Patterns of exploration in rats distinguish lisuride from lysergic acid diethylamide

In order to further validate a previously proposed animal model of the effects of LSD in humans, doses of 5, 15, 30 and 60 micrograms/kg lisuride (a non-hallucinogenic congener of LSD) were studied using a behavioral pattern monitor (BPM). The BPM provided both quantitative measures of crossovers, rearings, and holepokes and qualitative measures of spatial patterns of locomotion. A holeboard chamber connected to a homecage provided two test situations. Rats were tested either with (free exploration) or without access to the homecage (forced exploration). In both situations, lisuride exhibited a biphasic dose-response curve for horizontal locomotion (low dose suppression and high dose enhancement), while rearing was significantly reduced at all doses. Lisuride also produced a dose-dependent increase in the perseverative quality of locomotor patterns. A comparison of these results with our previous studies with lysergic acid diethalmide (LSD) indicate that, with the exception of rearings, lisuride fails to mimic LSD's characteristic effects on exploratory activity. Rather, lisuride exhibited many similarities to the dopamine angonist apomorphine.     

Depletion of brain serotonin by 5,7-dihydroxytryptamine alters the response to amphetamine and the habituation of locomotor activity in rats

Awake Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 g 5,7-dihydroxytryptamine (5,7-DHT) through chronically implanted cannulae. Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 5,7-DHT. In a separate set of animals, liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 80–90% and caudate 5HT by 30–42% as early as 24 h after administration of 5,7-DHT. One or 3 days after lesioning, locomotor and exploratory behavior was characterized with a Behavioral Pattern Monitor (BPM). Relative to controls, lesioned rats exhibited a decreased rate of habituation of both locomotor activity and investigatory holepokes. Although the amount of locomotor activity elicited by amphetamine (1.0 mg/kg) was unchanged by the 5HT depletion, lesioned animals exhibited highly stereotyped patterns of locomotion during the last 30-min test session, in contrast to the relatively random patterns characteristic of control animals given amphetamine. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats.     

Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats

A behavioral pattern monitor was used to assess the effects of dizocilpine (MK-801) and phencyclidine on the spatial and temporal patterns of locomotion and investigatory behavior in rats. The monitor provided both quantitative measures of crossovers, rearings and holepokes and qualitative measurement of the spatial and temporal patterns of locomotion. Dizocilpine (0.004-0.5 mg/kg) and phencyclidine (0.25-5.0 mg/kg) produced similar, dose-dependent increases in locomotor activity. At small doses, dizocilpine and phencyclidine increased investigatory holepokes, while at larger doses, both drugs significantly decreased the number of holepokes. Rearings were reduced similarly by the larger doses of each drug. Both dizocilpine and phencyclidine produced perseverative spatial patterns of locomotion, especially at larger doses. However, the locomotor patterns produced by these drugs were found to be dissimilar in spatial quality. After phencyclidine, animals frequently circled the perimeter of the monitor chamber or moved repetitively in horseshoe or figure-8 patterns. By contrast, rats given dizocilpine completed small rotations about either end of the chamber. Pretreatment with a small dose (0.02 mg/kg) of haloperidol, prior to either dizocilpine (0.5 mg/kg) or phencyclidine (5.0 mg/kg) had no effect on the increase in locomotor activity or the decreases in investigatory holepokes produced by the drugs. However, haloperidol altered the effects of phencyclidine on the spatial and temporal patterns of locomotion, suggesting that sigma receptors or other haloperidol-sensitive binding sites, may influence the quality but not the quantity of phencyclidine-induced hyperactivity.     

LSD-induced alterations of locomotor patterns and exploration in rats

A free exploration test was used to examine the effects of LSD on investigatory responding and locomotor activity in a novel environment. Rats were injected with 20–30 g/kg LSD or saline prior to being placed in a home cage. After 10 min, a door was opened permitting entry into a larger holeboard chamber where crossovers, rearings, hole pokes, and routes of locomotion were monitored. When administered either 10 or 30 min prior to testing, LSD reduced the time spent in the holeboard chamber only during the first half of a 1-h session, resulting in a corresponding reduction in all holeboard activity measures. In the subsequent 30 min, LSD-treated rats maintained a steady level of responding, in contrast to the continual derement exhibited by controls. Despite their initial avoidance of the holeboard, LSD-treated rats made consistently longer hole pokes into floor holes and showed a more diversified pattern of locomotion than did controls throughout the 1-h session. Most striking was the failure of LSD-treated rats to establish the stereotyped excursion routes, characteristic of controls, from the home cage to various parts of the holeboard. It is suggested that LSD potentiates both neophobic (avoidance) and investigatory responses to a novel environment by retarding the rate of behavioral habituation.     

