Serotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat.

Theta activity has been related to the processing of spatial information and the formation of hippocampus-dependent memory. The medial septum (MS) plays an important role in the control and coordination of theta activity, as well as in the modulation of learning. It has been established that increased serotonergic activity may desynchronize theta activity, while reduced serotonergic activity produces continuous and persistent theta activity in the hippocampus. We investigate whether serotonin acting on the medial septum could modify spatial learning and the functional relationship between septo-hippocampal and septo-mammillary theta activity. The serotonin was depleted (5HT-D) from the medial septum by the injection of 5,7 DHT (5,7- dihydroxytryptamine). Theta activity was recorded in the dorsal hippocampus, MS and mammillary nuclei (SUM, MM) of Sprague-Dawley male rats during spatial learning in the Morris water maze. Spatial learning was facilitated, and the frequency of the hippocampal theta activity during the first days of training increased (to 8.5Hz) in the 5HT-D group, unlike the vehicle group. Additionally, the coherence between the MS-hippocampus and the MS-mammillary nuclei was higher during the second day of the test compared to the vehicle group. We demonstrated that septal serotonin depletion facilitates the acquisition of spatial information in association with a higher functional coupling of the medial septum with the hippocampus and mammillary nuclei. Serotonin, acting in the medial septum, modulates hippocampal theta activity and spatial learning.

Endogenous descending modulation: spatiotemporal effect of dynamic imbalance between descending facilitation and inhibition of nociception.

In conscious rats, we investigated the change of nociceptive paw withdrawal reflexes elicited by mechanical and heat stimuli during intramuscular (i.m.) 5.8% hypertonic (HT) saline elicited muscle nociception. i.m. injection of HT saline caused rapid onset, long lasting (around 7 days), bilateral mechanical hyperalgesia, while it induced bilateral, slower onset (1 day after the HT saline injection), long-term (about 1-2 weeks) heat hypoalgesia. Ipsilateral topical pre-treatment of the sciatic nerve with 1% capsaicin significantly prevented the occurrence of both the bilateral mechanical hyperalgesia and the contralateral heat hypoalgesia. Intrathecal administration of either 6-hydroxydopamine hydrobromide (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), and intraperitoneal injection of naloxone all markedly attenuated the HT saline induced bilateral heat hypoalgesia, but not the mechanical hyperalgesia. Combined with experiments with lesioning of the rostroventral medulla with kainic acid, the present data indicate that unilateral i.m. injection of HT saline elicits time-dependent bilateral long-term mechanical hyperalgesia and heat hypoalgesia, which were modulated by descending facilitatory and inhibitory controls, respectively. We hypothesize that supraspinal structures may function to discriminate between afferent noxious inputs mediated by Aδ- and C-fibres, either facilitating Aδ-fibre mediated responses or inhibiting C-fibre mediated activities. However, this discriminative function is physiologically silent or inactive, and can be triggered by stimulation of peripheral C-fibre afferents. Importantly, in contrast to the rapid onset of descending facilitation, the late occurrence of descending inhibition suggests a requirement of continuous C-fibre input and temporal summation. Thus, a reduction of C-fibre input using exogenous analgesic agents, i.e. opioids, may counteract the endogenous descending inhibition.

Localization of the serotonergic terminal fields modulating seizures in the genetically epilepsy-prone rat.

Serotonin (5-HT) has been shown to exert antiepileptic effects in a variety of generalized convulsive seizure models, particularly the genetically epilepsy-prone rat (GEPR). The present study was designed to identify the region/site(s) where 5-HT exerts anticonvulsant effects in the GEPR-9, a model in which sound-evoked generalized tonic-clonic seizures (GTCS) are highly sensitive to manipulations in 5-HT concentration. Because the 5-HT reuptake inhibitor, fluoxetine, was known to exert anticonvulsant effects in GEPR-9s via a 5-HT-dependent mechanism, we utilized selective regional 5-HT depletion in combination with systemic fluoxetine administration to find the site where a 5-HT deficit would prevent the anticonvulsant action of fluoxetine. Widespread destruction of serotonergic terminal fields or regionally specific terminal field destruction was achieved using intracerebroventricular and more target specific infusions of 5,7-dihydroxytryptamine. The capacity of fluoxetine to suppress seizures in GEPR-9s following a loss of 5-HT was then examined. The present findings show the anticonvulsant action of fluoxetine is markedly attenuated following the loss of midbrain 5-HT, particularly in the region of the superior colliculus, while forebrain and spinal cord 5-HT do not appear to play a role in the action of fluoxetine. The importance of the deep layers of the SC was confirmed by demonstrating that direct microinfusion of fluoxetine into the SC can suppress seizures in rats pretreated with the 5-HT(1A) receptor antagonist pindolol.

