Interactions between nitric oxide and corticosterone in the regulation of progenitor cell proliferation in the dentate gyrus of the adult rat.

It is well established that L-NAME, a generic NOS inhibitor, stimulates neurogenesis in the dentate gyrus of the adult rat and corticosterone reduces it. These experiments explore the interaction between L-NAME and corticosterone. L-NAME (50 mg/kg), as expected, increased proliferation, but also lowered plasma corticosterone levels. However, the stimulating action of L-NAME depends on the presence of rhythmic changes in plasma corticosterone, as it is abolished in rats treated with a subcutaneous implant of corticosterone, which flattens the diurnal rhythm. Adrenalectomized rats implanted with corticosterone also failed to respond to L-NAME. Giving them a single daily injection of corticosterone (2 mg/kg) in an attempt to replicate the diurnal rhythm restored the sensitivity of the progenitor cells to L-NAME. The mechanism for this result remains to be investigated. Excess corticosterone given by daily injection (40/mg/kg) reduced proliferation but did not alter the response to L-NAME, even though this occurred from a lower baseline. nNOS was demonstrable only in the inner (proliferative) layer of the dentate gyrus in control rats, and did not alter following excess corticosterone treatment. iNOS was detectable at low levels in control rats, but was increased markedly following corticosterone. eNOS was evident throughout the dentate gyrus, and also increased after corticosterone (particularly in the hilus). Aminoguanidine (100 mg/kg/day; an iNOS antagonist) significantly increased proliferation in corticosterone-treated rats (40 mg/kg/day) but not in controls without additional corticosterone, confirming that iNOS plays a role in corticosterone-regulated neurogenesis. Corticosterone may thus act on progenitor cells in part at least through increased nitric oxide (NO) formation. The effects of reduced NO on neurogenesis may rely on a dual mechanism: corresponding reductions in plasma corticosterone and increased induction of iNOS (and/or eNOS) within the dentate gyrus. The possibility that NO acts downstream of glucocorticoids in the dentate gyrus is suggested.     

Role of serotonergic input in the down-regulation of beta-adrenoceptors following long-term clorgyline treatment

Administration of the selective monoamine oxidase (MAO) type A-inhibiting antidepressant clorgyline (1 mg/kg per day) to rats for 21 days caused a significant decrease in cortical [3H]dihydroalprenolol binding. Selective lesioning of central serotonergic axons by 5,7-dihydroxytryptamine (5,7-DHT; confirmed by the presence of the serotonin syndrome in response to a 40 mg/kg dose of 5-hydroxytryptophan (5-HTP) or inhibition of 5-HT synthesis by parachlorophenylalanine (PCPA) caused significant 5-HT and 5-HIAA depletions in the cortex without much effect on NE and DA concentrations, but did not have any significant effect on beta-adrenoceptor density, and furthermore failed to attenuate clorgyline-induced decreases in beta-adrenoceptor density. Clorgyline treatment partially antagonized 5-HT depletion by the 5,7-DHT lesion or PCPA treatment. These findings suggest that due to their ability to raise 5-HT concentrations, MAO-inhibiting antidepressants may be a better alternative than the tricyclics in treating depressed patients with reduced 5-HT if down-regulation of beta-adrenoceptors is critical for antidepressant efficacy.     

The effect of serotonin depletion on the discriminability of LSD

Nine groups of rats were trained to discriminate LSD (0.12 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination procedure. After stable discriminative performance was obtained (>95% correct), groups were administered one of several treatments which lower the concentration of serotonin (5-HT) in brain: (1) 12.5, 25, 50, 100 or 200 microgram of 5,7-dihydroxytryptamine (5,7-DHT) intraventricularly (IVT); (2) 3 X 100 mg/kg of p-chlorophenylalanine (PCPA) intraperitoneally (IP); or (3) 20 mg/kg of p-chloroamphetamine (PCA) IP. Control rats received either IVT injections of 5,7-DHT vehicle or IP injections of PCA or PCPA vehicles. Beginning 12 days after treatment, lever preference following various doses of LSD was determined. The results indicated that only the 200 microgram dose of 5,7-DHT and PCPA caused a significant potentiation of LSD-lever responding at the 0.03 mg/kg dose of LSD while all treatments except 12.5 and 25 microgram of 5,7-DHT resulted in significant depletion of 5-HT. Moreover, amount of 5-HT and percent LSD responding following 0.03 mg/kg LSD were not significantly correlated. It was concluded that 5-HT depletion, per se, cannot account for supersensitivity to the behavioral effects of LSD.     

