Effects of local application of 5-hydroxytryptamine into the dorsal or median raphe nuclei on haloperidol-induced catalepsy in the rat

The effects of local application of the endogenous brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) into the dorsal (DR) or median (MR) raphe nuclei on haloperidol-induced catalepsy (CAT) in rats were studied. Local application of 5-HT (40 microg, -10 min) into the DR or MR, respectively, produced a significant reversal of haloperidol-induced CAT. Lower doses (5 or 25 microg) of 5-HT were ineffective. Compared to previous studies using the selective 5-HT1A receptor agonist 8-OH-DPAT, the non-selective endogenous serotonin receptor agonist 5-HT was significantly less potent in this paradigm. Furthermore, the observed anticataleptic effect of 5-HT was seen following injections into both DR or MR nuclei. The reversal of CAT by local application of 5-HT (40 microg) into the DR was significant also at 70 min after 5-HT administration, with the same tendency for 5-HT injections into the MR. At this time interval, other serotonergic behavioral symptoms like head twitches and wet-dog shakes also emerged. The early reversal of CAT by local 5-HT administration into the MR is in all probability mediated via stimulation of 5-HT1A autoreceptors on raphe serotonergic cell bodies. The reversal of CAT following 5-HT injections into the DR might alternatively be mediated via functional mechanisms other than stimulation of 5-HT1A autoreceptors. The anticataleptic effects observed at the later observation time could be due to stimulation of postsynaptic 5-HT2 receptors following diffusion of 5-HT into 5-HT2 receptor rich areas of the brain.     

Evidence that PGE2 in the dorsal and median raphe nuclei is involved in LPS-induced anorexia in rats

Anorexia is an element of the acute-phase immune response. Its mechanisms remain poorly understood. Activation of inducible cyclooxygenase-2 (COX-2) in blood-brain-barrier endothelial cells and subsequent release of prostaglandins (e.g., prostaglandin E2, PGE2) may be involved. Therefore, we sought to relate the effects of prostaglandins on the anorexia following gram-negative bacterial lipopolysaccharide treatment (LPS) to neural activity in the dorsal and median raphe nuclei (DRN and MnR) in rats. COX-2 antagonist (NS-398, 10 mg/kg; IP) administration prior to LPS (100 μg/kg; IP) prevented anorexia and reduced c-Fos expression the DRN, MnR, nucleus tractus solitarii and several related forebrain areas. These data indicate that COX-2-mediated prostaglandin synthesis is necessary for LPS anorexia and much of the initial LPS-induced neural activation. Injection of NS-398 into the DRN and MnR (1 ng/site) attenuated LPS-induced anorexia to nearly the same extent as IP NS-398, suggesting that prostaglandin signaling in these areas is necessary for LPS anorexia. Because the DRN and MnR are sources of major serotonergic projections to the forebrain, these data suggest that serotonergic neurons originating in the midbrain raphe play an important role in acute-phase response anorexia.     

Effects of local application of 5-HT and 8-OH-DPAT into the dorsal and median raphe nuclei on core temperature in the rat

The core temperature of male Wistar rats was measured after local application of 5-HT (10 µg) or 8-OH-DPAT (5 µg) into the dorsal (DR) or the median raphe (MR) nuclei. The core temperature was measured by a rectal thermistor probe, 20 and 60 min after the injection procedure started. The injected volume was 0.5 µl and injections were made by means of 31G needles, at a rate of 0.33 µl min^–1. The raphe nuclei were approached at 30° in order to avoid penetration of the cerebral aqueduct or to avoid the DR with injections aimed for the MR. The application of 5-HT or the 5-HT_1A agonist 8-OH-DPAT into the DR produced a marked decrease in core temperature, whereas injections into the MR had no effect. These results demonstrate an important role for the DR in temperature regulation in the rat. The fact that the 5-HT_1A agonist 8-OH-DPAT produced a decrease in core temperature, together with the observation that administration of the 5-HT₁ antagonist (–)pindolol antagonized the 5-HT as well as the 8-OH-DPAT-induced decrease, indicates the involvement of DR 5-HT_1A receptors in rat thermoregulation.     

Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study.

