Serotonergic Behavior Research Articles

A new approach to 'on-demand' treatment of lifelong premature ejaculation by treatment with a combination of a 5-HT1A receptor antagonist and SSRI in rats.

Lifelong premature ejaculation (PE) in men lacks an adequate on-demand pharmacological treatment. Although selective serotonin reuptake inhibitors (SSRIs) are used for PE they only work after chronic treatment, or if used on-demand, less adequately than chronic SSRI treatment. It has been shown that the addition of a behaviorally silent 5-HT1A-receptor antagonist to an SSRI can generate acute inhibitory effects on male rat sexual behavior. Atlas987 is a selective 5-HT1A-receptor antagonist with equal potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. To investigate whether Atlas987 together with the SSRI paroxetine, a combination called Enduro, induces acute inhibitory effects on male rat sexual behavior, we tested Enduro in Wistar rats in a dose-dependent manner. We first tested the 5-HT1A receptor antagonist Atlas987 in 8-OH-DPAT induced serotonergic behavior in rats. Second, we tested Enduro in a dose-dependent manner in male sexual behavior. Third, we tested the effective time window of Enduro's action, and lastly, we measured the plasma levels of Atlas987 and paroxetine over an 8-h period. Results showed that Enduro acutely and dose-dependently reduced the number of ejaculations and increased the ejaculation latencies. The behavioral pattern induced reflected a specific effect on sexual behavior excluding non-specific effects like sedation or sensoric-motoric disturbances. The time-window of activity of Enduro showed that this sexual inhibitory activity was at least found in a 1-4 h' time window after administration. Plasma levels showed that in this time frame both Atlas987 and paroxetine are present. In conclusion, in rats, Enduro is successful in acutely inhibiting sexual behavior. These results may be therapeutically attractive as "on demand" treatment for life-long premature ejaculation in men.

Ginsenoside Re attenuates 8-OH-DPAT-induced serotonergic behaviors in mice via interactive modulation between PKCδ gene and Nrf2

It has been recognized that serotonergic blocker showed serious side effects, and that ginsenoside modulated serotonergic system with the safety. However, the effects of ginsenoside on serotonergic impairments remain to be clarified. Thus, we investigated ginsenoside Re (GRe), a major bioactive component in the mountain-cultivated ginseng on (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist. In the present study, we observed that the treatment with GRe resulted in significant inhibition of protein kinase C δ (PKCδ) phosphorylation induced by the 5-HT1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) in the hypothalamus of the wild-type (WT) mice. The inhibition of GRe was comparable with that of the PKCδ inhibitor rottlerin or the 5-HT1A receptor antagonist WAY100635 (WAY). 8-OH-DPAT-induced significant reduction in nuclear factor erythroid-2-related factor 2 (Nrf2)-related system (i.e., Nrf2 DNA binding activity, γ-glutamylcysteine ligase modifier (GCLm) and γ-glutamylcysteine ligase catalytic (GCLc) mRNA expression, and glutathione (GSH)/oxidized glutathione (GSSG) ratio) was significantly attenuated by GRe, rottlerin, or WAY in WT mice. However, PKCδ gene knockout significantly protected the Nrf2-dependent system from 8-OH-DPAT insult in mice. Increases in 5-hydroxytryptophan (5-HT) turnover rate, overall serotonergic behavioral score, and hypothermia induced by 8-OH-DPAT were significantly attenuated by GRe, rottlerin, or WAY in WT mice. Consistently, PKCδ gene knockout significantly attenuated these parameters in mice. However, GRe or WAY did not provide any additional positive effects on the serotonergic protective potential mediated by PKCδ gene knockout in mice. Therefore, our results suggest that PKCδ is an important mediator for GRe-mediated protective activity against serotonergic impairments/oxidative burden caused by the 5-HT1A receptor.

Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction.

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.

5-HT2A receptor-mediated PKCδ phosphorylation is critical for serotonergic impairments induced by p-chloroamphetamine in mice

p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT1A receptor gene expression, but significantly increased 5-HT2A receptor gene expression. Furthermore, 5-HT2A receptor antagonist MDL11939, but not 5-HT1A receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT2A receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT2A receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT2A receptor-mediated serotonergic effects. Our results suggest that 5-HT2A receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ.