Fluoxetine does not affect the ischemia-induced increase of neurogenesis in the adult rat dentate gyrus

Ischemic insult enhances the proliferation of precursor cells in the dentate subgranular zone. This study was performed to determine whether fluoxetine further promotes the neurogenesis induced by transient forebrain ischemia in the rat dentate gyrus. Transient forebrain ischemia was induced by four-vessel occlusion for 10 min. First, to investigate whether the short-term treatment of fluoxetine influences ischemia-induced cell proliferation, rats were administered fluoxetine (5 mg/kg, i.p.) or a vehicle on days three to nine post-ischemia, and 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU, 75 mg/kg, i.p.) one hour after the last fluoxetine injection. On examination one day later, the number of BrdU-labeled cells was not significantly different between the fluoxetine- and vehicle-treated groups. Second, to identify whether the chronic treatment of fluoxetine has an effect on the survival of ischemia-induced newborn cells, rats were administered fluoxetine or a vehicle on days 3 to 23 post-ischemia, and BrdU (75 mg/kg, three times) nine days post-ischemia. On examination four weeks after the BrdU injection, the number of BrdU-labeled cells was not significantly different between the fluoxetine- and vehicle-treated groups. Also, the rate of neuronal maturation was not significantly different between the two groups. These results show that fluoxetine does not affect the ischemia-induced increase of neurogenesis in the dentate gyrus of the adult rat.     

Lesion of the median raphe nucleus: a combined behavioral and microdialysis study in rats

The purpose of the present study was to investigate the behavioral consequences and the neurochemical correlates of a 5,7-dihydroxytryptamine (5,7-DHT) lesion of the median raphe nucleus (MRN) in rats. Anxiety-related behavior was assessed in the elevated plus maze test on days 5, 14, and 21 after lesioning. In general, behavior of MRN-lesioned rats was unchanged when compared with sham-lesioned or untreated controls. Neurochemically, microinjection of 5,7-DHT into the MRN resulted in 87.5% depletion of hippocampal 5-HT content. Using the in vivo microdialysis technique, the exposure of 5,7-DHT-lesioned rats to the elevated plus-maze failed to increase extracellular 5-HT release (94%) in the hippocampus, as shown in sham-lesioned (150%) or untreated controls (194%). Moreover, application of fenfluramine (10 mg/kg, i.p.) evoked a 10-fold increase in hippocampal extracellular 5-HT levels in sham-lesioned animals, whereas in 5,7-DHT lesioned rats 5-HT was only slightly increased. The results demonstrate, that a marked reduction of 5-HT release from the MRN is not necessarily accompanied by anxiolytic-like behavior.     

Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats

RATIONALE: Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. OBJECTIVE: The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). METHODS: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. RESULTS: 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5-HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine-seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re-establishment of cocaine self-administration was not altered by 5,7-DHT. CONCLUSION: The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse.     

Partial serotonergic denervation decreases progenitor cell proliferation in the adult rat hippocampus, but has no effect on rat behavior in the forced swimming test

It has been hypothesized that impaired serotonin (5-HT) neurotransmission contributes to the pathophysiology of depression. Recently, it was shown in adult animals that antidepressants which influence 5-HT levels increase hippocampal progenitor cell proliferation, suggesting an important role of the 5-HT system in the regulation of adult neurogenesis. In this study, we investigated the effects of partial 5-HT denervation of the adult rat forebrain caused by a single para-chloroamphetamine (PCA) administration (10 mg/kg, s.c.) on hippocampal progenitor cell proliferation measured by Ki-67 immunohistochemistry over a 3-week time period. Moreover, behavior of rats was analyzed by using the forced swimming test which serves as a so-called animal model of depression. One week after PCA administration, a significant decrease of Ki-67 immunopositive cells and cell clusters (−25% and −53%, respectively) was found which was recovered over the 3-week period. The decrease in progenitor cell proliferation in the dentate gyrus per animal was positively correlated with the 5-HT denervation. Behavioral analysis of rats revealed no significant differences between vehicle and PCA-treated animals at any of the examined time points. These findings indicate a regulative role of 5-HT for hippocampal progenitor cell proliferation and neurogenesis, but its relation to animal models of depression remains to be elucidated.     