The effects of systemic administration of fluvoxamine on extracellular serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the frontal cortex and raphe nuclei of freely moving rats were examined. Fluvoxamine significantly increased extracellular 5-HT concentrations in both regions at the two doses used (1 and 10 mg/kg i.p.). However, the increase in the raphe nuclei was several-fold that in the frontal cortex. Dialysate 5-HIAA concentrations decreased after treatment with fluvoxamine. These results confirm that 5-HT uptake inhibitors preferentially increase extracellular concentrations of 5-HT in the vicinity of cell bodies and dendrites of serotonergic neurones.     

5-HT1A receptors in the dorsal hippocampus mediate the anxiogenic effect induced by the stimulation of 5-HT neurons in the median raphe nucleus.

We evaluated the involvement of dorsal hippocampus (DH) 5-HT1A receptors in the mediation of the behavioral effects caused by the pharmacological manipulation of 5-HT neurons in the median raphe nucleus (MRN). To this end, we used the rat elevated T-maze test of anxiety. The results showed that intra-DH injection of the 5-HT1A/7 agonist 8-OH-DPAT facilitated inhibitory avoidance, an anxiogenic effect, without affecting escape. Microinjection of the 5-HT1A antagonist WAY-100635 was ineffective. In the elevated T-maze, inhibitory avoidance and escape have been related to generalized anxiety and panic disorders, respectively. Intra-MRN administration of the excitatory amino acid kainic acid, which non-selectively stimulates 5-HT neurons in this brain area facilitated inhibitory avoidance and impaired escape performance, but also affected locomotion. Intra-MRN injection of WAY-100635, which has a disinhibitory effect on the activity of 5-HT neurons in this midbrain area, only facilitated inhibitory avoidance. Pre-administration of WAY-100635 into the DH blocked the behavioral effect of intra-MRN injection of WAY-100635, but not of kainic acid. These results indicate that DH 5-HT1A receptors mediate the anxiogenic effect induced by the selective stimulation of 5-HT neurons in the MRN.     

Modulatory effect of p-chlorophenylalanine microinjected into the dorsal and median raphe nuclei on cocaine-induced behaviour in the rat.

The present study examined whether a potentiation of cocaine-induced behaviour in rats following peripheral pretreatment with the 5-hydroxytryptamine (5-HT) biosynthesis inhibitor p-chlorophenylalanine may be due to depletion of 5-HT in the dorsal raphe nucleus and/or median raphe nucleus. Following peripheral pretreatment with p-chlorophenylalanine (100 mg/kg, i.p.) for 3 consecutive days, a potentiation of cocaine-induced locomotor activity and rears was observed. To investigate a possible involvement of serotonergic neurones arising in the midbrain raphe nuclei in the observed potentiation, p-chlorophenylalanine (0.5 microg) was microinjected in either the dorsal raphe nucleus or median raphe nucleus followed by behavioural testing 48 h later. Application of p-chlorophenylalanine in the dorsal raphe nucleus resulted in an enhancement of cocaine-induced locomotor activity and head bobs. In contrast, the stimulant effect of cocaine on behaviour was not altered by microinjection of p-chlorophenylalanine in the median raphe nucleus. Peripheral and central administration of p-chlorophenylalanine did not consistently alter the baseline behaviour of saline-treated animals. Biochemical results indicated only a moderate depletion of 5-HT in the midbrain raphe nuclei following peripheral p-chlorophenylalanine administration. Surprisingly, the central application of p-chlorophenylalanine in the dorsal raphe nucleus and median raphe nucleus did not alter the 5-HT levels in the midbrain raphe nucleus investigated. In addition, peripheral and central administration of p-chlorophenylalanine did not alter the 5-HT levels in the nucleus accumbens. In conclusion, the behavioural results suggest that the potentiation of cocaine-induced behaviour following peripheral p-chlorophenylalanine administration may be attributed to the dorsal raphe nucleus but not the median raphe nucleus suggesting that, serotonergic dorsal raphe nucleus neurones may normally mediate a tonic inhibitory effect on cocaine-induced behaviour. Furthermore, the biochemical data may indicate the existence of neurochemical resistance of the midbrain raphe nuclei to the 5-HT depleting effects of p-chlorophenylalanine.     