5-HT1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox

Serotonin syndrome is an adverse reaction due to increased serotonin (5-hydroxytryptophan: 5-HT) concentrations in the central nervous system (CNS). The full 5-HT1A receptor (5-HT1AR) agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) has been recognized to elicit traditional serotonergic behaviors. Treatment with 8-OH-DPAT selectively increased PKCδ expression out of PKC isoforms and 5-HT turnover rate in the hypothalamus of wild-type mice. Treatment with 8-OH-DPAT resulted in oxidative burdens, co-immunoprecipitation of 5-HT1AR and PKCδ, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT1AR or PKCδ in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT1AR antagonism (i.e., WAY100635), PKCδ inhibition (i.e., rottlerin and genetic depletion of PKCδ), or NADPH oxidase/p47phox inhibition (i.e., apocynin and genetic depletion of p47phox). However, WAY100635, apocynin, or rottlerin did not exhibit any additive effects against the protective effect by inhibition of PKCδ or p47phox. Furthermore, apocynin, rottlerin, or WAY100635 also significantly protected from pro-inflammatory/pro-apoptotic changes induced by 8-OH-DPAT. Therefore, we suggest that 8-OH-DPAT-induced serotonergic behaviors requires oxidative stress, pro-inflammatory, and pro-apoptotic changes, that PKCδ or p47phox mediates the serotonergic behaviors induced by 8-OH-DPAT, and that the inhibition of PKCδ-dependent p47phox activation is critical for protecting against serotonergic behaviors.

PKCδ Knockout Mice Are Protected from Dextromethorphan-Induced Serotonergic Behaviors in Mice: Involvements of Downregulation of 5-HT1A Receptor and Upregulation of Nrf2-Dependent GSH Synthesis.

We investigated whether a specific serotonin (5-HT) receptor-mediated mechanism was involved in dextromethorphan (DM)-induced serotonergic behaviors. We firstly observed that the activation of 5-HT1A receptor, but not 5-HT2A receptor, contributed to DM-induced serotonergic behaviors in mice. We aimed to determine whether the upregulation of 5-HT1A receptor induced by DM facilitates the specific induction of certain PKC isoform, because previous reports suggested that 5-HT1A receptor activates protein kinase C (PKC). A high dose of DM (80mg/kg, i.p.) induced a selective induction of PKCδ out of PKCα, PKCβI, PKCβII, PKCξ, and PKCδ in the hypothalamus of wild-type (WT) mice. More importantly, 5-HT1A receptor co-immunoprecipitated PKCδ in the presence of DM. Consistently, rottlerin, a pharmacological inhibitor of PKCδ, or PKCδ knockout significantly protected against increases in 5-HT1A receptor gene expression, 5-HT turnover rate, and serotonergic behaviors induced by DM. Treatment with DM resulted in an initial increase in nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation and DNA-binding activity, γ-glutamylcysteine (GCL) mRNA expression, and glutathione (GSH) level. This compensative induction was further potentiated by rottlerin or PKCδ knockout. However, GCL mRNA and GSH/GSSG levels were decreased 6 and 12h post-DM. These decreases were attenuated by PKCδ inhibition. Our results suggest that interaction between 5-HT1A receptor and PKCδ is critical for inducing DM-induced serotonergic behaviors and that inhibition of PKCδ attenuates the serotonergic behaviors via downregulation of 5-HT1A receptor and upregulation of Nrf2-dependent GSH synthesis.

Activity of Serotonin 5-HT1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties.

Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.

NLX-112, a highly selective 5-HT1A receptor agonist: Effects on body temperature and plasma corticosterone levels in rats

NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT1A receptor agonists in humans.NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT1A receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31–0.63mg/kg p.o.).The doses of NLX-112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed.

