Bulbospinal serotonin neurons and hypotensive effects of methyldopa in the spontaneously hypertensive rat

Systemic methyldopa administration in genetically hypertensive rats evoked a hypotension which was attenuated after prior treatment with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) given either intracerebroventricularly, to produce a generalised ablation of serotonin nerves in brain and spinal cord, or by injection into the cervical spinal cord, to cause a selective destruction of descending serotonin pathways. Direct microinjection of methyldopa into the ventrolateral medulla in the area of the B1 and B3 serotonin cells was also effective in lowering arterial pressure. The hypotensive response to this medullary administration of methyldopa was again attenuated by 5,7-DHT given either intracerebroventricularly or by intraspinal injection. On the other hand, prior treatment intracerebroventricularly with 6-hydroxydopamine did not affect the hypotensive effect of methyldopa injected into the region of the ventrolateral B1 and B3 cells, supporting the suggestion that this effect of methyldopa is mediated by bulbospinal serotonin neurons and not by descending catecholamine nerves. The fact that methyldopa injection into the ventrolateral medulla in a region coinciding with the B1 and B3 cells lowers blood pressure is consistent with previous studies demonstrating that these neurons serve to maintain or elevate arterial pressure.     

Midline B3 serotonin nerves in rat medulla are involved in hypotensive effect of methyldopa

Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.     

Effects of intrathecal administration of methysergide, phentolamine, and pindolol on pressor responses to electrical stimulation of the rostral ventrolateral medulla

Neurons projecting from the rostral ventrolateral medulla (RVLM) to the spinal cord are important in blood pressure control. The present experiments examined the role of spinal adrenoreceptors and serotonin receptors in mediating the pressor effects of electrical stimulation of the RVLM. Accordingly the effects on blood pressure of electrical stimulation of the RVLM were studied before and after intrathecal administration of adrenergic or serotonergic antagonists in normotensive and hypertensive rats. Electrical stimulation in the area of the RVLM-B3 serotonin-containing neurons in Wistar-Kyoto (WKY) rats increased blood pressure, and the pressor responses were reduced by intrathecal methysergide (30 and 100 micrograms). Similar findings were seen in spontaneously hypertensive rats (SHR). In WKY, electrical stimulation in the area of the RVLM-C1 epinephrine-containing neurons, increased mean arterial pressure (MAP), but the pressor responses were unaffected by intrathecal phentolamine (15 micrograms), pindolol (2 micrograms), or methysergide (30 and 100 micrograms), or saline. The results suggest that the pressor effects of stimulation of the RVLM-B3 area are mediated at least in part through activation of spinal serotonin receptors. The lack of effect of phentolamine and pindolol on the RVLM-C1 area pressor responses raises a question regarding the importance of spinal adrenergic receptors in mediating these effects.     

Spinal 5-HT pathways and the antinociception induced by intramedullary clonidine in rats

Summary The possible involvement of spinal 5-hydroxytryptamine (5-HT) pathways in antinociception induced by microinjection of clonidine into the ventrolateral surface of the medulla oblongata was investigated in rats. Microinjection of clonidine (10-20 µg), but not yohimbine (1 µg) or 0.9% saline, into the lateral medulla prolonged the hot plate latency in rats. This clonidine-induced antinociception was abolished by intramedullary injection of the alpha₂-adrenoceptor antagonist, yohimbine. Selective destruction of spinal 5-HT neurons produced by intraspinal injection of 5,7-dihydroxytryptamine (5,7-DHT; 10 µg) or postsynaptic blockade of spinal 5-HT receptors produced by intrathecal injection of cyproheptadine (1 µg; a mixed 5-HT₁/5-HT₂ antagonist) also abolished clonidine-induced antinociception. Rats given 5,7-DHT intraspinally or cyproheptadine intrathecally showed a decrease in hot plate latency as compared with the controls. In anesthetized rats, the 5-HT release from the thoracic spinal cord was enhanced by microinjection of clonidine into the lateral medulla. This enhanced spinal 5-HT release evoked by intramedullary injection of clonidine was abolished by pretreatment of rats with intraspinal injection of 5,7-DHT. These results indicate that 5-HT pathways to the spinal cord mediate the antinociceptive effect induced by microinjection of clonidine into the ventrolateral surface of the medulla oblongata in rats.This study was supported by grants from the National Science Council (Taipei, Taiwan, Republic of China) Send offprint requests to M.T. Lin at the above address     