Central serotonergic mechanisms on head twitch response induced by benzodiazepine receptor agonists.

Intraperitoneal injection of benzodiazepine receptor agonists (estazolam, zopiclone, triazolam: 0.03-0.24 mmol/kg) induces the head twitch response (HTR). The present study was undertaken to examine the possible participation of the serotonergic system in the mechanism of head twitches induced by benzodiazepine receptor agonists (BZ-RAs). The HTR induced by BZ-RAs was suppressed by pretreatment with ketanserine (1 mg/kg, i.p.), a selective 5-HT(2) receptor antagonist. Pretreatment with fluoxetine (10 mg/kg, i.p.), a 5-HT reuptake inhibitor, and 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT(1A) receptor agonist, also suppressed the HTR induced by BZ-RAs. These results suggest that the HTR induced by BZ-RAs may be the result of an activation of postsynaptic 5-HT(2) receptors, probably due to direct action.

Serotonin depletion by 5,7-dihydroxytryptamine does not affect G protein subunit levels in rat cortex.

To investigate the role of G proteins in denervation supersensitivity of the CNS serotonergic system, we examined the effect of lesioning serotonergic neurons on the abundance of cerebral cortical membrane G protein subunits in rats. Three weeks after intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT), which significantly reduced cortical 5-hydroxytryptamine (5-HT; -90%) and 5-hydroxyindoleacetic acid (approximately 98%) levels, no statistically significant differences were observed for G alpha s-1, G alpha s-s, G alpha i1, G alpha i2, G alpha q/11, G alpha 0, G beta 1 and G beta 2 immunoreactivity levels between sham-lesioned and 5,7-DHT lesioned rats. These data suggest that the functional supersensitivity of 5-HT neuronal system often observed following lesions of 5-HT fibers may not involve changes at the level of G proteins but may instead encompass other downstream elements of the 5-HT receptor signaling cascade.

[Influence of 5.7-dihydroxytryptamine on electro-acupuncture analgesia and substance P level in central nervous system of the arthralgic rats].

The relation between electroacupuncture (EA) analgesia (A) and substance P (SP) level in the brain stem (BS) and lumbar spinal cord (LSC) of arthralgic rats was investigated. The rats were divided into three groups: 1)5.7-dihydroxytryptamine (5.7-DHT) + EA, 2) vehicle (V) + EA, and 3)5.7-DHT. All the animals were induced arthralgesia by injecting Freund's adjuvant 7 days after cisterna injection of 5.7-DHT or vehicle. The SP level in the BS and LSC was determined by RIA. The results indicated that in V + EA group the EA could prolong tail flick latency by 39.6%, but in other two groups did not. The SP level in LSC of V + EA group (179.1 +/- 11.5 pmol/g) was higher than that in the 5.7-DHT + EA (135.9 +/- 9.3pmol/g) and 5.7-DHT (125.8 +/- 10.0 pmol/g) groups. It suggested that both EA and arthralgia could activate the descending 5-HTergic inhibitory system to inhibit the release of SP in LSC. When the 5-HTergic system was destroyed by 5.7-DHT, the EAA was attenuated, and the SP level in LSC was lowered due to its release was decreased by EA and arthralgia.

[Ultrastructure identification of raphe-spinal serotonergic pain modulating system in rats].

5,6-dihydroxytryptamine was microinjected into the nucleus raphe magus (NRM) of rats. The sections of upper cervical segments were processed for immunoreactive substance P (SP). The degenerated axon terminals and immunoreactive fibers were identified by electron microscopy. The results show that the degenerated axon terminals and immunoreactive positive dendrites and axons were found in the laminae I and II of the dorsal horn. The electron-dense axon terminals were in contact with unlabelled dendrites, some also in contract with immunoreactive dendrites. In lamina II, one of degenerated axon terminals as a center was contacted by several unlabelled axonal boutons. SP labelled terminals were synapsed with unlabelled dendrites and dendritic spine; in addition, unlabelled axo-axonal synapse was found in lamina II. These results suggest that 5-HT axon terminals from NRM directly innervate SP and non-SP neurons in the laminae I and II.