Effect of chronic and acute administration of fluoxetine and its additive effect with morphine on the behavioural response in the formalin test in rats

Serotonergic systems are involved in the central regulation of nociceptive sensitivity. Fluoxetine, a selective inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT), was administered orally (0.16, 0.32, 0.8 mg kg(-1) daily for 7 days), intraperitoneally (0.04, 0.08, 0.16 mg kg(-1) day(-1) for 7 days and a single dose of 0.32 mg kg(-1)) and intracerebroventricularly (10 microg/rat) to rats and nociceptive sensitivity was evaluated using the formalin test (50 microL of 2.5% formalin injected subcutaneously). The effect of fluoxetine was also studied in the presence of 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT) and after co-administration with morphine. Oral (0.8 mg kg(-1)), intraperitoneal (0.16 and 0.32 mg kg(-1)) and intracerebroventricular (10 microg/rat) fluoxetine induced antinociception in the late phase of the formalin test. Furthermore, intrathecal administration of 5-HT (100 microg/rat) induced an analgesic effect. The analgesic effect of fluoxetine (0.16 and 0.32 mg kg(-1), i.p.) and 5-HT (100 microg/rat, i.t.) was abolished by pre-treatment with 5,7-DHT (100 microg/rat, i.t.). In addition, the analgesic effect of 5-HT (100 microg/rat, i.t.) was decreased by pre-treatment with naloxone (2 mg kg(-1), i.p.). Morphine (5 mg kg(-1), i.p.) induced analgesia that was increased by fluoxetine (0.32 mg kg(-1), i.p.). These results suggest that fluoxetine has an antinociceptive effect in tonic inflammatory pain through functional alteration of the serotonergic system and also potentiates the analgesic effect of morphine.     

Chronic 3,4-methylenedioxymethamphetamine treatment suppresses cell proliferation in the adult mouse dentate gyrus

We investigated the influence of chronic 3,4-methylenedioxymethamphetamine (MDMA) treatment on cell proliferation in the adult dentate gyrus. Mice were orally treated with MDMA (1.25 mg/kg-40 mg/kg) or saline for 30 days. To label dividing cells, mice were given 5-bromo-2'-deoxyuridine (BrdU) for 4 days from the day after the last administration of MDMA, and their brains were examined 24 h later. MDMA dose-dependently induced a decrease in the number of BrdU-positive cells in the male and female dentate gyrus. Our results suggest that chronic exposure to MDMA suppresses cell proliferation in the dentate gyrus.     

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.     

Anxiety-like behavior in rats neonatally and adultly treated with 5,7-dihydroxytryptamine]

A large body of evidence has shown the involvement of serotonin (5-HT) in anxiety. The administration of serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into adult rats has been shown to produce a prolonged reduction in the content of brain 5-HT along with anxiolytic effects. In this experiment, 5,7-DHT was administrated intraventricularly to neonatal and adult rats. All rats were tested in an elevated plus maze at 30, 50, 70, and 90 days old to evaluate the anxiety level. Adult treatment increased the time spent in open-arm, and decreased the brain 5-HT content in all the regions measured. In contrast, neonatal treatment decreased the time spent in open-arm, and 5-HT contents in these animals did not decrease in the hypothalamus and medulla oblongata. A 5-HT syndrome test was conducted once when the rats were 91 to 97 days old to evaluate the sensitivity of 5-HT recepotors. It was found that 5-HTP (25 mg/kg) produces a severe serotonin syndrome in the adult 5,7-DHT-treated rats, but only a moderate syndrome in the neonatal-treated animals. Significant negative correlation coefficients were obtained between the score of serotonin syndrome and 5-HT content in the hypothalamus, midbrain, medulla oblongata, and cerebellum of the neonatal 5,7-DHT-treated rats. The results suggest that neonatal 5,7-DHT treatment produces an anxiogenic effect in contrast with the anxiolytic effect with adult treatment.     