IMPORTANCE OF CENTRAL SEROTONIN NEURONS IN THE HYPOTENSIVE ACTION OF METHYLDOPA IN THE RAT

1. Normotensive (WKY) and stroke prone spontaneously hypertensive (SHR-SP) rats were given methyldopa (200 mg/kg i.p.) daily for five days and their brains were then sectioned and processed with the Faglu method for catecholamine fluorescence. 2. This treatment with methyldopa induced a green fluorescence not seen in control animals, in cells coinciding with the B1–B9 groups of serotonin neurons in the brainstem. 3. Pretreatment with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, i.c.v.), which is relatively specific for serotonin neurons, prevented the appearance of this green fluorescence in the serotonin cell groups of rats given methyldopa. 4. Pretreatment with 5,7-DHT, i.c.v. approximately halved the magnitude of the hypotensive response to a single dose of methyldopa (80 mg/kg i.p.). 5. We suggest that central serotonin nerves contribute to the hypotensive action of methyldopa. 6. It is our hypothesis that methyldopa is taken up by these serotonin cells and that the green fluorescence reflects the production of α-methyldopamine, as a result of decarboxylation by the ubiquitous enzyme, L-aromatic amino acid decarboxylase.     

Contribution of noradrenergic and serotonergic neurons to the circulatory effects of centrally acting clonidine and alpha-methyldopa in rabbits

The effects of intracisternal clonidine (0.04, 0.2, and 1.0 microgram/kg) and of alpha-methyldopa (alpha-MD; 400 micrograms/kg) on mean arterial pressure (MAP) and heart rate (HR) were studied in conscious rabbits before, and 7 and 14 days after, intracisternal injection of (a) vehicle, (b) 6-hydroxydopamine (6-OHDA; 600 micrograms/kg), or (c) 5,6-dihydroxytryptamine (5,6-DHT; 633 micrograms/kg) (n = 6 per group). In the initial control experiment clonidine and alpha-MD produced similar falls in MAP and HR in each group; there was also good reproducibility of responses in vehicle-treated rabbits on the 3 experimental days. But after 6-OHDA or 5,6-DHT administration the circulatory effects of clonidine and alpha-MD were markedly attenuated. On day 14 after injection of 6-OHDA, the clonidine-induced falls in MAP and HR averaged 38 and 18%, respectively, of the control responses (p less than 0.001). On day 14 after 5,6-DHT administration, the falls in MAP and HR after clonidine administration were reduced to 27 and 13% of control, respectively (p less than 0.01), while the corresponding responses after alpha-MD administration were 39 and 61% of control (p less than 0.05). Neurochemical findings suggest that 6-OHDA affected noradrenergic (NA), dopaminergic (DA), but not serotonergic (5HT) neurons, and that 5,6-DHT affected 5HT but not NA and DA neurons. We conclude that the circulatory effects of clonidine and alpha-MD are mediated through both central NA and 5HT neurons.     

Evidence that the dorsal raphe area is involved in the effect of clonidine against pentylenetetrazole-induced seizures in rats

Summary Injections of 5,7-dihydroxytryptamine (5,7-DHT) in the rat ventromedial tegmentum, which depleted forebrain serotonin, and of 6-hydroxydopamine in the dorsal noradrenergic bundle, which causes a marked reduction of forebrain noradrenaline, intensified pentylenetetrazol (PTZ)-induced seizures. Neither condition significantly modified the inhibitory effect of 0.5 mg/kg clonidine on PTZ-induced seizures, with the exception of the effect on mortality which was reduced in 5,7-DHT treated animals. Electrolytic lesions in the nucleus raphe medianus or dorsalis potentiated PTZ-induced seizures but only lesions in the nucleus raphe dorsalis significantly attenuated the effect of clonidine on tonic seizures and mortality. Both lesions reduced clonidine's effect on latency to the first convulsion.The results indicate that the dorsal raphe area plays a role in the inhibitory effect of 0.5 mg/kg clonidine on PTZ-induced seizures. Serotonin neurons other than those innervating diencephalic and telencephalic structures may also contribute, particularly to the effect of clonidine on tonic seizures.     

