RESUMO
Benzodiazepine (BZD) and non-BZD hypnotics improve sleep induction and sleep maintenance. BZD induces a further reduction of slow wave sleep (SWS) and rapid eye movement (REM) sleep, whereas SWS and REM values remain decreased during non-BZD administration. There is evidence indicating that the nonselective serotonin 5-HT(2A/2C) receptor antagonists, ritanserin, ketanserin, seganserin and ICI-169369, the selective 5-HT(2A) receptor antagonist eplivanserin and the 5-HT(2A) receptor inverse agonist pimavanserin, increase SWS in subjects with normal sleep. In addition, it has been shown that prior administration of ritanserin prevents the nitrazepam-induced suppression of SWS in normal subjects. Of note, ritanserin also induced an increase of SWS in poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder. The 5-HT(2A) receptor inverse agonist APD-125 gave rise to a similar effect in patients with chronic primary insomnia. Thus, presently available evidence tends to indicate that the association of a 5-HT(2A) receptor antagonist or a 5-HT(2A) receptor inverse agonist with a BZD or a non-BZD hypnotic could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.
Assuntos
Hipnóticos e Sedativos/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adulto , Animais , Benzodiazepinas/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologiaRESUMO
The effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of enzyme nitric oxide synthase (NOS), on spontaneous sleep during the light period, was studied in adult rats implanted for chronic sleep recordings. L-NAME was injected by subcutaneous (s.c.) route or was infused directly into the dorsal raphe nucleus (DRN). Subcutaneous (46.0--185.0 micromol/kg) administration of L-NAME increased waking (W), slow wave sleep (SWS) and rapid-eye-movement sleep (REMS) latency, whereas SWS, REMS and the number of REM periods were reduced. Direct application of L-NAME into the DRN (0.37--1.1 micromol) induced an increment of W and a reduction of SWS and REMS. Values corresponding to SWS and REMS latency, and the number of REM periods remained within control levels. Subcutaneous administration of the GABA(A) receptor agonist muscimol (1.7--3.5 micromol/kg) or the adenosine A(1) receptor agonist L-PIA [L(-)N(6)-(2-phenylisopropyl)adenosine] (0.1--0.3 micromol/kg) induced slight but inconsistent changes of W, light sleep (LS), SWS and REMS that did not attain significance. Pretreatment with muscimol (1.7--3.5 micromol/kg, s.c.) or L-PIA (0.1--0.3 micromol/kg, s.c.) antagonized the increase of W and reduction of SWS and REMS induced by s.c. (92.0 micromol/kg) or intra-DRN (0.74 micromol) administration of L-NAME. However, neither muscimol nor L-PIA prevented the increase of REMS latency induced by L-NAME 92.0 micromol/kg, s.c. Our findings tend to indicate that the change of behavioral state observed after systemic or intra-DRN administration of L-NAME is partly related to the reduction of GABA and adenosine at critical sites in the CNS.
