Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat

Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT₂ receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT₂ receptor antagonist ritanserin injected intraperitoneally (IP) (0.04–2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT₂ receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16–2.5 mg/kg) or with cinanserin (2.5–5 mg/kg), another 5-HT₂ receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT₁ receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16–2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT₂ receptors are involved in this action. In addition it is suggested that 5-HT₁ receptor subtypes are unlikely to interact with 5-HT₂ receptors in the sleep-wakefulness modulation mediated through 5-HT₂ receptors.     

Characterization of 5-hydroxytryptamine-induced depolarizations in rat isolated vagus nerve

An additional component of the depolarization induced by 5-hydroxytryptamine (5-HT) in the rat isolated vagus nerve has recently been attributed to activation of 5-HT₄ receptors. To confirm and extend this finding, extracellular recordings of D.C. potentials were made using the ‘grease-gap’ technique during continuous superfusion of the isolated nerve. Beginning at 1 nM, 5-HT induced small depolarizations that displayed a slow onset. At concentrations 1 μM, large depolarizations with rapid onset were elicited. In the presence of the 5-HT₃ receptor antagonists, granisetron or ondansetron, 5-HT responses were diminished and exhibited an increased latency to peak. These small, slow depolarizations were not reduced by 5-HT₁ or 5-HT₂ receptor antagonists, but were potently inhibited by the 5-HT₄ receptor antagonist GR 113808 (pA₂ = 9.3), and mimicked by 5-methoxytryptamine (pEC₅₀ = 5.3). 5-HT₄-mediated responses were larger at 37°C than at 31°C, but also showed marked diminution with repeated 5-HT applications at concentrations greater than 1 μM. Conversely, 5-HT₃ receptor responses were potentiated at lower temperatures (31°C). Consistent with the reported positive coupling of 5-HT₄ receptors to adenylyl cyclase, forskolin and 8-Br-cAMP produced slowly developing depolarizations which were qualitatively similar to 5-HT₄ receptor activation. Pre-depolarization of nerves with 10 μM forskolin or 300 μM 8-Br-cAMP diminished the effect of 5-HT₄ receptors. This study has confirmed the presence of 5-HT₄ receptors on the vagus nerve of the rat and defined some conditions that optimize their pharmacological isolation. The rat isolated vagus nerve constitutes a simple and robust preparation for studying 5-HT₄ receptors in the peripheral nervous system.     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

Is 5-hydroxytryptamine mediating descending inhibition in the neonatal rat spinal cord through different receptor subtypes?

The long-lasting descending inhibition of lumbar segmental reflexes in the neonatal rat spinal cord has been investigated in vitro by recording from lumbar ventral roots on stimulation of a single lumbar dorsal root. Descending inhibition was elicited by a single stimulus to the latero-ventral thoracic cord. A number of strategies were used to clarify the role of 5-hydroxytryptamine (5-HT) in inhibiting the monosynaptic reflex, the ipsilateral polysynaptic response and the contralateral fast response evoked on the opposite side of the lumbar cord. The 5-HT uptake inhibitor, citalopram (10 nM), potentiated both short-interval (0.5–2 s) inhibition and long-interval (5–100 s) inhibition of the monosynaptic reflex, and also inhibition of the polysynaptic response 10–100 s after the thoracic stimulus. Inhibition of the monosynaptic reflex was blocked by ketanserin (1 μM), spiperone (1 μM) and methiothepin (1 μM), but not by spiroxatrine (0.1 μM) or sulpiride (1 μM). Sumatriptan (20 nM) and methysergide (10 nM) enhanced inhibition of the monosynaptic reflex 0.2–1 s after the thoracic stimulus. It was concluded that 5-HT acting through 5-HT_2A/2C receptors is the transmitter responsible for monosynaptic reflex inhibition, at intervals of 0.5–100 s, but a stronger stimulus to the thoracic cord may elicit a non-serotonergic component at intervals of 0.1–2 s. There was no unequivocal evidence that endogenous 5-HT activates 5-HT₁ receptors to produce inhibition. 5-HT acting through 5-HT_2A/2C receptors is also responsible for part of the inhibition of the polysynaptic response, but the transmitter(s) responsible for the ketanserin-resistant component of inhibition and for inhibition of the contralateral fast response has still to be identified.     