Effects of repeated phencyclidine administration on adult hippocampal neurogenesis in the rat

Dysfunctional maturation of neural networks, particularly hippocampus-prefrontal networks, may be of particular interest in determining the pathophysiology of schizophrenia. Phencyclidine (PCP)-induced symptoms in humans appear to offer a more complete model of schizophrenia than do amphetamine-induced symptoms. This study investigated the effects of intermittent i.p. injections of PCP (7.5 mg/kg) on cell proliferation and survival of granule cells in the dentate gyrus of the rat brain using quantitative immunohistochemical techniques for 5-bromo-2'-deoxyuridine (BrdU)-positive cells. After repeated PCP injection for 14 days, mean scores for stereotyped behavior increased with the number of injections, while scores for ataxia and backpedaling as serotonergic behaviors gradually decreased. The number of BrdU-positive cells decreased by 23% in the subgranular zone of the dentate gyrus by 24 h after repeated injections. However, decreased levels of BrdU-positive cells returned to control levels within 1 week. Differentiation of newly formed cells was not influenced. Repeated PCP administration after BrdU injection did not exert any effects on survival of newly generated cells. These findings suggest that transient disturbances of cell proliferation in the dentate gyrus occur under PCP-related behavioral abnormalities. Whether disturbed cell proliferation would thus be closely implicated in the development of behavioral sensitization induced by PCP administration is unclear, but this would possibly result from adaptation to new pharmacological conditions under behavioral sensitization or stressful conditions of PCP-related abnormal behaviors. Further studies are required to elucidate the biological significance of hippocampal neurogenesis in the mechanisms underlying the development of cognitive dysfunctions and the psychosis of schizophrenia.

Serotonergic function and suicidal behavior in schizophrenia

Serotonergic function and suicidal behavior in schizophrenia

Nitric oxide synthase inhibitors enhance 5-HT 2 receptor-mediated behavior, the head-twitch response in mice

The purpose of this study was to characterize behavioral interactions between nitric oxide synthase (NOS) inhibitors and serotonergic 5-HT 2 receptors. In the present study, NOS inhibitors, N G-nitro-L-arginine, N G-nitro-L-arginine methylester, N G-monomethyl-L-arginine, 7-nitroindazole, trifluoperazine and NO scavenger, methylene blue markedly enhanced 5-hydroxytryptamine (5-HT)-induced selective serotonergic behavior, the head twitch response (HTR), in mice. However NO generators, sodium nitroprusside, 3-morpholinosydnonimine and S-nitroso-N-acetylpenicillamine as well as NO precursor, L-arginine markedly inhibited 5-HT induced HTR in mice. In the previous study, it was demonstrated that the N-methyl-D-aspartate (NMDA) receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, whereas NMDA itself inhibited 5-HT-induced HTR in mice. In the present study, it was demonstrated that the inhibition by a NMDA receptor agonist, NMDA of 5-HT-induced HTR was reversed by the treatment with NOS inhibitors, N G-nitro-L-arginine and N G-nitro-L-arginine methylester. The suppressive action by a NO generator, S-nitroso-N-acetylpenicillamine of 5-HT-induced HTR was also reversed by the treatment with NMDA receptor antagonists, MK-801 and dextromethorphan. These results have shown that the NO system is located down stream of NMDA receptors involved in modulation of 5-HT 2-mediated HTR. Therefore, the enhanced effects of NOS inhibitors on 5-HT-induced HTR support experimental evidence for the NO/5-HT 2 as well as NMDA/5-HT 2 receptor interactions indicating that NO plays an important role in the glutamatergic modulation of the serotonergic function at the 5-HT 2 receptor.

NMDA receptor antagonists enhance 5-HT2 receptor-mediated behavior, head-twitch response, in PCPA-treated mice.

Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) receptor antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both competitive (AP-5 and CPP) and noncompetitive (MK-801, ketamine, dextrorphan and dextromethorphan) NMDA receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA receptor in 5-HT-induced HTR at the postsynaptic 5-HT2 receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA receptor antagonist, NMDA and a serotonin 5-HT2 receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA receptors play an important role in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 receptors.