[Central presynaptic receptors]. / Zentrale präsynaptische Rezeptoren.

Experiments on two different inhibitory presynaptic receptor systems are presented. 1. Superfused and electrically stimulated brain slices are a widely used experimental model to study the release of noradrenaline and its modulation by inhibitory alpha-2 adrenoceptors. By using a minisuperfusion chamber we succeeded in studying the simplest case of autoinhibition, i.e. the release of transmitter induced by a single pulse and two consecutive pulses, respectively. When electrical stimulation is performed using a single pulse, no autoinhibition is possible, whereas following stimulation with two pulses the transmitter released by the first pulse will inhibit the effect of the second pulse. By systemically varying the time interval between the two pulses the minimal time requirement for development of autoinhibition was determined to be 100 ms. Short pulse trains of high frequency such as 4 pulses within 30 ms circumvent autoinhibition and cause inhibition-free release by each applied pulse. The release of transmitter evoked in this way is not only free from autoinhibition but, in addition, easily measurable, which makes this method of stimulation very suitable for analyses at presynaptic receptors. By using this approach it became possible, for the first time, to determine dissociation constants of antagonists and agonists at the central presynaptic alpha-2 adrenoceptor without the distortion introduced by autoinhibition occurring during release. 2. There is a substantial body of evidence for a role of medullary serotonergic nerve cells in the regulation of blood pressure and heart rate. It is hypothesized that the serotonergic neurons project to the thoracic spinal cord exerting a tonic excitatory influence on presynaptic sympathetic neurons of the intermediolateral cell column. Experiments were performed in pentobarbital anaesthetized rats to reduce this excitatory tone by activating inhibitory autoreceptors which are located on the perikarya and dendrites on the serotonergic cells and which have been shown to belong to the 5-HT1A subtype. Local stereotactic injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a decrease in mean arterial blood pressure (MAP) and heart rate (HR). The effects were blocked by pretreatment of the animals with the 5-HT1A antagonist spiroxatrine. Moreover, neurochemical lesioning of serotonergic neurons by intracisternal injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) abolished the effects of 8-OH-DPAT. Bilateral intraspinal injection of 5,7-DHT, which interrupts the medullo-spinal serotonergic pathway, markedly attenuated the effects of local intramedullary injection of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)

Supersensitivity to intrathecal 5-hydroxytryptamine, but not noradrenaline, following depletion of spinal 5-hydroxytryptamine by 5,7-dihydroxytryptamine administered into various sites.

The present study was conducted (a) to determine if cross-supersensitivity at spinal noradrenergic receptors could be demonstrated in antinociceptive tests following depletion of spinal cord 5-hydroxytryptamine (5HT) by the intrathecal (i.t.) and intracerebroventricular (i.c.v.) administration of 5,7-dihydroxytryptamine (5,7DHT), and (b) to compare the pattern of supersensitivity at spinal 5HT receptors following these manipulations and 5,7DHT microinjected into the ventral raphe (VR) region and the nucleus raphe magnus (NRM). Both i.t. and i.c.v. administration of 5,7DHT produced a marked depletion of spinal cord 5HT (greater than 75%) and supersensitivity to the i.t. injection of 5HT in the tail flick and hot plate tests. No supersensitivity to the i.t. injection of noradrenaline (NA) was observed. Microinjection of 5,7DHT into the VR and NRM produced less depletion of spinal cord 5HT (40-57%), and supersensitivity to the i.t. injection of 5HT was observed only in the hot plate test following microinjection of 5,7DHT into the VR. An increased incidence of signs of the 5HT behavioural syndrome, particularly tremor and Straub tail, was observed in all 5,7DHT-pretreated groups. These results indicate that cross-supersensitivity to spinal NA receptors does not occur following depletion of spinal cord 5HT. In addition, responses mediated by 5HT receptors show a differential pattern of development of supersensitivity. Thus, the 5HT behavioural syndrome (presumably mediated by 5HT1A receptors) more readily reflects the development of supersensitivity than the tail flick test (presumably mediated by 5HT2 receptors), while the hot plate test (uncharacterized subtype) shows an intermediate development of supersensitivity.

Enhanced spatial discrimination learning in rats following 5,7-DHT-induced serotonergic deafferentation of the hippocampus.