Assuntos
Inibidores Enzimáticos/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Agonistas do Receptor Purinérgico P1 , Sono REM/fisiologia , Sono/fisiologia , Vigília/efeitos dos fármacos , Animais , Injeções Subcutâneas , Masculino , Microinjeções , Muscimol/farmacologia , NG-Nitroarginina Metil Éster/antagonistas & inibidores , Fenilisopropiladenosina/farmacologia , Núcleos da Rafe , RatosRESUMO
The effects of pindolol, melatonin, and the melatonin receptor agonist agomelatine were studied in rats implanted for chronic sleep procedures. Administration of pindolol (1.0-4.0 mg/kg) during the light phase induced a significant reduction of rapid-eye-movement sleep (REMS) and an increase of waking (W). In the rats recorded after receiving 1.0-6.0 mg/kg melatonin no significant differences were found in sleep or W compared with controls. Agomelatine (1.0-6.0 mg/kg) induced a significant increase of light sleep during the first 3 h of the recording period. Pretreatment with melatonin partly prevented the pindolol-induced suppression of REMS. However, agomelatine was ineffective in this respect. Overall, these data suggest that the decreased production of melatonin could play a role in REMS suppression related to pindolol administration.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Melatonina/metabolismo , Pindolol/farmacologia , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Acetamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Melatonina/farmacologia , Ratos , Ratos Wistar , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de MelatoninaRESUMO
Melatonin is synthesized and secreted during the dark period of the light-dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located in mammals within the suprachiasmatic nucleus (SCN), and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system that can 'read' the message. In addition, direct effects of the hormone on the SCN could explain some of the melatonin effects on the circadian system. Duration of the melatonin nocturnal secretion is directly proportional to the length of the night and it has experimentally been demonstrated to be the critical parameter for photoperiod integration. The sites and mechanisms of action of melatonin for circadian and photoperiodic responses are far from being elucidated, but action through specific membrane receptor sites starts to emerge. A possible bicompartmental model of distribution for melatonin, the first compartment in plasma acting on peripheral organs and the second in the cerebrospinal fluid affecting neurally mediated functions at a much higher concentration, has recently been proposed. From earlier studies it was concluded that melatonin administration to humans reduces sleep latency and induces sleepiness and fatigue. More recently, the effect of lower pharmacologic or physiologic doses of melatonin was examined in different laboratories. These studies included young normal volunteers and patients with chronic insomnia, as well as dementia patients exhibiting sundowning syndrome. Irrespective of the method of assessment, melatonin showed effects in insomniac patients in most studies. With some exceptions, melatonin administration reduced sleep latency and/or increased total sleep time and sleep efficiency. Furthermore, melatonin was more effective when given to elderly insomniacs, or Alzheimer disease patients, although sleep improvement was not strictly correlated with prior levels of the hormone.
Assuntos
Melatonina/farmacologia , Sono/efeitos dos fármacos , Adulto , Fatores Etários , Relógios Biológicos , Ritmo Circadiano , Demência , Humanos , Pessoa de Meia-Idade , Fotoperíodo , Distúrbios do Início e da Manutenção do SonoRESUMO
Cholinergic neurons in the laterodorsal (LDT) and the pedunculopontine (PPT) tegmental nuclei act to promote REM sleep (REMS). The predominantly glutamatergic neurons of the REMS-induction region of the medial pontine reticular formation are in turn activated by cholinergic cells, which results in the occurrence of tonic and phasic components of REMS. All these neurons are inhibited by serotonergic (5-HT), noradrenergic, and presumably histaminergic (H2 receptor) and dopaminergic (D2 and D3 receptor) cells. 5-Hydroxytryptamine-containing neurons in the dorsal raphe nucleus (DRN) virtually cease firing when an animal starts REMS, consequently decreasing the release of 5-HT during this state. The activation of GABA(A) receptors is apparently responsible for this phenomenon. Systemic administration of the selective 5-HT1A receptor agonist 8-OHDPAT induces dose-dependent effects; i.e. low doses increase slow wave sleep and reduce waking, whereas large doses increase waking and reduce slow wave sleep and REM sleep. Direct injection of 8-OHDPAT or flesinoxan, another 5-HT1A agonist into the DRN, or microdialysis perfusion of 8-OHDPAT into the DRN significantly increases REMS. On the other hand, infusion of 8-OHDPAT into the LDT selectively inhibits REMS, as does direct administration into the DRN of the 5-HT1A receptor antagonists pindolol or WAY 100635. Thus, presently available evidence indicates that selective activation of the somatodendritic 5-HT1A receptor in the DRN induces an increase of REMS. On the other hand, activation of the postsynaptic 5-HT1A receptor at the level of the PPT/LDT nuclei decreases REMS occurrence.