The cardiovascular actions of clonidine and neuropeptide-Y in the ventrolateral medulla of the rat.

1. The cardiovascular responses to neuropeptide-Y (NPY) (25 and 50 pmol) and clonidine (10 and 20 nmol) were examined following microinjection into the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Mean arterial pressure (MAP) and heart rate (HR) were measured in anaesthetized rats, pre- and post-injection. 2. The alpha 2-adrenoceptor agonist clonidine (10 and 20 nmol) reduced MAP and HR significantly when microinjected into the CVLM and RVLM. 3. NPY (25 and 50 pmol) microinjected into the CVLM decreased MAP and HR. However, in the RVLM neither dose had a significant cardiovascular effect. 4. The possibility of a functional interaction between the adrenergic system and NPY was examined by co-administration of clonidine and NPY in doses that gave submaximal blood pressure responses. In the CVLM this produced hypotension and bradycardia which was similar in magnitude to the sum of their individual responses, indicating that in this area their actions appear to be independent. 5. In the RVLM, where NPY has no significant cardiovascular effects, co-administration with clonidine, did not alter the response to clonidine. 6. It appears that in the areas investigated, there is no functional interaction between NPY and clonidine.     

Sympathoinhibitory effects of clonidine are transmitted by the caudal ventrolateral medulla in cats

We examined mechanisms of the central sympathoinhibitory actions of systemically administered clonidine in anesthetized cats. To avoid influences of sympathetic chemo- and baroreflexes, the animals were deafferentated by cutting the carotid sinus and vagal nerves bilaterally. Intravenous (i.v.) injections of clonidine (25-250 nmol/kg) caused significant (50-90%) decreases in preganglionic sympathetic nerve activity (SNA) recorded from the white ramus of the third thoracic segment. Microinjections (500 nl) into the rostral ventrolateral medulla (RVLM) of clonidine at doses (50-500 pmol in 500 nl), which probably produced higher local concentrations than produced by systemic administration, caused only slight reductions of SNA and small decreases in arterial blood pressure (BP). Furthermore, sympathoinhibition and hypotension caused by intravenous clonidine was almost unaffected by prior microinjection of alpha2-receptor antagonist rauwolscine (500 pmol) into the RVLM. Microinjections of clonidine into the caudal ventrolateral medulla (CVLM), which provides important inhibitory input to the RVLM, had no significant effects. However, chemical lesions of the CVLM with kainate (5.0 nmol), effectively blocked the sympathoinhibitory effects of subsequently administered intravenous clonidine. The results suggest that the central sympathoinhibitory effects of therapeutically relevant doses of systemically administered clonidine may be primarily mediated by pathways that activate the CVLM rather than by direct actions within the RVLM.     

Clonidine-induced hypothermia: Possible involvement of cholinergic and serotonergic mechanisms

The thermoregulatory effects (including metabolic, vasomotor and respiratory activities) produced by an injection of clonidine (1-3 micrograms in 0.5 microliter) into the preoptic anterior hypothalamus were assessed in conscious rats at ambient temperatures (Ta) of 8, 22 and 30 degrees C. Intrahypothalamic administration of clonidine caused a dose-dependent fall in rectal temperature at Ta 8 degrees C and 22 degrees C. The hypothermia in response to clonidine was due to decreased metabolic heat production and/or cutaneous vasodilation. There was no change in respiratory evaporative heat loss. The clonidine-induced hypothermic response was attenuated by pretreatment of the rats with either 5,7-dihydroxytryptamine (10 micrograms, administered intrahypothalamicly, 14 days before clonidine injection), yohimbine (0.2 microgram, administered intrahypothalamicly, 10 min before clonidine injection), cyproheptadine (1 microgram, administered intrahypothalamicly, 10 min before clonidine injection), or atropine (0.1 microgram, administered intrahypothalamicly, 10 min before clonidine injection). The data indicate that clonidine may act on alpha-adrenoceptors located on a serotonin-acetylcholine pathway within the preoptic anterior hypothalamus to induce hypothermia by promoting a reduction in metabolic heat production and/or an enhancement in dry heat loss in rats.     

