurons in actively reorganizing the behavior of other respiratory neurons during fictive vomiting are discussed. In particular, the firing of many I-DEC neurons was found to be appropriate to inhibit inspiratory, and two types of expiratory, bulbospinal neurons during fictive vomiting.     

Effect of atmospheric ions on hippocampal pyramidal neuron responsiveness to serotonin

The effect of long-term exposure to positive or negative atmospheric ions on the responsiveness of rat forebrain neurons to serotonin (5-HT) was studied. Male Sprague-Dawley rats were exposed to positive or negative ions (1.5 X 10(6) ions/ml) for 21 days, and a third group of rats served as controls. Unitary extracellular recordings from pyramidal neurons of the CA1 and CA3 regions of the dorsal hippocampus were obtained under urethane anesthesia, and their responsiveness to microiontophoretically applied acetylcholine (ACh), norepinephrine (NE) and 5-HT was assessed. Spontaneous rate of discharge and sensitivity to NE and ACh of hippocampal neurons were not affected by exposure to atmospheric ions. Exposure to negative ions increased and that to positive ions decreased the responsiveness of these neurons to 5-HT. During the winter, a circadian rhythm of responsiveness to 5-HT was observed in the control group, sensitivity being lowest in the morning and highest in the evening. Exposure to ions disrupted this circadian rhythm; in rats exposed to negative ions, responsiveness throughout the day was similar to that observed in the evening in the controls, whereas in rats exposed to positive ions, the circadian rhythm of responsiveness to 5-HT was inverted. Brain concentrations of 5-HT, tryptophan, and 5-hydroxyindoleacetic acid were unchanged by exposure to atmospheric ions.     

Morphological features and electrophysiological properties of serotonergic and non-serotonergic projection neurons in the dorsal raphe nucleus. An intracellular recording and labeling study in rat brain slices

The morphology and electrophysiological properties of serotonergic and non-serotonergic projection neurons in the dorsal raphe nucleus (DRN) of the rat were examined in frontal brain slices. Biocytin was injected intracellularly into the intracellularly recorded neurons. Then the morphology of the recorded neurons was observed after histochemical visualization of biocytin. The recorded neurons extending their main axons outside the DRN were considered as projection neurons. Subsequently, serotonergic nature of the neurons was examined by serotonin (5-HT) immunohistochemistry. The general form of the dendritic trees is radiant and poorly branching in both 5-HT- and non-5-HT neurons. However, the dendrites of the 5-HT neurons were spiny, whereas those of the non-5-HT neurons were aspiny. The main axons of both 5-HT- and non-5-HT neurons were observed to send richly branching axon collaterals to the DRN, ventrolateral part of the periaqueductal gray and the midbrain tegmentum. In response to weak, long depolarizing current pulses, the 5-HT neurons displayed a slow and regular firing activity. The non-5-HT neurons fired at higher frequencies even when stronger current was injected. Some other differences in electrophysiological properties were also observed between the 5-HT-immunoreactive spiny projection neurons and the 5-HT-immunonegative aspiny projection neurons.     

Modified coeruleo-cortical noradrenergic neurotransmission after serotonin depletion by PCPA: electrophysiological studies in the rat

To detect eventual modifications in the efficacy of the noradrenergic (NA) coeruleo-cortical system after serotonin (5-HT) depletion by parachlorophenylalanine (PCPA), three electrophysiological parameters were investigated in urethane-anesthetized rats which were treated for 2 days with daily injections of this inhibitor of 5-HT synthesis. 1) The spontaneous activity of locus coeruleus (LC) noradrenergic neurons showed a significant increase in PCPA-treated compared to control rats (4.3 vs. 2.6 Hz). 2) The sensitivity of NA autoreceptors was measured in the LC by the effect of intravenous administrations of clonidine or microiontophoretic applications of NA on spontaneous neuronal firing. In treated rats, clonidine and NA induced a lesser reduction of LC neuron firing than in the controls (27 vs. 75% decreases and 1,367 vs. 280 nC, respectively). 3) The responsiveness of cortical neurons to electrical stimulation of the LC was assessed by peristimulus time histograms in the dorsal fronto-parietal cortex. Following stimulation at 2 or 4 Hz, a majority of spontaneously firing cortical units was inhibited by electrical stimulation of the LC, but the percentage of such units was reduced and showed a decreased responsiveness after PCPA treatment. These findings suggest that following 5-HT depletion by PCPA, cortical NA neurotransmission is markedly reduced in its efficacy in spite of some increase in the spontaneous activity of coeruleo-cortical NA neurons.     