Idazoxan (RX 781094) selectively antagonizes alpha 2-adrenoceptors on rat central neurons

We have studied the alpha-adrenoceptor antagonist effects of idazoxan (RX 781094) in extracellular recordings from single locus coeruleus and dorsal raphe neurons of chloral hydrate-anesthetized rats. Idazoxan blocked alpha 2 responses with an ED50 of 14 +/- 8 micrograms/kg i.v., while the potency at alpha 1-receptors was only 420 +/- 190 micrograms/kg. A similar alpha 2 selectivity was seen when idazoxan was applied microiontophoretically. Idazoxan at doses which blocked alpha 1-receptors had little or no effect on locus coeruleus responses to morphine or dorsal raphe responses to LSD. When sodium pentobarbital was used as the anesthetic, systemically administered idazoxan slowed the firing rate of locus coeruleus cells, but iontophoretic experiments showed this to be an interaction with the anesthetic and not a direct agonist effect. We conclude that in rat brain idazoxan is a pure antagonist and that it has a selectivity for alpha 2- over alpha 1-receptors markedly superior to piperoxane, yohimbine, or rauwolscine.     

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission.

1-(2-Pyrimidinyl)-piperazine (1-PP) is a common metabolite of the antidepressant/anxiolytic 5-HT1A agonists, tandospirone (SM-3997), gepirone, buspirone and ipsapirone. The present electrophysiological studies were undertaken to characterize in vivo the effect of 1-PP on noradrenergic (NE) neurotransmission in rat brain. At small doses, 1-PP (ED50 = 80 micrograms/kg, i.v.) reversed the depressant effect of the alpha 2-adrenoceptor agonist, clonidine (20 micrograms/kg, i.v.) on the firing activity of NE neurones of the locus coeruleus. After long-term treatment with tandospirone (10 mg/kg/day, s.c. x 14 days), the responsiveness of these NE neurones to intravenous administration of clonidine was decreased but their mean firing frequency remained within the control range. The effect of 1-PP on the postsynaptic alpha 2-adrenoceptor of pyramidal neurones in the hippocampus was investigated: intravenous administration of 1-PP (2-8 mg/kg, i.v.) reduced the effect of microiontophoretically-applied NE on CA3 pyramidal neurones of the dorsal hippocampus, without affecting their responsiveness to GABA and 5-HT. The effect of the electrical stimulation of NE neurones of the locus coeruleus in reducing firing activity of pyramidal neurones, which is mediated by postsynaptic alpha 1-adrenoceptors, was increased by 47% after acute administration of 1-PP (4 mg/kg, i.v.), presumably as a result of blockade of terminal alpha 2-autoreceptors. The effectiveness of these stimulations remained unchanged after long-term treatment with tandospirone. Furthermore, the decrease in the effectiveness of stimulation of the locus coeruleus, obtained by increasing the frequency from 1 to 5 Hz, a phenomenon due to an increased activation of terminal alpha 2-adrenergic autoreceptors by endogenous NE, remained unaltered after long-term treatment with tandospirone. In addition to the initial depressant effect, stimulation of the locus coeruleus induces a late activation of these neurones which is mediated by a beta-adrenoceptor. The degree of activation induced by stimulation of the locus coeruleus was similar in controls and in long-term tandospirone-treated rats. It is concluded that 1-PP acts as an antagonist at somatodendritic and terminal alpha 2-adrenergic autoreceptors, as well as at postsynaptic alpha 2-adrenoceptors, in the central nervous system of the rat. However, the levels of 1-PP attained after long-term administration of tandospirone were not sufficient to modify NE neurotransmission.     

Stimulation and destruction of the locus coeruleus: opposite effects on 3-methoxy-4-hydroxyphenylglycol sulfate levels in the rat cerebral cortex

The effect of electrical stimulation or electrothermic destruction of the locus coeruleus on cortical (including hippocampus) levels of 3-methoxy-4-hydroxyphenylglycol sulfate (MHPG-sulfate) was studied in rats. The locus coeruleus, which consists of norepinephrine (NE-containing nerve cell bodies, projects to the cerebral cortex and the hippocampus. 10 days after unilateral destruction of the locus coeruleus NE was decreased 78% and MHPG-sulfate, a central NE metabolite, was lowered by 69% in these areas. No alterations in levels of norepinephrine or MHPG-sulfate were observed on the contralateral side.Stimulation of the locus coeruleus induced a frequency-dependent increase in MHPG-sulfate. The most effective frequency was 20 pulses per sec. After 15 min of stimulation the MHPG-sulfate had reached a new steady state level of about 80% over the contralateral side.These findings indicate that MHPG-sulfate levels are dependent upon the integrity of NE neurons and that the level of rate of formation of MHPG-sulfate in the brain can be a reflection of the physiological activity of these neurons.     