In vivo increase in hypothalamic cyclic AMP following 5-hydroxytryptophan administration in rats

Summary The administration of 5-hydroxytryptophan (5-HTP, 100 mg/kg, i.p.) consistently increased hypothalamic cyclic AMP levels in rats treated 10 days earlier with the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), to produce 5-HT receptor supersensitivity. However 5-HTP (100 mg/kg), failed to cause an increase in hypothalamic cyclic AMP in rats not pretreated with 5,7-DHT. The 5-HTP-induced increase in cyclic AMP was blocked by the decarboxylase inhibitor, benserazide (RO 44602, 800 mg/kg) and by the 5-HT antagonist metergoline (5 mg/kg). Other treatments that caused a significant elevation of hypothalamic cyclic AMP included: (a) l-Tryptophan plus the monoamine oxidase inhibitor, tranylcypromine, and (b) the serotonin agonist, 1-(m-trifluromethylphenyl)-1-piperazine.The 5-HT antagonist, methysergide, blocked the serotonin receptor mediated behavioral syndrome, but failed to prevent the increase in hypothalamic cyclic AMP. Moreover, the 5-HT agonist, 5-methoxy-N, N-dimethyltryptamine, (5-Me-DMT), induced a strong behavioral syndrome but failed to significantly increase hypothalamic cyclic AMP. These findings suggest that activation of 5-HT receptors some-where in the brain causes an increase in hypothalamic cyclic AMP, but further studies will be needed to determine whether this is a direct result of activation of the 5-HT receptors in the hypothalamus.     

Increased m-CPP-induced oral dyskinesia after lesion of serotonergic neurons

Peripheral administration of the 5-hydroxytryptamine (5-HT)(2C/1B) agonist 1-(m-chlorophenyl)piperazine (m-CPP) produces abnormal orofacial movements in rats. We have previously shown that this behavior is mediated by 5-HT(2C) receptors in the subthalamic nucleus [Neuroscience 72 (1996) 117]. The present studies examined this effect after serotonin depletion to determine whether removal of endogenous serotonin affected this behavioral response and/or subthalamic 5-HT(2C) receptors. Rats received an intraventricular infusion of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 100 mg/10 ml) or vehicle after desipramine pretreatment (25 mg/kg ip). The efficacy of serotonin depletion was confirmed by a decrease in serotonin uptake sites measured by autoradiography. Oral dyskinesia induced by peripheral administration of m-CPP (1.0 mg/kg ip) was markedly increased in lesioned rats compared to sham-operated controls 4 and 8 but not 12 days after the lesion. A subset of lesioned rats that displayed transient seizures after m-CPP injection did not prevent the measurement of oral dyskinesia during the observation period. No differences in 5-HT(2C) receptor levels were found with ligand-binding autoradiography in the subthalamic nucleus, or in other brain regions that express this receptor, in rats sacrificed 5 days following 5,7-DHT lesions. The data indicate that lesion of serotonergic neurons in adult rats induces a transient increase in motor responses mediated by subthalamic 5-HT(2C) receptors. These data suggest that functional alterations in serotonergic transmission in the subthalamic nucleus may be involved in the pathophysiology of hyperkinetic movement disorders.     

The effects of lesions produced by 5,7-dihydroxytryptamine on 5-hydroxytryptamine-mediated behaviour induced by amphetamine in large doses in the rat