NMDA receptor antagonists enhance 5-HT 2 receptor-mediated behavior, head-twitch response, in mice

The purpose of this study was to characterize behavioral interactions between glutamatergic and serotonergic 5-HT 2 receptors. Both competitive (AP-5 [D-2-amino-5-phosphovalerate] and D-CPP [3-(2carboxypiperazine-4yl)-propylphosphonate]) and noncompetitive (MK-801 [dizocilpine], ketamine, dextrorphan and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists markedly enhanced a selective serotonergic behavior, the head twitch response (HTR), in mice. In contrast, NMDA itself inhibited 5-hydroxytryptamine (5-HT)-induced HTR in mice. These results suggest that glutamatergic neurotransmission may modulate serotonergic function at the 5-HT 2 receptor.

P.6.062 Serotonergic parameters and stereotyped behavior in mentally retarded subjects

P.6.062 Serotonergic parameters and stereotyped behavior in mentally retarded subjects

A neural shift theory of migraine.

Migraine headache may lend itself to epidemiological inquiry that includes disruptive serotonergic psychosocial behaviors. To advance our knowledge of the etiology of this neurologic disorder, measurable psychosocial behaviors that are correlated with variability in monoamine neurotransmission need to be examined in the migraine population in a controlled fashion. It may be that those with migraine have a more difficult time adapting to internal or external environmental changes based on a different distribution of serotonin levels or activity. Psychosocial behaviors are outlined as possible serotonin indicator variables for future migraine investigation.

Brainstem 5-hydroxytrytamine1A binding sites are not down-regulated by agonists which induce tolerance in the rat: myoclonus and other serotonergic behaviors.

To study the regulation of 5-HT1A receptors in the brainstem, the region most relevant to the serotonin syndrome and to serotonin-responsive human myoclonic disorders, we chronically treated rats with various 5-HT1A agonists and labeled 5-HT1A sites with [3H]8-OH-DPAT. Daily injection for 30 consecutive days of 10 mg/kg ip 8-OH-DPAT (pre- and post-synaptic 5-HT1A agonist) significantly decreased 8-OH-DPAT-evoked flat body posture, forelimb myoclonus, and hypothermia compared to chronic vehicle injection. There was no cross tolerance to 8-OH-DPAT in rats chronically injected with ipsapirone or buspirone (presynaptic 5-HT1A agonists). However, none of the 5HT1A agonists significantly altered Bmax of brainstem 5-HT1A binding sites. Chronic injection with other drugs such as 1-propranolol, (+/-) pindolol and spiperone (5-HT1A and 5-HT2 antagonists), methysergide (5-HT1 and 5-HT2 antagonist), and agonists and antagonists at various other 5-HT receptors also had no effect on binding parameters. These data demonstrate lack of cross-tolerance between pre- and post-synaptically acting 5-HT1A agonists and absence of down-regulation of presynaptic 5-HT1A sites at doses which induced tolerance of 5-HT1A-mediated behaviors of the serotonin syndrome. They suggest changes in the post-synaptic cell rather than the receptor recognition site as the mechanism of tolerance.

Psychoactive drugs and human sexual behavior: the role of serotonergic activity.

A wide range of both prescription and nonprescription drugs has been reported to affect human sexual functioning. While the sexual side effects resulting from drug use have often been attributed to adrenergic, anticholinergic or dopaminergic activity, the present review considers the potential role of serotonin. Based on animal studies, serotonin has been shown to either facilitate or inhibit sexual activity depending on which serotonin receptor subtype is activated. However, few studies have been done in the human that assess the effects of drugs that bind selectively to serotonin receptors. Consequently, little is known about the role of serotonin in human sexual functioning. In this review, a wide range of drugs that affect both brain serotonergic systems and human sexual behavior is examined in an effort to determine the possible role of serotonin in human sexual behavior. A review of the literature is consistent with the hypothesis that the 5-HT1A and the 5-HT2 receptor subtypes play a facilitatory role in human sexual behavior. The evidence suggests that drugs that act as agonists on these receptor sites enhance sexual functioning in the human, while those that act as antagonists inhibit sexual functioning.