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 μg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 μg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.     

Effects of 6-hydroxydopamine lesions of locus coeruleus on startle in rats

To examine the possible involvement of the norepinephrine (NE) containing neurons of the locus coeruleus in the modulation of behavioral reactivity to sensory stimulation, bilateral chemical lesions of the locus coeruleus were made by local injection of the catecholamine neurotoxin 6-hydroxydopamine. Both histochemical and biochemical analyses confirmed the effectiveness of the lesions in specifically eliminating the NE containing cell bodies of the locus coeruleus and reducing the NE content of the hippocampus and substantia nigra by 45% and 69% respectively. Rats were tested both 5 and 36 days after lesioning for their startle response to a repetitive series of tactile stimuli. On both days, locus coeruleus lesioned rats exhibited consistently reduced startle responses throughout the stimulus series. Additionally, lesioned rats showed a far more rapid rate of response habituation, particularly in the first test. The results are discussed in terms of a possible influence of the locus coeruleus on the process of sensitization to sensory stimuli.     

Significance of central noradrenergic system on harmaline induced tremor.

Since there is degeneration of substantia nigra concomitant with that of locus coeruleus (LC) in patients with Parkinson's disease, the study was performed to determine the role of central norepinephrine (NE) on harmaline induced tremor. The duration of harmaline (10 mg/kg IP) induced tremor was significantly reduced by intraventricular administration of L-thero-3,4-dihydroxyphenylserine (200 micrograms/rat) and 1-NE (50 micrograms/rat) was increased NE levels in the cerebral cortex, striatum, diencephalon, cerebellum and brain stem. Electrical stimulation of bilateral LC suppressed harmaline-induced 10-12/sec EMG activities in the neck muscle. Bilateral LC lesion upon electrocoagulation and 6-hydroxydopamine treatment resulted in a significant prolongation of the duration of harmaline induced tremor, reducing NE levels in the brain. These data suggest that central NE originating in the LC neurons has an inhibitory effect on the development of the tremor induced by harmaline.     

Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists

Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that MBDB (1.25, 2.5, 5.0 or 10.0 mg/kg), the alpha-ethyl derivative of MDMA that produces little or no direct DA release, also induced locomotor hyperactivity that lasted for greater than 60 min after the 5.0 and 10.0 mg/kg doses. MBDB produced spatial patterns of locomotor hyperactivity and suppression of exploratory activity (holepokes and rearings) very similar to the behavioral syndrome produced by MDMA. MBDB-induced hyperactivity was blocked by pretreatment with the selective 5-HT uptake inhibitor fluoxetine (2.5 or 10 mg/kg), suggesting that MBDB produced behavioral effects via uptake-carrier mediated release of 5-HT. Similarly, fluoxetine pretreatment blocked the locomotor hyperactivity produced by S-(+)3,4-methylenedioxyamphetamine (3.0 mg/kg) or p-chloroamphetamine (2.5 mg/kg), supporting a serotonergic basis for the action of these drugs. Tissue levels of 5-HT and its metabolite 5-HIAA were decreased 40 min after administration of S-(+)MDMA (3.0 mg/kg) or MBDB (5.0 mg/kg), and these decreases were prevented by fluoxetine pretreatment. S-(+)MDMA also produced a fluoxetine-sensitive increase of tissue DA levels, suggesting that 5-HT release may indirectly result in increased DA release, although MBDB did not significantly increase DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subthalamic 5-HT(1A) and 5-HT(1B) receptor modulation of RU 24969-induced behavioral profile in rats