In vivo control of 5-hydroxytryptamine release by terminal autoreceptors in rat brain areas differentially innervated by the dorsal and median raphe nuclei

Selective serotonin reuptake inhibitors (SSRIs) reduce the 5-HT release in vivo. This effect is due to the activation of somatodendritic 5-HT_1A receptors and it displays a regional pattern comparable to that of selective 5-HT_1A agonists, i.e., preferentially in forebrain areas innervated by the dorsal raphe nucleus (DRN). However, despite a comparatively lower 5-HT_1A-mediated inhibition of 5-HT release and a greater density of serotonergic uptake sites in hippocampus, the net elevation produced by the systemic administration of SSRIs is similar in various forebrain areas, regardless of the origin of serotonergic fibres. As terminal autoreceptors may also limit the SSRI-induced elevations of 5-HT in the extracellular brain space, we reasoned that a differential control of 5-HT release by terminal autoreceptors in DRN- and median raphe-innervated areas might be accountable. To examine this possibility, we have conducted a regional microdialysis study in the DRN, MRN and four forebrain regions preferentially innervated either by the DRN (frontal cortex, striatum) or the median raphe nucleus (MRN; dorsal and ventral hippocampus) using freely moving rats. Dialysis probes were perfused with 1 μM of the SSRI citalopram to augment the endogenous tone on terminal 5-HT autoreceptors. The non-selective 5-HT₁ antagonist methiothepin (10 and 100 μM, dissolved in the dialysis fluid) increased extracellular 5-HT in frontal cortex and dorsal hippocampus in a concentration-dependent manner. The 5-HT_1B/1D antagonist GR 127935 was ineffective at 10 μM and tended to reduce 5-HT in dorsal hippocampus at 100 μM. The local infusion of 100 μM methiothepin significantly elevated the extracellular 5-HT concentration to 142–173% of baseline (mean values of 260 min post-administration) in the DRN, MRN, frontal cortex, striatum and hippocampus (dorsal and ventral). Comparable elevations were noted in the four forebrain regions examined. As observed in frontal cortex and dorsal hippocampus, the perfusion of 10 μM GR 127935 did not elevate 5-HT in DRN, MRN, striatum or ventral hippocampus. Because the stimulated 5-HT release in the DRN has been suggested to be under control of 5-HT_1B/1D receptors, we examined the possible contribution of these receptor subtypes to the effects of methiothepin in the DRN. The perfusion of sumatriptan (0.01–10 μM) or GR 127935 (0.01–10 μM) did not significantly modify the 5-HT concentration in dialysates from the DRN. Thus, the present data suggest that the comparable effects of SSRIs in DRN- and MRN-innervated forebrain regions are not explained by a preferential attenuation of 5-HT release by terminal 5-HT_1B autoreceptors in hippocampus, an area with a low inhibitory influence of somatodendritic 5-HT_1A receptors. Methiothepin-sensitive autoreceptors (possibly 5-HT_1B) appear to play an important role not only in the projection areas but also with respect to the control of 5-HT release in the DRN and MRN. In addition, our findings indicate that GR 127935 is not an effective antagonist of the actions of 5-HT at rat terminal autoreceptors. Received: 27 February 1998 / Accepted: 12 June 1998     

Differential clonidine effects on EEG following lesions of the dorsal and median raphe nuclei in rats

The effects of clonidine on EEG activity and gross behavior were studied in rats with electrolytic lesions of the median (MR) and dorsal (DR) raphe nuclei. Lesioned animals showed significant depletion in forebrain serotonin concentrations. Clonidine (0.1 mg/kg and 0.2 mg/kg IP) produced synchronization in cortical EEG pattern and markedly increased alpha and theta activities in unlesioned animals. Clonidine treatment resulted also in a sedative response. In MR lesioned rats clonidine effect upon EEG was significantly reduced and, additionally, sedative response was not seen. On the other hand clonidine effect on EEG was markedly increased in rats with lesioned DR. These results are discussed on the basis of possible interaction between serotonergic and noradrenergic neurons in the brain.     