Learning in rats trained in the Stone 14-unit T-maze, a complex, positively reinforced spatial discrimination task was assessed following cytotoxic (5,7-dihydroxytryptamine; 5,7-DHT) deafferentation of the serotonergic inputs to the hippocampus. Serotonergic deafferentation was accomplished by infusing the cytotoxin in to the fornix-fimbria/cingulum bundle. Lesioned rats reached criterion (i.e. learned) in significantly fewer trials and made significantly fewer errors throughout training than either vehicle-injected or sham-operated controls. This represents the first time that the effects of selective chronic destruction of serotonergic inputs to the hippocampus have been investigated. The present results provide, therefore, evidence in support of a neuromodulatory role for serotonin (5-HT) within the rat hippocampus in the mediation of the processes underlying learning and memory for this task. Other studies are, therefore, warranted in order to determine whether hippocampal 5-HT also plays a role in the mediation of the processes underlying learning and memory in other types of tasks.

Trypanocidal effects of catecholamines and indolealkylamines.

Catecholamines, indolealkylamines and their analogues are oxidized at neutral or alkaline pH, producing hydrogen peroxide, quinones and free radicals. Several of these amines were tested for trypanocidal effects on Trypanosoma brucei, which possess a well-documented vulnerability to such oxidation products. Dopamine, 5-hydroxydopamine (5-OHDA), 6-hydroxydopamine (6-OHDA), 5-hydroxytryptamine (5-HT), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) killed the parasites in vitro, using a fibroblast feeder layer cell culture system, in four to 48 hours at concentrations of 10(-5)-10(-7) M. The 5-OHDA, 6-OHDA, 5,6-DHT and 5,7-DHT were also effective in vivo when tested by intraperitoneal injection of infected mice.

Injection of 5,7-dihydroxytryptamine into the B3 raphe region of neonatal rat pups induces hyperalgesia but only slight alterations in ingestion-related behaviors.

The effects of intrabrainstem injections of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the B3 raphe region (nucleus raphe magnus and nucleus reticularis paragigantocellularis) on early ingestive behavior and nociception were assessed in Sprague-Dawley rat pups during the first postnatal week. Lesions resulted in a marked depletion of serotonin (5HT) in hindbrain without influencing 5HT levels in forebrain. Pretreatment with desipramine (DMI) resulted in a sparing of noradrenergic neurons from neurotoxic effects. The B3 lesion resulted in significant hyperalgesia as reflected by decreased latencies in tail flick testing. Although nipple attachment latencies in suckling tests were slightly increased by the lesion, no notable effects on mouthing or other ingestive-related behaviors were observed in testing conducted in an independent ingestion paradigm. These results suggest that whereas B3 serotonergic neurons may be functioning in an adult-typical manner to regulate analgesia during the early postnatal period, this raphe region may play only a slight role in the modulation of ingestion-related behaviors early in life.

[Compensation in behavioral disorders in rats receiving 5,7-DHT neonatally and by transplantation of embryonic raphe nucleus tissue]. / Kompensatsiia narushenii povedeniia krys, neonatal'no poluchavshikh 5,7-DOT, putem transplantatsii émbrional'noi tkani iader shva.

In 62 male Wistar rats the influence was studied of the transplanted embryonal tissue of raphe nuclei (NR) on the mechanisms of compensation of disturbances of exploratory activity, sensory attention, learning and emotional reactivity induced by neonatal injection of 5,7-DHT. In histochemical studies by Falk-Hillarp method the presence of yellow fluorescence confirmed the specificity of transplanted 5-HT neurones. It is found that NR transplantation causes in animals after 3 months recovery of orienting reaction to sensory stimuli, reduces rats reactivity in the open field, restores the ability to discrimination of emotionally positive influence, disturbed by neonatal injection of 5,7-DHT. The obtained data show the possibility of compensation of behaviour disturbances caused by chronic deprivation of 5-HT system activity by transplantation in the neocortex parenchyma of the embryonal tissue, containing serotoninergic neurones.

A general role for serotonin in the control of behavior: studies with intracerebral 5,7-dihydroxytryptamine.