The effects of systemic administration of the serotonin (5-HT)(1A/1B) agonist 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)1H-indole (RU 24969) on locomotor and investigatory behavior in rats have been well characterized using the behavioral pattern monitor (BPM). To elucidate the neural circuitry underlying this behavioral profile, intracerebral dose--response studies were conducted at two sites with high densities of 5-HT(1B) receptors, the subthalamic nucleus (STN) and substantia nigra. Infusion of RU 24969 into the STN produced systemic RU 24969-like changes in locomotor activity and patterns but an uncharacteristic increase in investigatory holepokes. Intra-STN administration of the selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) produced RU 24969-like changes in locomotor patterns only, while the 5-HT(1B) receptor agonist 3(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one dihydrochloride (CP-93,129) increased locomotor activity, produced no change in locomotor patterns and nonsignificantly increased holepokes. Intranigral infusion of RU 24969 produced systemic and intra-STN RU 24969-like increases in locomotor activity. Intranigral RU 24969, however, failed to produce any changes in locomotor patterns or investigatory holepokes. Intranigral infusions of CP-93,129 or 8-OH-DPAT had no effects on locomotor activity, locomotor patterns or investigatory holepokes. These results provide evidence for multiple-site mediation of the locomotor-activating effects of RU 24969 and for a dissociation of the neural substrates underlying locomotor and investigatory components of the RU 24969-induced behavioral profile.     

Noradrenergic and serotonergic mediation of the locomotor and antinociceptive effects of clonidine in infant and adult rats

This experiment examined the necessity for intact noradrenergic and serotonergic function for the locomotor and nociceptive effects of clonidine in 10- and 100-day-old rats. Newborn rats were administered systemically 6-hydroxydopamine (100 micrograms/g; 12 and 24 hours after birth) to deplete norepinephrine (NE), and at 10 or 100 days they were injected with para-chlorophenylalanine (300 mg/kg PCPA; 5 and 24 hours before testing) to deplete serotonin (5-HT). They were then tested for the locomotor and analgesic effects of one of various clonidine doses (0, 10, 100 or 1000 micrograms/kg). Clonidine enhanced locomotion at 10 days. This effect was potentiated by NE depletion and reduced by 5-HT depletion. Clonidine reduced locomotion at 100 days, and again this was augmented by NE depletion but reduced by 5-HT depletion. NE depletion did not have an enduring effect on clonidine antinociception whereas 5-HT depletion reduced it at both ages. It is concluded that the locomotor effects of clonidine in both infant and adult rats, despite reversing with maturation, reflect its agonist action at postsynaptic alpha2 adrenoceptors. The results also add to the accumulating evidence for an early maturing and behaviorally relevant serotonergic system(s).     

RU 24722, a new eburnamine derivative, induces selective alterations in cerebral glucose utilization in freely moving rat

The effect of a new eburnamine derivative, RU 24722, a putative phasic activator of catecholaminergic systems on local cerebral glucose utilization was studied in freely moving rats 15 min, 90 min and 6 h after the intraperitoneal administration of the drug (25 mg/kg). Of the 53 brain regions examined, 9 exhibited significant time-dependent increases of glucose utilization (up to 45-55%). Some changes were early and transient, as in the substantia nigra reticulata and the paraventricular nuclei. Other areas showed sustained (median septal nucleus) or delayed increases of glucose utilization (lateral septum, dorsal subiculum, hippocampal fimbria, fronto-parietal motor cortex and ventral cochlear nucleus). No significant alterations of glucose utilization could be elicited in the locus coeruleus and raphe nuclei, and none of the brain regions showed a decrease in glucose consumption. Our findings suggest that RU 24722 preferentially stimulates the activity in some brain areas involved in cognitive, vegetative and locomotor functions.     

Effects of chronic desipramine treatment on rat brain noradrenergic responses to alpha-adrenergic drugs

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central beta-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 microgram/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic alpha-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic (alpha 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.     

Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain.