Neostriatal evoked inhibition and effects of dopamine on globus pallidal neurons in rat slice preparations

Spontaneous unit discharges were recorded extracellularly from globus pallidal (GP) neurons in rat slice preparations. The firing rates of GP neurons ranged from 2.0 to 24.0 spikes/s and their firing patterns were predominantly of two types: regular and irregular. Stimulation of the neostriatum evoked two distinct types of inhibition which were dependent on GP neuronal firing patterns, a brief inhibition (about 75 ms) followed by resetting rhythmic neuronal activities and a relatively long-term inhibition (about 100 ms). These inhibitions evoked by neostriatal stimulation were attenuated or completely blocked by bath application of either bicuculline or strychnine (2 X 10(-5)-10(-4) M) but not by naloxone. Bath application of dopamine (10(-4)-10(-3) M) produced slow increases in the firing rates by 30-65% in about a half of GP neurons tested. Iontophoretic application of dopamine (10-20 nA) attenuated inhibition in GP neurons by 40-55% induced by either iontophoretically applied GABA (5-30 nA) or neostriatal stimulation without affecting their spontaneous firings. These results suggest that dopamine may produce change in the firing patterns of GP neurons by either acting directly or attenuating GABAergic inhibitory transmission from the neostriatum.     

Diurnal rhythms in the responsiveness of hippocampal pyramidal neurons to serotonin, norepinephrine, gamma-aminobutyric acid and acetylcholine

Radioligand binding studies have revealed the existence of endogenous circadian rhythms in the number of several receptors in the rat brain. The present microiontophoretic study was undertaken to assess diurnal rhythms in the responsiveness of rat hippocampal pyramidal neurons to serotonin (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA), and acetylcholine (ACh). Between December and April, there was a significant diurnal variation in the responsiveness of hippocampal pyramidal neurons to 5-HT and ACh. Between May and August, the responsiveness to NE and ACh showed a diurnal variation. There was no diurnal variation in the responsiveness to GABA in either period of the year. Short-term exposure to constant light or darkness produced a phase-shift of the serotoninergic and cholinergic rhythms, suggesting their endogenous nature and their synchronization to clock-time by the light-dark cycle. The diurnal rhythms in responsiveness to 5-HT and NE underwent phase-shifts from the December-April to the May-August period in rats entrained to 12:12 light-dark cycle, suggesting the existence of seasonal modulation of these rhythms. These circadian rhythms in the postsynaptic responsiveness of hippocampal pyramidal cells and their seasonal fluctuation may be related to the diurnal variation of mood seen in major depression as well as to the seasonal incidence of this illness.     

Effect of monoamines on firing rate and thermal sensitivity of neurons in the preoptic area of awake rabbits

Single units in the preoptic/anterior hypothalamus (POAH) were studied by changing local temperature of the POAH with a water-perfused thermode. Norepinephrine (NE) or 5-hydroxytryptamine (5-HT) was injected either into the lateral ventricle or directly into the POAH. In some experiments the POAH temperature was changed both before and after the injection of a monoamine. The firing activity of cold-sensitive cells was increased by intraventricular and direct injections of NE and decreased by 5-HT. Ventricular 5-HT tended to facilitate warm-sensitive neurons. Ventricular NE and direct injections of NE and 5-HT had uniform effects on the activity of warm-sensitive neurons. Ventricular NE inhibited the majority of thermal-insensitive neurons. 5-HT consistently converted warm- and cold-sensitive units into thermal-insensitive units. NE converted cold-sensitive units into warm-sensitive units or increased the cold sensitivity of cold-sensitive neurons. Some insensitive units were converted into warm- or cold-sensitive units by the monoamines. The effects of 5-HT and NE on cold-sensitive neurons conforms to past investigations dealing with the role of these neurotransmitters in thermoregulation. Recording single-neuron activity in the unanesthetized preparation demonstrates that monoamine-induced changes in firing rate and thermal sensitivity of POAH neurons precedes changes in the thermoregulatory motor output.     

Effect of neurokinin-I receptor antagonists on the function of 5-HT and noradrenaline neurons

Substance P antagonists have been proposed to be a new class of antidepressants. The present study aimed to determine the effect of the selective non-peptide rat neurokinin-1 (NK1) receptor antagonists WIN 51,708 and CP-96,345 on the firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. While WIN51,708 (2mg/kg, i.v.) and CP-96,345 (0.15 mg/kg, i.v.) did not modify the firing activity of 5-HT and NA neurons, both antagonists attenuated the suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of both types of neurons. In contrast, the responsiveness of 5-HT neurons to the i.v. administration of the 5-HT autoreceptor agonist LSD and the 5-HT1A receptor agonist 8-OH-DPAT remained unchanged. These findings suggest that NK1 receptor antagonists affect markedly the NA system via an attenuation of the function of alpha2-adrenoceptors on the cell body of NA neurons and, consequently, may also modulate 5-HT neurotransmission.