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT_2C/5-HT_2B receptors was assessed using a putative in vivo model of 5-HT_2C/5-HT_2B receptor function, mCPP-induced hypolocomotion. mCPP (2,4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily × 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily × 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o.daily × 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT_2C/5-HT/_2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.     

5-HT1A receptor-mediated inhibition in the hippocampus of the alert rat — effects of repeated gepirone treatment

The effects of acute and repeated treatment with the 5-HT_1A receptor ligand gepirone on hippocampal excitatory synaptic transmission were investigated. Recordings of the electrically evoked field population excitatory postsynaptic potentials (e.p.s.p.s.) were made in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert male Wistar rats. Acute injection of gepirone reduced the e.p.s.p. amplitude in a transient dose-dependent (0.5 – 10 mg/kg, i.p.) manner. This effect was blocked by the 5-HT_1A receptor antagonist MDL 73005EF (8-[2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethys]-8-azaspirol[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg, i.p.). Gepirone (1 mg/kg per day, i.p.) administered for 7 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a concomitant reduction of the acute response to the drug. The chronic baseline reduction was transiently reversed by the 5-HT_1A receptor antagonist spiroxatrine and complete recovery to pretreatment levels was observed 48 h after the last gepirone dose. The data indicate that with repeated administration, a prolongation and enhancement of the 5-HT_1A receptor-mediated reduction in the e.p.s.p. by gepirone occurs. This delayed effect may contribute to the slow onset of therapeutic action of gepirone.     

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists.

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT₃ receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT₃ receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT₃ receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.     

5-HT_3受体拮抗剂抑制化疗致吐的研究进展

目的通过对5-HT3受体特点的研究和5-HT3受体参与的化疗致吐机制的剖析,阐明5-HT3受体拮抗剂对抗化疗致吐方面的作用机制和临床应用。方法综述国内外相关文献19篇,对相关研究的进展和成果进行总结。结果5-HT3受体拮抗剂通过在外周和中枢选择性拮抗5-HT3受体,有效控制化疗致吐的发生。因其效果显著、不良反应小而得到了较好的临床应用。结论5-HT3受体拮抗剂可选择性阻断5-HT3受体,从而有效控制化疗导致的呕吐。     

Effects of selective activation of the 5-HT1B receptor with CP-94,253 on sleep and wakefulness in the rat

The effects of the 5-HT_1B receptor agonist CP-94,253 were compared with those of the mixed β-adrenoceptor and 5-HT_1A/B receptor antagonist (±)pindolol in rats implanted for chronic sleep recordings. CP-94,253 (5.0–10.0 mg/kg) significantly increased waking and reduced slow wave sleep (SWS) and REM sleep (REMS). At 2.0–4.0 mg/kg (±)pindolol reduced REMS. Pretreatment with (±)pindolol (2.0–4.0 mg/kg) reversed the effect of CP-94,253 on waking and SWS, while REMS remained suppressed. It is suggested that the 5-HT_1B receptor together with other 5-HT receptor subtypes may have a direct regulatory action on sleep and waking in the rat.     

Pharmacogenetics and the serotonin system: initial studies and future directions

Serotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive–compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents—available and in development—and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research.     

Effect produced by acute and chronic administration of the selective 5-HT3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat

This study examined the effect of acute and chronic administration of the selective 5-HT₃ receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose-response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01-0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)-apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2-fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose-response curve of BRL 46470A. © 1994 Wiley-Liss, Inc.     

5-HT2/5-HT1C receptor-mediated facilitatory action on unit activity of ventral horn cells in rat spinal cord slices.