Different behavioral responses of rats to kainate injections into the dorsal and median raphe nuclei

A local injection of kainic acid (KA) into the dorsal raphe nucleus (NRD) increased the motor activity and produced head shakes, hind limb abduction, forepaw treading and sniffing. This syndrome was antagonized partly by cyproheptadine and completely by naloxone. An injection of KA into the median raphe nucleus (NRM) produced sedation, catalepsy and analgesia, which were accompanied by a decrease in the beta-endorphin immunoreactivity in the mesencephalon. Naloxone completely reversed the behavioral inhibition after KA injections into the NRM, while a pretreatment with cyproheptadine augmented the catalepsy. KA injected into the NRD and NRM depressed the forebrain level of serotonin and slightly elevated that of 5-hydroxyindoleacetic acid. The results demonstrate that besides serotonin the opioid system is also involved in various effects induced by activation of the raphe nuclei.     

Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide.

Major depressive disorder (MDD) and suicide are associated with deficient serotonergic neurotransmission. Tryptophan hydroxylase (TPH) is the rate-limiting biosynthetic enzyme for serotonin. Previously, we reported elevated levels of TPH protein in the dorsal raphe nucleus (DRN) of depressed suicides and now examine expression of neuronal TPH2 mRNA in a cohort of matched controls and depressed suicides (n = 11 pairs). DRN TPH2 mRNA was measured by densitometric analysis of autoradiograms from in situ hybridization histochemistry experiments. TPH2 mRNA is confirmed as the raphe-specific isoform of TPH in human brain, and is expressed in neurons throughout the anteroposterior extent of the DRN and median raphe nucleus (MRN). TPH2 mRNA expression correlates with TPH protein distribution in the DRN, and has a negative correlation with age. In drug-free suicides, TPH2 expression is 33% higher in the DRN and 17% higher in the MRN as compared to matched nonpsychiatric controls. Higher levels of TPH2 mRNA were found throughout the entire extent of the rostrocaudal axis of the DRN, and were not specific to any single subnucleus. Higher TPH2 mRNA expression may explain more TPH protein observed in depressed suicides and reflect a homeostatic response to deficient brain serotonergic transmission.     

A GABA cardiovascular mechanism in the dorsal raphe of the rat

An injection of gamma-aminobutyric acid (GABA) and the GABA agonist, muscimol, into the dorsal raphe reduced both heart rate and blood pressure in the urethane-anesthetized rat. Picrotoxinin (3.4 nmol) did not affect blood pressure and slightly reduced the heart rate when injected into the dorsal raphe, but it blocked the decrease in both cardiovascular responses produced by GABA. These decreases in heart rate and blood pressure most likely result from stimulation of a GABAA receptor, as the GABAB agonist, baclofen, appeared to elevate heart rate and blood pressure by a mechanism occurring outside the dorsal raphe area. The changes in blood pressure and heart rate induced by muscimol occurred whether or not respiration was supported. Finally, it can be inferred that these GABAergic actions on blood pressure and heart rate probably involve both an inhibition of central sympathetic outflow and an excitation of parasympathetic outflow, as the quaternary muscarinic blocker, atropine methyl nitrate, blocked the decrease in heart rate induced by muscimol, but not the decrease in blood pressure.     

Effect of prolonged administration of tianeptine on 5-HT neurotransmission: an electrophysiological study in the rat hippocampus and dorsal raphe

Extracellular unitary recordings of dorsal hippocampus CA₃ pyramidal neurons and of dorsal raphe 5-hydroxytryptamine (5-HT) neurons were used to assess the effect of tianeptine, a putative antidepressant, on the efficacy of 5-HT neurotransmission. Sustained tianeptine administration (20 mg/kg/day, s.c. × 14 days) did not modify the firing activity of 5-HT neurons in the dorsal raphe. Their responsiveness to the intravenous injection of LSD, an agonist of the somatodendritic 5-HT autoreceptor, and of 8-OH-DPAT, a selective 5-HT_1A agonist, was also unaffected by this treatment. The responsiveness of CA₃ pyramidal neurons to microiontophoretic application of 5-HT remained unchanged after sustained tianeptine administration, but it was markedly enhanced in rats treated with repeated electroconvulsive shocks. Finally, the duration of suppression of firing activity of CA₃ pyramidal neurons produced by electrical stimulation of the ascending 5-HT pathway, delivered at 1 Hz and 5 Hz, was not modified in rats treated with tianeptine. Methiothepin, an antagonist of the terminal autoreceptor enhanced the effectiveness of 5-HT pathway stimulation to the same extent in control and tianeptinetreated rats. The present results indicate that, administered at a dose known to stimulate 5-HT reuptake (20 mg/kg/day, s.c.; by minipump), and for a period of time (14 days) for which other antidepressant treatments have been shown to enhance 5-HT function, tianeptine does not modify the efficacy of 5-HT synaptic transmission in the rat hippocampus.     

Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

Rationale

Blockade of α₂ adrenoceptors and histamine H₁ receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine.

Objectives

However, it remains unclear how mirtazapine’s actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei.

Method

Using dual-probe microdialysis, we determined the roles of α₂ and H₁ receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices.

Results

Mirtazapine (<30 μM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT_1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H₁ receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H₁ agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H₁ receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α₂ adrenoceptor blockade was attenuated by concurrent DRN H₁ blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α₂ adrenoceptor inhibition was unaffected by concurrent MRN H₁ receptor blockade.

Conclusion

These results suggest that enhanced serotonergic transmission resulting from α₂ adrenoceptor blockade is offset by subsequent activation of 5-HT_1A receptors and, in the DRN but not MRN, H₁ receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.     

Chemical lesions of both dorsal and median raphe nuclei and changes in social and aggressive behaviour in rats

Microinjections of 5,7-dihydroxytryptamine into both the dorsal and median raphe nuclei resulted in 90% depletions of striatal and hippocampal 5-HT concentrations. Compared with vehicle-injected controls the lesioned rats showed reduced active social interaction scores in all four of the test conditions and also reduced levels of locomotor activity. The lesioned rats did not differ from the controls in their latency to start drinking in a novel environment; or in their response to intruder rats placed in their homo cages, or in their behaviour as intruders when they were placed in the home-cages of unoperated rats. The difficulties of interpreting the behavioural effects of a lesion when the lesion produces hypoactivity, and the differences between the effects of these joint lesions of both dorsal and median raphe nuclei and the effects of separate lesions of each nucleus are discussed.     

Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition.

While an involvement of brain serotonin systems in schizophrenia has been suggested by many studies, the relative role of different serotonergic projections in the brain remains unclear. We therefore examined the effects of selective brain serotonin depletion on psychotropic drug-induced locomotor hyperactivity and prepulse inhibition, two animal models of aspects of schizophrenia. Pentobarbital-anesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically microinjected with 1 microl of a 5 microg/microl solution of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the dorsal or median raphe nucleus. At 2 weeks after the surgery, rats with dorsal raphe lesions did not show changes in psychotropic drug-induced locomotor hyperactivity, but displayed partial disruption of prepulse inhibition. In contrast, rats with median raphe lesions showed significant enhancement of phencyclidine-induced, but not amphetamine-induced locomotor hyperactivity and a marked disruption of prepulse inhibition. These results provide evidence for differential involvement of serotonergic projections in locomotor hyperactivity and prepulse inhibition. This study may help to explain the role of different serotonin projections in the brain in the pathophysiology of schizophrenia.     

Effects of imipramine on raphe nuclei and prefrontal cortex extracellular serotonin levels in the rat

 The effect of acute administrations of three doses of imipramine (1, 5 and 10 mg/kg SC), a widely used tricyclic antidepressant, on extracellular levels of serotonin (5-HT) has been studied by intracerebral microdialysis in raphe nuclei and prefrontal cortex of conscious rats. Imipramine 1 mg/kg SC did not change extracellular 5-HT in either raphe nuclei and prefrontal cortex. However, with the dose of 5 mg/kg SC imipramine induced in raphe nuclei, a brief increase of extracellular 5-HT followed by a lowering (55–65% basal release) of the neurotransmitter. The same dose of imipramine decreased (60–70% of basal value) extracellular 5-HT in prefrontal cortex. Imipramine 10 mg/kg SC significantly increased 5-HT levels in both raphe nuclei (190 ± 20% above basal value) and prefrontal cortex (280 ± 15% above basal value). Pretreatment with (-)pindolol (5 mg/kg SC), a non-selective 5-HT_1A subtype receptor antagonist, 30 min before imipramine 5 mg/kg, modified the effect of the antidepressant: an increase, instead of a decrease, on prefrontal cortex dialysate 5-HT was observed. (-)Pindolol (10 mg/kg SC) increased extracellular 5-HT in both raphe nuclei (155 ± 20% above basal value) and prefrontal cortex (160 ± 8% above basal value). These data show that acute administration of imipramine modifies extracellular 5-HT at the level of the raphe nuclei and prefrontal cortex. 5-HT_1A autoreceptors in the raphe nuclei, which this study suggests to be tonically active, may be stimulated after systemic administration of high doses of imipramine. Received: 10 April 1997 / Final version: 30 June 1997     