The role of 5-hydroxytryptamine (5-HT)-containing terminals in the spinal cord and basal ganglia in behavioural responses induced by amphetamine in large doses have been investigated using the neurotoxin for 5-HT, 5,7-dihydroxytryptamine (5,7-DHT). The effects of pretreatment with 5,7-DHT were also examined using the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). d-Amphetamine (25 mg/kg) induced several classical 5-HT-dependent behavioural responses (head weaving, forepaw treading, hind limb abduction, “wet dog” shakes, Straub tail), together with some classical dopamine (DA)-dependent behaviour and backward locomotion which requires both transmitters. Pretreatment with 5,7-DHT, given into the striatum significantly decreased “wet dog” shakes and virtually abolished backward walking. Pretreatment with 5,7-DHT in the nucleus accumbens or substantia nigra did not significantly alter behaviour. Pretreatment with 5,7-DHT intraspinally did not significantly alter behaviour induced by amphetamine, although a decrease of Straub tail just failed to reach significance (P = 0.056). Similar pretreatment in rats given 5-MeODMT (8 mg/kg) significantly enhanced both Straub tail and tremor but did not alter the other behavioural responses induced by this drug (limb abduction, forepaw treading, head weaving). The results in general suggest that behavioural responses induced by 5-HT can be classified into 3 groups (a) those requiring striatal 5-HT (“wet dog” shakes and backward locomotion), (b) those requiring spinal 5-HT (Straub tail, tremor) and (c) those requiring neither spinal nor striatal 5-HT (hind limb abduction, head weaving and forepaw treading).     

Effects of p-chloroamphetamine and 5,7-dihydroxytryptamine on the sexual behavior of gonadectomized male and female rats

Treatment with the 5-HT neurotoxins p-chloroamphetamine (PCA, 2× 10 mg/kg) or 5,7-dihydroxytryptamine (5,7-DHT, 2×6 μg intracerebrally) stimulated the display of all aspects of sexual behavior, including ejaculations, by castrated male rats in the absence of testosterone (T) treatment and increased the behavioral sensitivity to a low level of T stimulation. The reduction of the (³H) 5-HT uptake after PCA treatment was more pronounced in the cortex than in the hypothalamus. 5,7-DHT treatment reduced the (³H) 5-HT uptake in the septum, hippocampus, amygdala, hypothalamus and cortex but the behavioral effects produced by the 5,7-DHT treatment could not be correlated to the biochemical effects in any of these brain areas. Since the behavioral effect of PCA appears to be stronger than that of 5,7-DHT, the 5-HT neurotoxins may exert their effect on sexual behavior in forebrain structures rather than in the hypothalamus. PCA treatment had a very small effect on mounting behavior but 5,7-DHT treatment stimulated the display of mounts and intromission patterns by ovariectomized female rats given no hormone treatment. Neither PCA nor 5,7-DHT had any effect on lordosis behavior tested before and after treatment with estradiol benzoate alone or in combination with progesterone. The observations support the conclusion that 5-HT is involved in the control by T of sexual behavior in male rats, but argue against a role of 5-HT in the neural control of lordosis behavior.     

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats. Received: 22 November 1995 / Final version: 25 November 1996     

Asymmetry in enhanced neurogenesis in the rostral dentate gyrus following kainic acid-induced status epilepticus in adult rats

Neurogenesis in the suprapyramidal and infrapyramidal blades of the rostral dentate gyrus was investigated following kainic acid (KA)-induced status epilepticus (SE) in adult rats. Rats were injected with KA (14 mg/kg, i.p.) or saline, with convulsions terminated by an intraperitoneal injection of diazepam. Five days after the induction of SE, the rats were injected with 5-bromo-2-deoxyuridine-5-monophosphate (BrdU; 75 mg/kg, i.p.), a marker of cell division. One day after the BrdU injection, the numbers of BrdU-labeled cells in the supra- and infrapyramidal blades were significantly higher in the KA-injected rats compared to the saline-injected rats. In the saline-injected rats, the number of BrdU-labeled cells in the infrapyramidal blade was greater than in the suprapyramidal blade. Twenty-eight days after the BrdU injection, the number of BrdU-labeled cells remained significantly higher in the KA-injected rats than the saline-injected rats, but only in the infrapyramidal blade. In addition, when the extent of cell death was examined with Fluoro-Jade B (a marker of dead and dying cells) 3 days after the induction of SE, degenerating cells were more numerous in the infrapyramidal blade than in the suprapyramidal blade. Our results suggest that there is an asymmetry of neurogenesis and cell death in the rostral dentate gyrus of rats following KA-induced SE.     

Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex. Effects of 5,7-dihydroxytryptamine and p-chlorophenylalanine.