5-Methoxy-N,N-dimethyltryptamine (5-McODMT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) facilitate motoneuron excitability through 5-HT_1C/5-HT₂ receptors in rats. Using spinal cord slices prepared from adult rals, we recorded unitary cell discharges, evoked by local stimulation of the adjacent site, extracellularly in the motor nuclei of the ventral horn. 5-MeODMT, DOI, 5-hydroxytryptamme (5-HT), 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and tandospirone facilitated the probability of firing in the motor nuclei, with 5-MeODMT and DOI being the most potent. The effect of 5-MeODMT was significantly suppressed by ketanserin (a 5-HT₂ receptor-selective antagonist), spinerone (a 5-HT_1A/5-HT₂ receptor antagonist) and cyproheptadine (a 5-HT_1A/5-HT₂ receptor antagonist), but not by 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, a 5-HT₃ receptor-selective antagonist) or pindolol (a 5-HT_1A/5-HT_1B receptor antagonist). This suggests that 5-HT₂ and/or 5-HT_1C receptors are involved in the facilitatory effects of 5-HT receptor agonists on the synaptic activity of ventral horn cells.     

Sleep-wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

The present study examined the effects of meta-chlorophenyl piperazine (mCPP) and mianserin on the sleep-wake cycle of the clomipramine-induced behaviorally screened depressed rats. Six-hour polygraphic recordings were made between 06:00 and 12:00 h, after a single injection of either saline or mianserin or mCPP into the lateral cerebral ventricle (i.c.v.) of both the depressed (n=12) and control rats (n=12). The injection of mCPP in the depressed rats caused a significant reduction in the total duration and number of rapid eye movement (REM) sleep episodes while it increased the REM sleep onset latency compared to the control saline injections. The injection of mianserin in the depressed rats also caused a significant reduction in the total duration and number of REM sleep episodes without changing the REM sleep latency. These results demonstrate for the first time that the central administration of mCPP and mianserin could act as an antidepressant in the clomipramine-induced rat model of depression.     

Effect of quinine on autoreceptor-regulated serotonin release in the rat hippocampus

The involvement of K⁺ channels in the autoregulation of terminal serotonin (5-hydroxytryptamine, 5-HT) release was investigated by microdialysis in the hippocampus of conscious rats. Extracellular 5-HT was increased concentration-dependently by the K⁺ channel blocker quinine (10, 100 and 1000 μM in perfusate), and tetrodotoxin (10 μM) but not fluoxetine (5 μM) exerted a partially attenuating influence. The 5-HT_1/2/6 receptor antagonist methiothepin (50 μM) increased dialysate 5-HT, most likely through 5-HT_1B autoreceptors tonically activated in the hippocampus of awake rats as opposed to the previously reported lack of effect 5-HT_1B autoreceptor blockade in anesthetized rats. The effect of methiothepin was greatly reduced by preperfusion with quinine (100 μM), consonant with a role for quinine-sensitive K⁺ channels in the autoregulation of 5-HT release in the hippocampus by 5-HT receptor antagonism. In contrast, the reduction in dialysate 5-HT induced by the 5-HT₁ receptor agonist RU 24969 (1 μM), in the presence of fluoxetine (5 μM), persisted in the co-presence of quinine, consonant with the involvement of (extrasynaptic?) 5-HT autoreceptors not coupled with quinine-sensitive K⁺ channels.     

Survey on the pharmacodynamics of the new antipsychotic risperidone

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT₂ receptor blockade as shown by displacement of radioligand binding (K_i: 0.16 nM), activity on isolated tissues (EC₅₀:0.5 nM), and antagonism of peripherally (ED₅₀: 0.0011 mg/kg) and centrally (ED₅₀:0.014 mg/kg) acting 5-HT₂ receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT₂ receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D₂ receptor antagonist as indicated by displacement of radioligand binding (K_i: 1.4 nM), activity in isolated striatal slices (IC₅₀: 0.89 nM), and antagonism of peripherally (ED₅₀: 0.0057 mg/kg in dogs) and centrally acting D₂ receptor agonists (ED₅₀: 0.056–0.15 mg/kg in rats). Risperidone shows all effects common to D₂ antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4–10 times less potent than haloperidol as a central D₂ antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT₂ antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D₂ antagonism; synergism of combined 5-HT₂/D₂ antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D₂ receptors and at D₂ receptors from various rat brain regions. The binding affinity for D₄ and D₃ receptors is 5 and 9 times weaker, respectively, than for D₂ receptors; interaction with D₁ receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H₁ and -adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D₂ antagonist with predominant 5HT₂ antagonistic activity and optimal pharmacokinetic properties.Unpublished research reports are available from Documentation Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium     

The effects of 8-OH-DPAT on medulllary 5-HT neurons and sympathetic activity in baroreceptor-denervated animals