Chronic ACTH treatment: Influence on 5-HT2 receptors and behavioral supersensitivity induced by 5,7-dihydroxytryptamine lesions

The capacity of the serotonin (5-HT) precursor 5-HIP to induce the ACTH-responsive myoclonic-convulsive disorder infantile spasms in patients with Down's syndrome has been cited as evidence for altered serotonergic neurotransmission in infantile spasms. Since there is no animal model of infantile spasms, the suitability of behavioral supersensitivity (myoclonus) evoked by 5-HTP in rats with 5,7-dihydroxytryptamine (DHT) lesions as a model was tested by determining the effect of chronic treatment with ACTH (40 IU/kg) on 5-HTP-evoked myoclonus. In rats treated with DHT as adults, ACTH administration did not alter the "serotonergic behaviors," such as myoclonus, induced by 30 mg/kg 5-hydroxytryptophan (5-HTP), but induced a small significant increase in Bmax of neocortical 5-HT2 sites of the DHT group, with no change in rats without lesions. In rats treated with DHT as neonates, there was also no significant difference in behaviors evoked by several doses of 5-HTP. These data suggest that ACTH minimally modifies the effects on 5-HT receptors of DHT lesions, but the intracisternal DHT model is not a suitable model for infantile spasms because chronic ACTH was not antimyoclonic.

Serotonergic mechanisms and suicidal behavior

SummaryDisturbances in central serotonin (5-hydroxytryptamine, 5-HT) were first described in depression. They were inferred to exist based on the finding of lowered baseline and post-probenecid concentrations of 5-HIAA in CSF. Initially, depressed patients with and without deimonstrable disturbances in central 5-H1 seemed psychopathologically indistinguishable. Interpreting the available data, at that time, we introduced in 1971 the concept of biochemical heterogeneity of depression. Some forms, we postulated, are linked to disturbances in 5-HT functions, others are not or, to a much lesser extent. Subsequently, we showed the concept of a separate «5-HT depression» to be untenable. It seems more likely now that 5-HT disturbances in depression are not linked to a particular syndromal depression type, but to particular psychopathological dimensions, i.e. heightened anxiety and disturbed aggression regulation. These dimensions might form a prominent aspect of depression or may be virtually absent. They are moreover not specific for depression, but can occur in other psychiatric disorders as well. This might explain the seemingly capricious occurrence of 5-HT disorders in depression as well as their nosological non-specificity.Based on the dimensional 5-HT hypothesis one might expect drugs that increase 5-HT availability in the brain to be effective in the various anxiety disorders, in depressions marked by increased anxiety and disturbed aggression regulation and in personality disorders with strong aggressive tendencies.

The guinea pig myoclonic model: behavioral supersensitivity to 5-hydroxytryptophan induced by intracisternal 5,7-dihydroxytryptamine

To study the species difference of guinea pigs and rats in response to 5-hydroxytryptophan (5-HTP), we injected both animals intracisternally with 5,7-dihydroxytryptamine. In rats with 5,7-dihydroxytryptamine lesions, 5-HTP evoked the well described myoclonic-serotonergic syndrome. In the guinea pig, 5,7-dihydroxytryptamine lesions significantly increased the severity of myoclonic response to 5-HTP (150 mg/kg) compared to vehicle controls, resulting in lethal convulsions. Guinea pigs treated with 5,7-dihydroxytryptamine did not develop spontaneous myoclonus, or when treated with 5-HTP, other ‘serotonergic behaviors’ such as lateral head weaving, hindlimb abduction, and forepaw tapping. Guinea pigs tolerated intracisternal 5,7-dihydroxytryptamine less well than rats, with a higher mortality, although immediate post-injection convulsions were less severe and did not require phenobarbital prophylaxis. Staged lower doses of 5,7-dihydroxytryptamine (100–200 μg) were better tolerated than a single high dose of neurotoxin (400 μg). The regional profile of 5,7-dihydroxytryptamine lesions in the guinea pig resembled that of the rat, with maximal depletion of 5-HT in spinal cord and selected forebrain structures, and little effect in diencephalon and midbrain. Depletions in the guinea pig were less selective for 5-HT using desipramine pretreatment than in the rat. In naive guinea pigs and rats, regional content of 5-HT was similar. These data suggest that the functional integrity of serotonergic neurons is not requisite for the expression of myoclonus induced by 5-HTP in the guinea pig. 5,7-Dihydroxytryptamine lesions in the guinea pig resulted in behavioral and neurochemical similarities and differences in comparison with the rat.