Multiple injections of 5,7-dihydroxytryptamine (5,7-DHT) into the rat brainstem reduced forebrain levels of serotonin and 5-hydroxyindoleacetic acid to 3-10% of the levels observed in control rats that had received intrabrainstem injection of a Locke's solution vehicle. This treatment reduced or abolished atropine-resistant cerebral activation (ARCA) in most cases. In rats in which ARCA was impaired or lost, a number of behavioral abnormalities were observed. These included: high levels of locomotion in an open field test; a deficiency in swimming to, and climbing upon, a visible platform in a water-filled tank; deficient social behavior; and impaired performance in a simple test of active avoidance. These deficits were not due to low level motor impairment. The 5,7-DHT-treated rats displayed a circadian rhythm of activity in running wheels. It is proposed that ascending serotonergic projections are an important component in the cerebral control of the Type 1 behavior with which the occurrence of ARCA is closely linked. Since Type 1 behavior includes such motor patterns as walking and manipulation of objects with the limbs, which are essential components of a great variety of behavioral performances, it is to be expected that a loss of ascending serotonergic function will result in a generalized deficit in behavior.

The role of serotonin in the control of cerebral activity: studies with intracerebral 5,7-dihydroxytryptamine.

Intact rats treated with centrally acting antimuscarinic (atropinic) drugs display large amplitude irregular slow waves in both the neocortex and hippocampus during behavioral immobility and some stereotyped automatic behaviors (Type 2 behavior). However, rhythmical slow activity in the hippocampus and low voltage fast activity in the neocortex occur in close correlation with spontaneous changes in posture, head movement, walking, rearing, swimming or struggling when held (Type 1 behavior). It has previously been proposed that these waveforms, jointly referred to as atropine-resistant cerebral activation (ARCA) are dependent on ascending serotonergic projections. As a further test of this hypothesis, we have studied rats in which forebrain levels of serotonin and 5-hydroxyindoleacetic acid were reduced to 3-10% of control levels as a result of multiple intrabrainstem injections of 5,7-dihydroxytryptamine. This treatment strongly reduced or abolished ARCA in most cases but did not reduce atropine-sensitive cerebral activation which appears to be dependent on ascending cholinergic projections from the basal forebrain to the cerebral cortex. Therefore, ARCA appears to be dependent on ascending serotonergic inputs to the forebrain.

Characterization of the inducible serotonin-sensitive dihydroalprenolol binding sites with low affinity for isoproterenol.

The previous findings that the inducible [3H]-dihydroalprenolol (DHA) binding sites with low affinity for isoproterenol (RL) could be regulated by serotonin (5-HT) in vitro and by 5-hydroxytryptophan and the 5-HT uptake inhibitor fluoxetine in vivo, prompted the present pharmacologic characterization of these receptor sites, using nonlinear regression analysis of competition binding curves. If isoproterenol was used as the displacing agent, lesioning with 5,7-dihydroxytryptamine selectively increased [3H]-DHA binding sites with low micromolar affinity. By contrast, if 5-HT was used as the displacing agent, the receptor population with high agonist affinity showed a fourfold increase whereas the density of [3H]-DHA sites with low micromolar affinity for 5-HT was not altered. Neither the 5-HT1A agonist, 8-OH-DPAT, nor mianserin, a 5-HT2 and 5-HT1C antagonist, altered the induced RL receptor population, whereas the selective 5-HT1B agonist CGS-12066B reduced the increase in the RL receptor population with a potency equal to that of 5-HT. These results strengthen the notion that the [3H]-DHA sites with low agonist affinity for isoproterenol represent 5-HT1B receptors induced following a reduction of serotonergic neuronal function.

Brainstem serotonergic hyperinnervation modifies behavioral supersensitivity to 5-hydroxytryptophan in the rat.

Rat pups were injected intracisternally (i.c.) or intraperitoneally (i.p.) with 5,7-dihydroxytryptamine (5,7-DHT) or saline and challenged 2 and 14 weeks later with the 5-HT precursor 5-hydroxytryptophan (5-HTP), which evokes behavioral supersensitivity in adult rats, 5,7-DHT induced transient postinjection convulsions in rats injected i.c. but not i.p. Rats with either type of 5,7-DHT lesions displayed supersensitive behavioral responses to 5-HTP. However, rats lesioned by i.p. injections exhibited significantly greater shaking behavior (+1445%) in response to 5-HTP than their i.c. counterparts, who instead showed more forepaw myoclonus (+250%) and head weaving (+270%), the core features of the 5-HT syndrome. Differences in 5-HT syndrome behaviors were already present 2 weeks after lesioning, whereas the difference in shaking behavior was not. After 14 weeks, 5-HT was selectively depleted (-43 to -92%) in hippocampus, spinal cord, and frontal cortex, and differences between i.c. and i.p. 5,7-DHT routes were insignificant except in frontal cortex. Brainstem 5-HT concentrations were significantly increased (+35%) after i.p. 5,7-DHT injections in contrast to reduction (-89%) after i.c. 5,7-DHT; 5-hydroxyindole acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) ratios were decreased (-20%) with either route. These data suggest that brainstem 5-HT hyperinnervation following i.p. 5,7-DHT injection modifies the functional consequences of injury in abating the 5-HT syndrome, but does not result in complete recovery since shaking behavior is enhanced. Loss of presynaptically mediated autoregulation or receptor dysregulation may play a major role in behavioral supersensitivity induced by 5-HTP in rats with 5,7-DHT lesions. To the extent that the 5-HT syndrome is mediated by 5-HT1A receptors and shaking behavior by 5-HT2 sites, differential responses to injury of 5-HT1A and 5-HT2 receptors may contribute to these behavioral differences.