These experiments examined the impact of extensive depletions of forebrain 5-hydroxytryptamine (5-HT; serotonin) levels on prepulse inhibition (PPI) of the acoustic startle reflex in rats. In Experiment 1, injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei disrupted PPI. This deficit was observed beginning 2 days after lesioning and was still apparent 8 weeks later. Basal startle reactivity was not altered. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg) and the dopamine receptor agonist apomorphine (1mg/kg) also disrupted PPI; the effect of 8-OH-DPAT, but not apomorphine, was potentiated in 5-HT-depleted rats. Basal startle reactivity was enhanced by 8-OH-DPAT in sham-lesioned rats but not in 5,7-DHT-lesioned rats. In Experiment 2, a second method for depleting 5-HT was used. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) also disrupted PPI without altering basal startle reactivity. Again, 8-OH-DPAT disrupted PPI in control animals; this effect was not altered in PCPA-treated rats but the increase in basal startle reactivity induced by 8-OH-DPAT was not observed in PCPA-treated rats. Taken together with the results of previous experiments involving drugs that enhance 5-HT neurotransmission it appears that both increases and decreases in 5-HT activity disrupt PPI.     

Prolonged corticosterone treatment alters the responsiveness of 5-HT1A receptors to 8-OH-DPAT in rat CA1 hippocampal neurons

Hippocampal 5-HT(1A) receptors have been shown to be suppressed by glucocorticoids in a variety of animal studies, however the molecular mechanism and the functional meaning of this effect are still not well understood. The present study was designed to investigate the impact of repeated administration of corticosterone (10 mg/kg s.c. twice daily for 7 days) on the functional consequences of 5-HT(1A) receptor stimulation measured electrophysiologically in hippocampal slices. Additionally, the effects of corticosterone on 5-HT(1A) receptor binding and on receptor mRNA levels in the hippocampus were studied. Prolonged, but not acute treatment with corticosterone attenuated (+/-)-8-hydroxy-2-di- N-propylamino)tetralin hydrobromide (8-OH-DPAT)-induced inhibition of population spikes, and 8-OH-DPAT-induced hyperpolarization in rat CA1 hippocampal neurons. Chronic, but not acute treatment with corticosterone also decreased 5-HT(1A) receptor binding in the CA1 region (in the ventral part only) and the dentate gyrus. A single dose of corticosterone increased [(3)H]8-OHDPAT binding in the dentate gyrus and in the CA3 and CA4 hippocampal regions. Only acute, but not prolonged treatment with corticosterone decreased the level of 5-HT(1A) receptor mRNA in the CA1 region and dentate gyrus of the hippocampus. 5-HT turnover in the hippocampus was not influenced by chronic corticosterone. It is concluded that a chronically elevated level of corticosterone can induce functional desensitization of 5-HT(1A) receptors in the CA1 area of the hippocampus, although this effect is not always followed consequently by decreases in 5-HT(1A) receptor synthesis in this or other areas of the hippocampus.     

Neonatal serotonin (5-HT) depletion does not disrupt prepulse inhibition of the startle response in rats

The neurodevelopmental hypothesis of many brain disorders is based on the notion that environmental factors have significant effects on brain maturation. Because serotonin (5-HT) dysfunction in development may be involved in disease etiology, the present investigation assessed the effects of neonatal 5-HT depletion on prepulse inhibition of the startle response (PPI) in rats. Three-day-old Sprague-Dawley rats were pretreated with desipramine (20 mg/kg), followed by an intraventricular injection of the selective 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 70 μg dissolved in 2 μl of 0.1% saline solution in ascorbic acid) on each side. Three months later, the rats' PPI was tested. Despite a severe and permanent decrease (80-100%) in hippocampal, prefrontal and striatal 5-HT levels, treatment with 5,7-DHT caused no disruption of PPI. In contrast to this lack of effect, the 5,7-DHT treatment increased basal startle activity, as measured in response to a 120 dB stimulus. Thus, our results clearly indicate that neonatal 5-HT depletion does not interrupt prepulse inhibition in rats. Studies involving lesions of brain structures or chemical systems run the risk of inducing compensatory changes in brain function, resulting in an amelioration of any deficit. The development of such compensatory mechanisms seems likely in the current study, due to the severe and long-lasting effect of neonatal 5,7-DHT-induced reduction on 5-HT levels.