Assuntos
Núcleos da Rafe/fisiologia , Receptores de Serotonina/fisiologia , Sono REM/fisiologia , Eletrofisiologia , Humanos , Mesencéfalo/fisiologia , Neurônios/fisiologia , Receptores 5-HT1 de Serotonina , Formação Reticular/fisiologiaRESUMO
STUDY OBJECTIVE: The purpose of this study was 1) to assess the effect of zolpidem or a placebo on sleep in two groups of insomniac patients with a diagnosis of moderate-to-severe chronic primary insomnia and 2) to determine the effect of zolpidem on sleep structure using spectral analysis. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Sleep laboratory of the Department of Pharmacology and Therapeutics at the Clinics Hospital. PARTICIPANTS: 12 female outpatients with chronic primary insomnia. INTERVENTIONS: Zolpidem was given at a daily dose of 10 mg for 15 nights. RESULTS: The hypnotic drug reduced sleep latency and waking time after sleep onset, and increased total sleep time and sleep efficiency. Values corresponding to visually scored slow wave sleep (stage 3 and 4) showed no significant changes. All-night spectral analysis of the EEG revealed that power density in NREM sleep was significantly increased in the low frequency band (0.25-1.0 Hz) in the zolpidem group during the first 2-h interval. CONCLUSIONS: In agreement with previous findings obtained in patients with chronic primary insomnia, zolpidem significantly improved sleep induction and maintenance. Moreover, zolpidem increased power density in the 0.25-1.0 Hz band during short-term and intermediate-term treatment. Nevertheless, other frequency bands in the delta range showed a relative decrease which was not statistically significant.
Assuntos
Hipnóticos e Sedativos/uso terapêutico , Piridinas/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Sono/efeitos dos fármacos , Sono/fisiologia , Adulto , Análise de Variância , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Método Duplo-Cego , Eletroencefalografia , Feminino , Humanos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , ZolpidemRESUMO
The effects of the benzodiazepine1 (BZ1) receptor agonist SX-3228 were studied in rats (N = 12) implanted for chronic sleep procedures. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228, sc, to rats 1 h after the beginning of the light phase of the light-dark cycle induced a significant reduction of rapid-eye-movement sleep (REMS) during the third recording hour. Moreover, slow wave sleep (SWS) was increased during the fourth recording hour after the two largest doses of the compound. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228 one hour after the beginning of the dark period of the light-dark cycle caused a significant and maintained (6-h recording period) reduction of waking (W), whereas SWS and light sleep (LS) were increased. REMS values tended to increase during the entire recording period; however, the increase was statistically significant only for the 1.0 mg/kg dose during the first recording hour. In addition, a significant and dose-related increase of power density in the delta and the theta regions was found during nonREM sleep (LS and SWS) in the dark period. Our results indicate that SX-3228 is a potent hypnotic when given to the rat during the dark period of the light-dark cycle. Moreover, the sleep induced by SX-3228 during the dark phase closely resembles the physiological sleep of the rat.
Assuntos
Hipnóticos e Sedativos/farmacologia , Naftiridinas/farmacologia , Sono/efeitos dos fármacos , Animais , Escuridão , Iluminação , Ratos , Ratos Wistar , Sono REM/efeitos dos fármacos , CaminhadaRESUMO
The effects of the benzodiazepine1 (BZ1) receptor agonist SX-3228 were studied in rats (N = 12) implanted for chronic sleep procedures. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228, sc, to rats 1 h after the beginning of the light phase of the light-dark cycle induced a significant reduction of rapid-eye-movement sleep (REMS) during the third recording hour. Moreover, slow wave sleep (SWS) was increased during the fourth recording hour after the two largest doses of the compound. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228 one hour after the beginning of the dark period of the light-dark cycle caused a significant and maintained (6-h recording period) reduction of waking (W), whereas SWS and light sleep (LS) were increased. REMS values tended to increase during the entire recording period; however, the increase was statistically significant only for the 1.0 mg/kg dose during the first recording hour. In addition, a significant and dose-related increase of power density in the delta and the theta regions was found during nonREM sleep (LS and SWS) in the dark period. Our results indicate that SX-3228 is a potent hypnotic when given to the rat during the dark period of the light-dark cycle. Moreover, the sleep induced by SX-3228 during the dark phase closely resembles the physiological sleep of the rat
Assuntos
Animais , Ratos , Hipnóticos e Sedativos/farmacologia , Naftiridinas/farmacologia , Sono/efeitos dos fármacos , Escuridão , Iluminação , Ratos Wistar , Sono REM/efeitos dos fármacos , CaminhadaRESUMO
The effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of enzyme nitric oxide synthase (NOS), on spontaneous sleep during the light period, was studied in adult rats implanted for chronic sleep recordings. L-NAME was injected by subcutaneous (s.c.) or intracerebroventricular (i.c.v.) routes or was infused directly into the dorsal raphe nuclei (DRN). Subcutaneous (1.25-5.0 mg/kg) or i.c.v. (0.25-1.0 mg) administration of L-NAME increased waking (W) and reduced slow wave sleep (SWS) and rapid-eye-movement sleep (REMS) during the first 3 h of recording. On the other hand, direct application of L-NAME into the DRN (50.0-150.0 microg) induced an increment of W and a reduction of SWS without suppressing REMS. Values of W and SWS were significantly different compared with those of controls during the 6-h recording period. The effects of L-NAME observed after s.c. or i.c.v. administration confirm previous studies in rabbits and rats, in which the NOS inhibitor reduced sleep and increased W in a dose-dependent manner. It is possible that REMS suppression after L-NAME could be related to a reduction of acetylcholine release in areas critical for REMS promotion. A decrease in gamma-aminobutyric acid (GABA) release after nitric oxide synthesis inhibition could play a role in the reduction of SWS.
Assuntos
NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/fisiologia , Fases do Sono/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Injeções Subcutâneas , Masculino , Óxido Nítrico Sintase/fisiologia , Coelhos , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , Fases do Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Sono REM/fisiologiaRESUMO
Effects of the 5-HT3 receptor agonist, m-chlorophenylbiguanide (10.0-40.0 microg), on sleep and waking were studied in control, vehicle-treated and 6-hydroxydopamine-injected rats. Bilateral injections of m-chlorophenylbiguanide into the nucleus accumbens of the control and the vehicle-infused animals significantly increased waking and reduced slow wave sleep. Rapid eye movement sleep (REM sleep) remained unchanged. Pretreatment with the selective 5-HT3 receptor antagonist, MDL 72222 (1aH,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg, s.c.), reversed the effects of m-chlorophenylbiguanide (10.0-20.0 microg) on sleep and waking in the control group. Administration of the 5-HT3 receptor agonist to the 6-hydroxydopamine-treated animals modified only slightly the time spent in wakefulness and slow wave sleep, while REM sleep was significantly and dose dependently reduced. Our findings further support the proposal that increase of wakefulness and reduction of slow wave sleep after activation of 5-HT3 receptors, is partly related to the release of endogenous dopamine.
Assuntos
Biguanidas/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Oxidopamina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Adrenérgicos/farmacologia , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Injeções Intraventriculares , Masculino , Microinjeções , Núcleo Accumbens/fisiologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Fases do Sono/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Tropanos/farmacologiaRESUMO
The effect of 3-mg melatonin capsules p.o. on sleep in ten elderly patients suffering from chronic primary insomnia was assessed by polysomnographic recordings. In general, melatonin significantly reduced wake time after sleep onset and increased total sleep time and sleep efficiency during the 2-week treatment period. In five of the ten patients treated with melatonin, the increase in total sleep time was clinically significant. Side effects were absent during the period of drug administration. A slight increase of power density in the delta and the theta regions was found during the early phase (i.e. nights 4-5) of melatonin administration, whereas the opposite changes were observed at a late phase of treatment (i.e. nights 15-16). No strict correlation was found between prior 6-sulphatoxymelatonin levels in urine and subsequent sleep improvement after receiving melatonin. Our results further support the proposal that melatonin is beneficial for sleep disturbances in elderly insomniacs.
RESUMO
Quantitation of 2 h sessions after administration of the D3 preferring dopamine (DA) agonist pramipexole (10-500 microg/kg) showed dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 microg/kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 microg/kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 microg/kg dose during the second recording hour. The mixed D2- and D3 receptor antagonist YM-09151-2 (30-500 microg/kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500-1000 microg/kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 microg/kg dose of the DA agonist. Pramipexole (30-100 microg/kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 microg/kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 microg/kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D3 receptor could be involved in the pramipexole-induced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D2 receptor.
Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Neostriado/metabolismo , Receptores de Dopamina D2/agonistas , Tiazóis/farmacologia , Animais , Benzamidas/farmacologia , Benzotiazóis , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Pramipexol , Ratos , Ratos Wistar , Receptores de Dopamina D3 , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacosRESUMO
A double-blind trial was carried out to determine the effect of zolpidem or a placebo on sleep in two groups of insomniac patients with a diagnosis of moderate chronic primary insomnia. Zolpidem was given at a daily dose of 10 mg for 27 nights and was preceded (two nights) and followed (three nights) by a placebo. Zolpidem induced a significant increase of total sleep time, while total wake time and wake time after sleep onset were reduced. Values corresponding to stage 2 sleep were augmented, while stage 3 sleep and REM sleep showed no significant changes. Tolerance did not develop during the zolpidem administration period, and rebound insomnia did not show following abrupt interruption of drug administration. In addition, patients on zolpidem had a more peaceful sleep with no decrement of levels of alertness.
Assuntos
Hipnóticos e Sedativos/administração & dosagem , Piridinas/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Fatores de Tempo , ZolpidemRESUMO
The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings. BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS. It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis , Iminas/farmacologia , Fenóis/farmacologia , Piperidinas/farmacologia , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The effects of the 5-HT1B receptor agonist CP-94,253 were compared with those of the mixed beta-adrenoceptor and 5-HT1A/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-HT1B receptor together with other 5-HT receptor subtypes may have a direct regulatory action on sleep and waking in the rat.
Assuntos
Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Fases do Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Pindolol/farmacologia , Ratos , Ratos WistarRESUMO
A double blind cross-over design trial was carried out to investigate the effect of simultaneous administration of alcohol (0.5 g/kg) and ritanserin (10 mg) on biological and behavioral functioning. Twenty healthy volunteers were selected to participate in the study. To assess the effect of treatments the following evaluations were performed: psychomotor tests, vital signs, intoxication, euphoria, and mood. In addition, ritanserin and alcohol plasma concentration were measured. Psychomotor performance and vital signs during the ritanserin session did not differ significantly from the placebo session. Similar results were obtained in regard to alcohol intoxication, euphoria, and mood, except for tiredness and alertness, which were significantly different compared to placebo. Differences in blood alcohol concentration between the ritanserin and the placebo sessions did not attain significance. Plasma ritanserin concentration was 143 ng/ml 1 h after alcohol administration and decayed to 53 ng/ml 6 h after alcohol consumption in the active treatment session. Our findings tend to indicate that ritanserin neither enhances the central nervous system depressant effect of alcohol nor produces a pharmacokinetic interaction during acute alcohol ingestion.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Ritanserina/farmacologia , Adulto , Afeto/efeitos dos fármacos , Antidepressivos de Segunda Geração/sangue , Pressão Sanguínea/efeitos dos fármacos , Depressores do Sistema Nervoso Central/sangue , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Etanol/sangue , Euforia/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ritanserina/sangueRESUMO
The effects of partial 5-HT1A receptor agonists buspirone (0.010-4.0 mg/kg), ipsapirone (0.010-6.0 mg/kg), and gepirone (0.025-4.0 mg/kg) on sleep and waking were studied in vehicle-treated and 5,7-dihydroxytryptamine (5,7-DHT)-injected rats. 5,7-DHT-treated animals showed a marked and significant serotonin and 5-HIAA depletion in the raphe regions of the pons and upper brain stem, cerebral cortex, hippocampus, and striatum. Subcutaneous administration of the partial agonists to both the vehicle-infused and the 5,7-DHT-treated animals significantly increased waking (W) and reduced light sleep (LS), slow-wave sleep (SWS), and REM sleep (REMS). Pretreatment with (-)pindolol (2.0 mg/kg) reversed the effects of buspirone and gepirone on W and non-REM sleep (LS + SWS) whereas REMS remained suppressed. (-)-Pindolol failed to reverse the effects of ipsapirone on sleep and W. The present results tend to indicate that increased W after acute administration of buspirone, ipsapirone, or gepirone depends upon the activation of postsynaptic 5-HT1A receptors. The well-known anxiolytic action observed after chronic administration of the azapirones seems to be related to mechanisms other that these involved in their stimulant effect.