Studies on the separate roles of forebrain and spinal serotonin in morphine analgesia

Summary 5,7-Dihydroxytryptamine (5,7-DHT) injections in the ventromedial tegmentum (VMT) at the level of nucleus interpeduncularis or in the ventral raphe area (VR) of the medulla oblongata were used to study the separate roles of forebrain and spinal 5-HT in the antinociceptive effect of morphine in rats. 5,7-DHT injections in the VMT, which caused marked, selective depletion of forebrain 5-HT, did not modify the effect of morphine in the hot plate and tail immersion tests. Direct injection of 5,7-DHT into the nucleus raphe medianus also failed to modify the effect of morphine in the two tests used to measure nociceptive responses. The effect of morphine was significantly reduced 30 min after injection to rats depleted of spinal 5-HT by 5,7-DHT injected in the VR but the areas under the curves between vehicle and 5,7-DHT treated animals were not significantly different. The data show that the integrity of 5-HT neurons in the forebrain is not necessary for the antinociceptive effect of morphine and a substantial amount of this effect is still present in rats with marked depletion of spinal 5-HT.     

Evidence for a central alpha-sympathomimetic action of clonidine in the rat.

The antihypertensive effects of clonidine (0.15 mg kg-1, i.p.) were studied in conscious DOCA/saline hypertensive rats having chronically implanted arterial cannulae. The response to clonidine was markedly reduced by simultaneously administered desipramine (3 mg kg-1, i.p.), antagonized dose-dependently by piperoxan (2-10 mg kg-1, i.v.) and prevented by pretreatment with phentolamine (0.2 mg, i.c.v.). Pretreatment with 6-hydroxydopamine (3 x 250 mu-g, i.c.v.), haloperidol (1 mg kg-1, i.p.), p-chloro-N-methylamphetamine (3.5 mg kg-1, i.p.) or 5,6-dihydroxytryptamine (50 mu-g and 25 mu-g, i.c.v.) did not significantly modify the antihypertensive response. It is concluded that the antihypertensive response to clonidine is mediated via stimulation of central alpha-adrenoceptors and is independent of central dopaminergic receptors and intact central serotoninergic neurons. The necessity for intact central noradrenergic neurons remains uncertain.     

The role of serotonin and dopamine in brain in the antidepressant-like effect of clonidine in the forced swimming test.

The effect of clonidine (0.1 mg/kg, i.p.), as a three-injection course, on behaviour in the forced swimming test was studied in rats injected intracerebroventricularly (i.c.v.) with 150 micrograms 5,7-dihydroxy-tryptamine (5,7-DHT) to destroy serotonin (5-HT) neurones or treated with 100 mg/kg (i.p.) (+/-)-sulpiride or 0.5 micrograms/0.5 microliter (-)-sulpiride in the nucleus accumbens. Clonidine significantly increased struggling and reduced floating and the effects were antagonized by both treatments with sulpiride but not by 5,7-DHT which markedly depleted 5-HT in brain. The results suggest that the mesolimbic dopaminergic system but not 5-HT neurones, plays a permissive role in the antidepressant-like effect of clonidine in the forced swimming test.     

Effects of pretreatment with 6-hydroxydopamine or noradrenergic receptor blockers on the clonidine-induced distruption of conditioned avoidance responding.

The effects of clonidine were assessed on conditioned avoidance responses (CAR) in control, 6-hydroxy-dopamine (6-OHDA)- and vehicle-treated rats, using a shuttle box device. Clonidine (100--400 micrograms/kg) produced a significant decrease of CAR in control and vehicle-treated animals. On the other hand, avoidance responding was only slightly inhibited in the 6-OHDA-lesioned rats. Pretreatment with the alpha-adrenergic blocking drugs yohimbine or phentolamine (1--8 mg/kg) prevented the CAR disrupting effects of clonidine. When animals were pretreated with the beta-adrenergic blocking agent propranolol (1--8 mg/kg) the ensuing injection of clonidine caused a greater CAR depression. Our results further support the hypothesis relating the conditioned performance depression observed after clonidine to the activation of a presynaptic negative feedback mechanism mediated by alpha-adrenoceptors. It is also suggested that propranolol increases the clonidine inhibition through the blockade of a positive feedback mechanism dependent on the activation of presynaptic beta-receptors.     

Inhibitory effects of clonidine on responses to sympathetic nerve stimulation in the pithed rat.