The effects of the 5HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on medullary 5-hydroxytryptamine (5-HT) neuronal firing and inferior cardiac sympathetic nerve activity were simultaneously determined in baroreceptor-denervated cats. 5-HT neuronal firing was inhibited by 50% at a 1 μg/kg i.v. dose of 8-OH-DPAT in the baroreceptor-denervated animal. Unit firing was completely inhibited by a 3 μg/kg dose. In contrast, 8-OH-DPAT inhibited inferior cardiac nerve activity between 10 and 100 μg/kg i.v. A similar relationship between the 8-OH-DPAT-induced inhibition of 5-HT unit activity and sympathetic nerve activity was observed in sham-operated control animals. These data suggest that the sympatholytic effects of 8-OH-DPAT cannot be explained on the basis of an autoreceptor effect of the drug.     

Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors

In animals given citalopram (10 mg/kg) twice daily for 14 days a further dose of 1 mg/kg, administered 24 h after the last dose, markedly increased cortical dialysate serotonin (5-hydroxytryptamine, 5-HT), but had no effect in control animals. The effect on dialysate 5-HT in the dorsal raphe was not increased by the chronic treatment. At 25 μg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin, an agonist at 5-HT_1A receptors, reduced cortical 5-HT output in controls but not in animals treated chronically with citalopram whereas 50 μg/kg reduced 5-HT output in both groups. These findings suggest that somatodendritic 5-HT_1A receptors are desentisized after chronic treatment with citalopram and this results in facilitation of its effect on cortical dialysate 5-HT. These results also agree with the concept that the effect of 5-HT re-uptake inhibitors on increasing 5-HT output in the frontal cortex is attenuated by their simultaneous ability to activate somatodendritic 5-HT_1A receptors via an increase of endogenous 5-HT in the raphe region.     

Distinct temporal pattern of the effects of the combined serotonin-reuptake inhibitor and 5-HT1A agonist EMD 68843 on the sleep EEG in healthy men

RATIONALE: EMD 68843 (EMD) has properties of a serotonin (5-HT)-reuptake inhibitor and a partial 5-HT1A agonist in one molecule in order to combine antidepressive and anxiolytic properties. OBJECTIVE: We investigated the effects of EMD on the sleep EEG in order to characterize how the complex interaction between these two properties influences the sleep EEG. METHODS: We performed a randomized crossover study in ten young normal male controls (20-30 years), receiving a single dose of 20 mg EMD or placebo orally at 2100 hours. Sleep EEG was recorded from 2300 to 0700 hours. RESULTS: After EMD, rapid eye movement (REM) sleep was nearly totally abolished. In the course of the night other effects on the sleep EEG occurred in distinct intervals. Slow wave sleep and EEG delta power increased in the first and third one-third of the night, whereas wakefulness was enhanced in the second and third one-third of the night. CONCLUSION: The sleep EEG effects of EMD fit with its pharmacological profile, which might lead to adaptive changes suggested to characterize an antidepressive substance.     

The head-twitch response to intraperitoneal injection of 5-hydroxytryptophan in the rat: antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, an LSD antagonist

The putative 5-hydroxytryptamine (5-HT) antagonists 2-bromo-LSD, cinanserin, cyproheptadine, pizotifen, methysergide, metitepine, mianserin and metergoline were found to reduce the frequency of the head-twitch response induced by intraperitoneal injections of 320 mg/kg of 5-hydroxytryptophan (5-HTP) in the rat. The antagonist dose-effect curve of these agents was biphasic. It consisted of an initial, steep, phase and a subsequent, shallower, phase. Analysis of the data by means of quantitative and quantal methods yielded different rank orders of potency of antagonist drugs. Only pirenperone, a drug identified earlier as a pure antagonist, produced a simple, monophasic dose-effect curve in antagonizing the effects of 5-HTP. The antagonist effects of pirenperone, and the first phase of the curve of the putative 5-HT antagonists, may reflect antagonist activity at 5-HT2 receptors. The data are consistent with earlier behavioural evidence that the putative 5-HT antagonists act complexly as mixed agonist-antagonists; only pirenperone exerted behavioural effects that suggest it to be a pure antagonist.