Assuntos
5,7-Di-Hidroxitriptamina/toxicidade , Antagonistas Adrenérgicos beta/farmacologia , Pindolol/farmacologia , Serotoninérgicos/toxicidade , Agonistas do Receptor de Serotonina/farmacologia , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Monoaminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Buspirona/farmacologia , Relação Dose-Resposta a Droga , Masculino , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Sono REM/efeitos dos fármacosRESUMO
Bilateral injection of the selective 5-HT3 receptor agonist m-chlorophenylbiguanide (5.0-40.0 micrograms) into the nucleus accumbens of the rat significantly increased waking and decreased slow wave sleep. Rapid eye movement (REM) sleep remained unchanged. Pretreatment with the 5-HT3 receptor antagonist MDL 72222 (1aH,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg s.c.) reversed the effects of m-chlorophenylbiguanide (10.0-20.0 micrograms) on sleep and waking. Blockade of the dopamine D1 or D2 receptor with (+)-SCH 23390 (0.25 mg/kg s.c.) or YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide) (0.5 mg/kg s.c.), respectively antagonized the increase of waking and reduction of slow wave sleep induced by m-chloro-phenylbiguanide (10.0 micrograms). Our results tend to indicate that the increase of wakefulness after injection of the selective 5-HT3 receptor agonist m-chlorophenylbiguanide into the nucleus accumbens is partly related to the release of endogenous dopamine. In addition, they suggest that concomitant stimulation of both accumbens dopamine D1 and D2 receptor-related mechanisms is a necessary prerequisite to increase wakefulness.
Assuntos
Biguanidas/farmacologia , Antagonistas de Dopamina/farmacologia , Núcleo Accumbens/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Vigília/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Benzazepinas/farmacologia , Biguanidas/administração & dosagem , Biguanidas/antagonistas & inibidores , Injeções , Masculino , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/administração & dosagem , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Tropanos/farmacologiaRESUMO
The effects of the selective histamine H1-receptor agonist, 2-(3-trifluoromethylphenyl)histamine, were studied in rats implanted with electrodes for chronic sleep recordings. 2-(3-Trifluoromethylphenyl)histamine (80-120 micrograms) injected into the left lateral ventricle increased wakefulness, whereas slow wave sleep was reduced. Pretreatment with pyrilamine (2.0 mg/kg) prevented the effects of the H1-receptor agonist on wakefulness and slow wave sleep. Our results further support the involvement of histamine in the modulation of the waking state.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Histamina/análogos & derivados , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Eletrodos Implantados , Histamina/administração & dosagem , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/administração & dosagem , Injeções Intraventriculares , Masculino , Pirilamina/farmacologia , Ratos , Ratos Wistar , Sono/efeitos dos fármacosRESUMO
In a parallel-group, placebo-controlled, polysomnographic study with randomization, the possible occurrence of rebound insomnia was evaluated in 24 patients suffering from moderate to severe chronic insomnia and receiving either triazolam 0.5 mg, zolpidem 10 mg, or placebo. Treatment duration was 27 nights, followed by three placebo-controlled withdrawal nights. Both drugs showed significant efficacy compared to placebo during the active treatment period. A trend toward tolerance was noted in the triazolam group but not in the zolpidem one. The increase in total sleep time in the zolpidem group was accompanied by an increase in the number of sleep cycles. When active treatment was discontinued, clear rebound insomnia was present in the triazolam group while it was not possible to observe any rebound in the placebo and zolpidem groups. Subjective feelings of the patients, which were assessed by means of visual analog scales, correlated well with polysomnographic data. Our findings tend to indicate that, even after long-term treatment, zolpidem does not induce rebound insomnia or daytime anxiety.