The present electrophysiological experiments were undertaken to investigate the effect of desipramine and d-amphetamine on noradrenergic neurotransmission in the rat central nervous system. The effectiveness of electrical stimulation of the locus coeruleus and of microiontophoretic application of norepinephrine (NE) in suppressing the firing activity of CA3 pyramidal neurons was studied in the dorsal hippocampus. Desipramine (0.5 and 5 mg/kg i.v.) and d-amphetamine (0.25 and 5 mg/kg i.v.) decreased the effectiveness of locus coeruleus stimulation and prolonged the effect of microiontophoretically applied NE on the same pyramidal neurons. Subsequent i.v. administration of idazoxan, an alpha 2-adrenoceptor antagonist, reversed the effects of desipramine and d-amphetamine on the effectiveness of locus coeruleus stimulation and decreased that of microiontophoretically applied NE. In addition, idazoxan prevented the effect of subsequent administration of desipramine (5 mg/kg i.v.) on the effectiveness of locus coeruleus stimulation. High doses of d-amphetamine (5 and 10 mg/kg i.v.) decreased the firing activity of hippocampus pyramidal neurons by 70 and 98%, respectively, whereas low doses of desipramine (0.5 mg/kg i.v.) or of d-amphetamine (0.25 mg/kg i.v.) were without effect. After lesioning of NE projections with 6-hydroxydopamine, the effect of the 5 mg/kg dose of d-amphetamine on the firing activity of hippocampus pyramidal neurons was markedly reduced, whereas the cumulative 10 mg/kg dose of d-amphetamine completely suppressed, as in control rats, the firing activity of these neurons. This effect of d-amphetamine in 6-hydroxydopamine-pretreated rats was reversed by the administration of the 5-HT1A receptor antagonist BMY 7378. These data provide evidence that acute administration of desipramine and d-amphetamine decreases the effectiveness of locus coeruleus stimulation by increasing the activation of terminal alpha 2-adrenoceptor autoreceptors. In addition, acute administration of high doses of d-amphetamine decreases the firing rate of hippocampus pyramidal neurons by increasing NE and serotonin release.     

Norepinephrine stimulates behavioral activation in rats following depletion of nucleus accumbens dopamine

Intraventricular (ICV) infusion of norepinephrine (NE) produces locomotor activation in rats that is greatly potentiated by prior depletion of whole brain catecholamines by ICV injection of 6-hydroxydopamine (6OHDA). In a series of experiments, the neural substrates of this potentiated locomotor response were examined. One group of animals received ICV infusion of 6OHDA to deplete whole brain catecholamines. Other rats were pretreated with desmethylimipramine (DMI) and then received 6OHDA infusions into the nucleus accumbens (NAC) to selectively deplete dopamine (DA) from this region. One week later, all animals were tested for their locomotor response to ICV infusion of NE. Both groups of rats exhibited a greatly potentiated locomotor response to ICV NE compared to corresponding sham-lesioned animals. Both ICV and NAC 6OHDA-injected animals also exhibited a supersensitive locomotor response to the DA receptor agonist apomorphine. These results suggest that NE-induced locomotor activation in ICV 6OHDA-treated rats results from the actions of NE on supersensitive NAC DA receptors.     

Clonidine-induced sedation is not modified by single or combined neurochemical lesions of the locus coeruleus, the median and dorsal raphe nuclei

Single or combined neurochemical lesions of the locus coeruleus, the dorsal and the median raphe nuclei were performed on different groups of rats. Starting 10 days after the lesion, the locomotor activity of all rats was measured for 5 min every day in an open-field. For the first 21 days all lesioned rats, independently of the lesion site, were significantly less active than controls, but from the 11th to the 16th day the locomotor activity of lesioned animals increased progressively and, thus on days 15 and 16, the mean activity of all lesioned groups was not significantly different from that of the controls. From the 17th day onwards the sedative effect of small doses of clonidine (5-100 micrograms/kg) was measured. Neither single nor combined lesions modified the response to clonidine and the linear decrease of activity produced by increasing doses of clonidine was the same in all groups, lesioned or not. Biochemical assays showed a marked loss of corresponding amines as a result of the lesions in cortex, hippocampus and the brainstem. These results suggest that the alpha 2-receptors involved in clonidine-induced sedation are located neither on noradrenergic fibers coming from the locus coeruleus, nor on serotoninergic fibers originating in the median and dorsal raphe nuclei.     

Serotonergic regulation of noradrenergic coerulean neurons: electrophysiological evidence for the involvement of 5-HT2 receptors

To determine the type of serotonergic receptor involved in the modulation of noradrenergic neuronal activity in the locus coeruleus, the effects of 4 systemically administered serotonergic drugs were tested on the firing rate of noradrenergic neurons in the locus coeruleus of rats under chloral hydrate anaesthesia. The serotonergic agonist, quipazine (1 mg/kg), and the selective 5-HT2 agonist, DOB (50-100 micrograms/kg), induced a pronounced decrease of the discharge frequency. This effect could be prevented or reversed by the selective 5-HT2 antagonist, ketanserin (4-8 mg/kg). Ketanserin alone and the 5-HT1 agonist, RU 24969, had no or a weak excitatory action on the neuronal activity of the locus coeruleus. We conclude that the serotonergic control of noradrenergic neurons in the locus coeruleus is mediated by post-synaptic 5-HT2 receptors because the quipazine-ketanserin effects on this unit activity persisted after depletion of serotonergic presynaptic stores.