1. The spinal sympathetic outflow to the eyelid, heart, splanchnic blood vessels, vas deferens and anococcygeus muscle was stimulated in pithed rats. 2. Clonidine inhibited sympathetic outflow to all of the tissues studied. The inhibitory effects of clonidine on cardiac nerves and hypogastric nerves were antagonized by phentolamine. 3. Clonidine produced a postsynaptic alpha-adrenoceptor agonist action on the eyelid, splanchnic blood vessels and the anococcygeus muscle. These effects were also antagonized by phentolamine. 4. The effects of clonidine, naphazoline and oxymetazoline on pre- and postsynaptic alpha-adrenoceptors were determined. 5. The presynaptic alpha-adrenoceptors employed were situated in either the sympathetic cardiac or hypogastric nerve terminals. Increases in diastolic blood pressure were used to assess concurrent postsynaptic alpha-adrenoceptor agonist activity. 6. The presynaptic alpha-adrenoceptor agonist potencies of clonidine, naphazoline and oxymetazoline were very similar on cardiac nerve terminals whereas on the hypogastric nerve terminals oxymetazoline was about 6 times more potent than either naphazoline or clonidine. 7. The results support the view that presynaptic alpha-adrenoceptors regulate transmitter release in sympathetic nerves. There appear to be subtle differences between the presynaptic alpha-adrenoceptors of different sympathetic nerve endings.     

Effects of clonidine on alpha-adrenoceptors in the autoperfused hindquarters of the pithed rat

The effects of clonidine were assessed in pithed rats on responses to spinal cord stimulation of heart rate (HR), systemic blood pressure (BP) and perfusion pressure (PP) in the autoperfused hindquarters. Graded increases in HR, BP and PP were elicited by 10 s periods of spinal stimulation at frequencies of 1, 3 and 10 Hz; the vasoconstrictor responses (BP and PP) were biphasic. Clonidine (3-100 micrograms/kg) caused dose-dependent reductions of HR responses and of the first phase of BP and PP responses to spinal stimulation; the reductions were to a lesser extent with increasing frequency of stimulation. Responses to exogenous noradrenaline were unaffected by clonidine. In contrast, the second phase of the vasoconstrictor responses to 10 Hz stimulation was enhanced by clonidine (3-30 micrograms/kg): this phase of the responses is probably mediated by adrenal catecholamines. Clonidine itself (10-100 micrograms/kg) increased resting levels of BP and PP but not HR. The direct effects of clonidine as well as the effects on responses to spinal stimulation were blocked by phentolamine (1 mg/kg). The results indicate that clonidine selectively activates prejunctional alpha-adrenoceptors in the rat heart and hindquarters in vivo. The results also indicate that clonidine may potentiate the release of adrenal catecholamines, and it is suggested that it may do so by acting as an antagonist at inhibitory alpha-adrenoceptors in the adrenal medulla.     

The cardiovascular effects of intraventricular clonidine and BAY 1470 in conscious hypertensive cats

1 Intraventricular administration of clonidine (5-30 mug) and an analogue, BAY 1470 (15-30 mug) to conscious renal hypertensive cats produced a fall in mean blood pressure lasting for approximately 3 hours. This fall in blood pressure was accompanied by a marked bradycardia.2 Pretreatment with intraventricular phentolamine (100-200 mug), piperoxan (40-200 mug) or tolazoline (75-200 mug) abolished the cardiovascular effects of intraventricular clonidine (20 mug).3 The cardiovascular effects of intraventricular clonidine (20 mug) were not modified by the pretreatment with either haloperidol (1 mg/kg i.p.) or desmethylimipramine (1 mg/kg i.p.).4 Emesis was observed 1-2 min after the administration of either clonidine (5-20 mug) or BAY 1470 (30 mug). This preceded the cardiovascular actions and was still seen after pretreatment with haloperidol, desmethylimipramine, phentolamine, piperoxan or tolazoline.5 It is concluded that the centrally mediated cardiovascular responses observed after intraventricular administration of small doses of clonidine are due to stimulation of central alpha-adrenoceptors and are independent of central catecholamine uptake mechanisms and dopamine receptors.     