Correction to: Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

Psychopharmacology - The authors have made unintentional errors in data analysis and consequently in four figures.     

Modulation of cocaine-induced locomotor activity, rears and head bobs by application of WAY100635 into the dorsal and median raphe nuclei of the rat

The present study investigated the role of somatodendritic 5-HT1A autoreceptors located in the dorsal and median raphe nuclei on the stimulant effect of cocaine on locomotor activity, rears and head bobs in female Glaxo Wistar rats. Cocaine was administered at a submaximal dose of 15 mg/kg i.p. to enable either a potentiation or attenuation to be observed. The selective 5-HT1A antagonist WAY100635 (0.21 ng or 21 ng) or saline was microinjected in the dorsal or median raphe nuclei followed by the peripheral administration of cocaine 60 min later. WAY 100635 microinjected in the dorsal or median raphe nuclei did not consistently alter the locomotor activity and the number of rears of saline-treated animals. Microinjection of WAY100635 in the dorsal raphe nucleus potentiated cocaine-induced locomotor activity and the number of head bobs. The number of rears induced by cocaine was not significantly altered by WAY100635 microinjected in the dorsal raphe nucleus. In contrast, microinjection of WAY100635 in the median raphe nucleus did not alter the stimulant effect of cocaine on locomotor activity, rears or head bobs. It may be suggested from these results that stimulation of somatodendritic 5-HT1A autoreceptors located in the dorsal raphe nucleus mediates an inhibitory effect on cocaine-induced locomotor activity and head bobs, whereas somatodendritic 5-HT1A autoreceptors in the median raphe nucleus are not involved in the inhibitory role of 5-HT on the stimulant effect of cocaine on locomotor activity and head bobs. A differential involvement of the midbrain raphe nuclei may exist controlling the stimulant effect of cocaine on locomotor activity and head bobs.     

Evidence that 5-HT2 receptor activation decreases noradrenaline release in rat hippocampus in vivo.

1. Recent electrophysiological studies have shown that 5-HT2/5-HT1C receptor agonists inhibit the electrical activity of noradrenergic neurones in the rat locus coeruleus. Here we examine the effect of various agonists and antagonists of 5-HT2/5-HT1C receptors on noradrenaline release in hippocampus of anaesthetized rats using microdialysis. 2. Subcutaneous administration of the 5-HT2/5-HT1C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI: 0.2 and 0.5 mg kg-1), caused a marked decrease (50% of pre-drug levels 60 min after injection) of noradrenaline in hippocampal dialysates which was long-lasting (greater than 120 min). Noradrenaline output also decreased in response to administration of the structural analogue of DOI, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB: 1 mg kg-1, s.c.). 3. The effect of DOI on noradrenaline output was prevented by pretreatment with the 5-HT2/5-HT1C receptor antagonist, ritanserin (0.4 mg kg-1, s.c.). Spiperone (0.2 and 1 mg kg-1, s.c.), a 5-HT2/dopamine D2 receptor antagonist which has low affinity for 5-HT1C receptors, also antagonized the effect of DOI (0.5 mg kg-1, s.c.). Sulpiride (50 mg kg-1, s.c.), a dopamine D2 receptor antagonist did not alter the response to DOI (0.5 mg kg-1, s.c.). 4. Both the non-selective 5-HT receptor agonist, quipazine (1 mg kg-1, s.c.), and the 5-HT-releasing agent, p-chloroamphetamine (2 mg kg-1, s.c.), decreased noradrenaline release in hippocampus and these effects were antagonized by pretreatment with ritanserin (0.4 mg kg-1, s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)