1-5-Hydroxytryptophan-induced flat body posture in the rat: antagonism by ritanserin and potentiation after 5,7-dihydroxytryptamine.

1-5-Hydroxytryptophan (1-5-HTP)-induced flat body posture (FBP) was antagonized by ritanserin in doses that were lower than those needed to antagonize head-twitches (HTW) and forepaw treading (FPT). 5,7-Dihydroxytryptamine (5,7-DHT) potentiated 1-5-HTP-induced FBP but not HTW or FPT. Ritanserin interacted with 5-HT2 and 5-HT1c receptors. 1-5-HTP-induced FBP could be mediated by postsynaptic 5-HT1c receptors and could serve as a behavioral model of postsynaptic 5-HT1c receptor stimulation in the CNS.

The amine-depleting effects of 5,7-dihydroxytryptamine (5,7-DHT) in C57BL/6 mice do not increase with age.

A recent approach to identifying the factors that predispose neurons to an early death in Parkinson's or Alzheimer's disease has been to study how the effect of specific neurotoxins are altered by increasing maturity. We determined the dose-related serotonin and norepinephrine-depleting effects of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), in C57BL/6 mice of 2 different ages. Norepinephrine and serotonin in the hippocampus were assayed 1 week after the intracerebroventricular (i.c.v.) administration of 5,7-DHT. 5,7-DHT produced an equivalent, dose-related depletion of hippocampal norepinephrine in both age groups. Since the effects of 5,7-DHT on noradrenergic neurons may, at least in part, depend on the monoamine oxidase (MAO)-generated formation of hydrogen peroxide and associated oxy-radicals, this result suggests that noradrenergic neurons do not become more vulnerable to oxidative stress with aging. We also found that the noradrenergic-depleting effects of 5,7-DHT were blocked by the non-selective MAO inhibitor pargyline (50 mg/kg, i.p.), while the selective MAO B inhibitor deprenyl (10 mg/kg, i.p.) failed to prevent this depletion. These latter results suggest that it is the A form of MAO that plays an important role in the mechanism of 5,7-DHT-induced noradrenergic toxicity. Somewhat unexpectedly, older mice were found to be less susceptible to the serotonin-depleting effects of 5,7-DHT. Although the mechanism by which this compound damages serotonergic neurons is uncertain, our results show that the increased susceptibility of serotonergic neurons to 5,7-DHT in young animals extends well beyond the neonatal period.

Alterations in serotonin binding sites after 5,7-dihydroxytryptamine treatment in the rat spinal cord.

The 5-HT1B subtype of serotonin (5-HT) receptor regulates the release of 5-HT in the rat spinal cord. In an attempt to confirm the presynaptic location of the 5-HT1B receptor, serotonergic nerves were destroyed neurochemically with 5,7-dihydroxytryptamine (5,7-DHT) administered intrathecally. At 3, 7 and 14 days post 5,7-DHT, competitive radioligand binding assays were performed using 2 nM [3H]5-HT and varying concentrations of trifluoromethylphenylpiperazine (TFMPP), a drug which interacts with 5-HT1B and 5-HT1A binding sites (affinity of 5-HT1B site greater than 5-HT1A site for TFMPP). The decrease in 5-HT1B sites that was expected was not observed at any time following the lesion. However, the binding capacity of the 5-HT1B site, as well as the 5-HT1A site, increased significantly by 7 and 14 days postlesion, respectively. Thus, it appears that an up-regulation of 5-HT1B sites occurred that may have obscured the ability to observe a reduction in a small population of sites located on the serotonergic nerve terminals.