Enhancement of clonidine-induced analgesia by lesions induced with spinal and intracerebroventricular administration of 5,7-dihydroxytryptamine

The role of serotonin (5-HT) in analgesia induced by clonidine was examined by determining the effect of intraspinal (i.s.) and intracerebroventricular (i.c.v.) injections of 5,7-dihydroxytryptamine (5,7-DHT) on analgesia produced by clonidine in the tail-flick and hot plate tests. Depletion of amines was verified by high performance liquid chromatography analysis. Intraspinal injections of 5,7-DHT potentiated the action of clonidine in both tests for analgesia and caused depletion of 5-HT in the spinal cord. Intracerebroventricularly injected 5,7-DHT also increased the action of clonidine and depleted 5-HT in brain as well as in the spinal cord. In the groups given intracerebroventricular injections, there appeared to be a biphasic increase in the action of the clonidine. Significant hyperalgesia from pretreatment with neurotoxin was observed only on a limited number of occasions. The present results indicate that 5-HT mechanisms in the CNS are important mediators of the analgesic action of clonidine. Interactions between clonidine and 5-HT systems at both spinal and supraspinal sites are considered.     

The effect of 5,7-dihydroxytryptamine treatment on the response to ethanol in mice

In order to assess the role of the serotonergic system in the development of tolerance to ethanol in the mouse, serotonin neurons in the CNS were lesioned with an intracerebroventricular injection of the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Mice injected with 5,7-DHT responded to an acute dose of ethanol with a longer sleep time and greater fall in body temperature than CSF-treated mice. The increased response to acute administration of ethanol was accompanied by higher circulating levels of ethanol in mice pretreated with 5,7-DHT. When mice were fed an ethanol-containing liquid diet for five days, a higher mortality rate was observed in the 5,7-DHT group compared to the CSF pretreated group of mice. When the groups of mice were tested for tolerance 24 hours after withdrawal, the 5,7-DHT group was less tolerant than the CSF group. Therefore, damage to the serotonin neurons results in altered ethanol disposition, altered initial sensitivity to ethanol, and an inhibition in the development of tolerance in the mouse.     

Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine.

The present study was designed to assess whether the antiaggressive effects of eltoprazine are mediated via presynaptic and/or postsynaptic 5-HT1 receptors. We describe the effects of central 5-HT depletion 1) on the behaviour of resident TMD-S3 rats in a territorial situation, 2) on the efficacy of eltoprazine to inhibit offensive aggression, and 3) on the 5-HT1A, 5-HT1B and 5-HT1C receptor binding in brains of rats previously used in behavioural studies. Male resident rats were given combined 5,7-dihydroxytryptamine (5,7-DHT) injections into the dorsal and median raphe nuclei. Two to four weeks after the lesions, rats were confronted with an intruder Wiser rat in their home cage for a 10-min period. The 5,7-DHT treatment resulted in a modest reduction of offensive behaviour, while having no effects on other social and nonsocial behaviours. Oral administration of eltoprazine (1 mg/kg) specifically reduced offensive aggression in both sham- and 5,7-DHT-lesioned animals, leaving social interest and exploration intact or even increasing it. A low dose (0.3 mg/kg) of eltoprazine did not affect the behavioural repertoire of sham-operated rats, whereas this dose significantly reduced offense behaviours in the 5,7-DHT-lesioned residents. Quantitative autoradiographic studies 5 weeks after 5,7-DHT treatment revealed a significant increase in radioligand binding to 5-HT1A, 5-HT1B and 5-HT1C sites in many brain regions studied, except for the raphe nuclei where [3H]8-OH-DPAT binding to 5-HT1A sites was markedly reduced. The concentrations of 5-HT and 5-HIAA in frontal cortex were reduced to approximately 10% of controls. The results indicate that serotonin has a stimulatory rather than an inhibitory influence on offensive aggressive behaviour. Central 5-HT depletion does not prevent the antiaggressive effects of eltoprazine, indicating a role for postsynaptic 5-HT1 receptors in the modulation of offensive aggression. The 5,7-DHT-induced overall upregulation of 5-HT1A, 5-HT1B and 5-HT1C binding sites suggests that these three receptor subtypes receive a tonic serotonergic influence. It is conceivable that this postsynaptic 5-HT1 receptor supersensitivity is reflected by the increased efficacy of eltoprazine to inhibit offensive aggression.