RESUMO
There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success. In this review, we outline previous methods for identifying and validating novel targets for CNS drug discovery, and, cognizant of previous failures, we discuss potential new strategies that may improve the probability of success of developing novel treatments for CNS disorders.
Assuntos
Fármacos do Sistema Nervoso Central/administração & dosagem , Doenças do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas/métodos , Descoberta de Drogas/normas , Transtornos Mentais/tratamento farmacológico , Animais , Fármacos do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Modelos Animais , Reprodutibilidade dos TestesRESUMO
Considerable attention has focused on regulation of central tryptophan hydroxylase (TPH) activity and protein expression. At the time of these earlier studies, it was thought that there was a single central TPH isoform. However, with the recent identification of TPH2, it becomes important to distinguish between regulatory effects on the protein expression and activity of the two isoforms. We have generated a TPH2-specific polyclonal antiserum (TPH2-6361) to study regulation of TPH2 at the protein level and to examine the distribution of TPH2 expression in rodent and human brain. TPH2 immunoreactivity (IR) was detected throughout the raphe nuclei, in lateral hypothalamic nuclei and in the pineal body of rodent and human brain. In addition, a prominent TPH2-IR fiber network was found in the human median eminence. We recently reported that glucocorticoid treatment of C57/Bl6 mice for 4 days markedly decreased TPH2 messenger RNA levels in the raphe nuclei, whereas TPH1 mRNA was unaffected. The glucocorticoid-elicited inhibition of TPH2 gene expression was blocked by co-administration of the glucocorticoid receptor antagonist mifepristone (RU-486). Using TPH2-6361, we have extended these findings to show a dose-dependent decrease in raphe TPH2 protein levels in response to 4 days of treatment with dexamethasone; this effect was blocked by co-administration of mifepristone. Moreover, the glucocorticoid-elicited inhibition of TPH2 was functionally significant: serotonin synthesis was significantly reduced in the frontal cortex of glucocorticoid-treated mice, an effect that was blocked by mifepristone co-administration. This study provides further evidence for the glucocorticoid regulation of serotonin biosynthesis via inhibition of TPH2 expression, and suggest that elevated glucocorticoid levels may be relevant to the etiology of psychiatric diseases, such as depression, where hypothalamic-pituitary-adrenal axis dysregulation has been documented.
Assuntos
5-Hidroxitriptofano/biossíntese , Dexametasona/análogos & derivados , Lobo Frontal/química , Proteínas do Tecido Nervoso/biossíntese , Núcleos da Rafe/enzimologia , Triptofano Hidroxilase/análise , Triptofano Hidroxilase/biossíntese , 5-Hidroxitriptofano/análise , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Dexametasona/farmacologia , Indução Enzimática/efeitos dos fármacos , Feminino , Lobo Frontal/efeitos dos fármacos , Humanos , Soros Imunes , Camundongos , Camundongos Endogâmicos C57BL , Mifepristona/farmacologia , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Ovariectomia , Fragmentos de Peptídeos/imunologia , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Mensageiro/biossíntese , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/imunologiaRESUMO
Caffeine is known to disrupt sleep and its administration to human subjects has been used to model sleep disruption. We previously showed that its effects on sleep onset latency are comparable between rats and humans. This study evaluated the potential use of caffeine as a model of sleep disruption in the rat, by assessing its effects on sleep architecture and electroencephalogram (EEG) frequency spectrum, and using sleep-promoting drugs to reverse these effects. Rats were implanted with radiotelemetry devices for body temperature, EEG, electromyogram and locomotor activity. Following recovery, animals were dosed with caffeine (10 mg/kg) alone or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg). Sleep was scored for the subsequent 12 h using automated analysis software. Caffeine dose-dependently disrupted sleep: it increased WAKE time, decreased NREM (non-REM) sleep time and NREM bout duration (but not bout number), and decreased delta activity in NREM sleep. It also dose-dependently increased locomotor activity and body temperature. When given alone, zolpidem suppressed REM whilst trazodone increased NREM sleep time at the expense of WAKE, increased NREM bout duration, increased delta activity in NREM sleep and reduced body temperature. In combination, zolpidem attenuated caffeine's effects on WAKE, whilst trazodone attenuated its effects on NREM sleep, NREM bout duration, delta activity, body temperature and locomotor activity. Caffeine administration produced many of the signs of insomnia that were improved by two of its most successful current treatments. This model may therefore be useful in the study of new drugs for the treatment of sleep disturbance.
Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Sono/efeitos dos fármacos , Animais , Temperatura Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Eletromiografia , Hipnóticos e Sedativos/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Telemetria , Trazodona/farmacologia , ZolpidemRESUMO
Caffeine is the world's most popular stimulant and is known to disrupt sleep. Administration of caffeine can therefore be used in healthy volunteers to mimic the effects of insomnia and thus to test the hypnotic effects of medication. This study assessed the effects of caffeine on sleep architecture and electroencephalography (EEG) spectrum alone and in combination with two different sleep-promoting medications. Home polysomnography was performed in 12 healthy male volunteers in a double-blind study whereby subjects received placebo, caffeine (150 mg), caffeine plus zolpidem (10 mg) and caffeine plus trazodone (100 mg) at bedtime in a randomised crossover design. In addition to delaying sleep onset, caffeine decreased total sleep time (TST), sleep efficiency (SE) and stage 2 sleep without significantly altering wake after sleep onset or the number of awakenings. Zolpidem attenuated the caffeine-induced decrease in SE and increased spindle density in the caffeine plus zolpidem combination compared with placebo. Trazodone attenuated the decrease in SE and TST, and it also increased stage 3 sleep, decreased the number of awakenings and decreased the spindle density. No significant changes in rapid eye movement (REM) sleep were observed, neither was any significant alteration in slow wave activity nor other EEG spectral measures, although the direction of change was similar to that previously reported for caffeine and appeared to 'normalise' after trazodone. These data suggest that caffeine mimics some, but not all of the sleep disruption seen in insomnia and that its disruptive effects are differentially attenuated by the actions of sleep-promoting compounds with distinct mechanisms of action.
Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Hipnóticos e Sedativos/farmacologia , Fases do Sono/efeitos dos fármacos , Adulto , Estudos Cross-Over , Método Duplo-Cego , Eletroencefalografia , Humanos , Masculino , Polissonografia , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Trazodona/farmacologia , Adulto Jovem , ZolpidemRESUMO
RATIONALE: Tiagabine is an anticonvulsant drug which may also have sleep-enhancing properties. It acts by inhibiting reuptake at the gamma-aminobutyric acid (GABA) transporter (GAT-1). OBJECTIVES: The aim of the study was to determine whether tiagabine acted as a discriminative stimulus and, if so, whether other GABAergic compounds would generalise to it. MATERIALS AND METHODS: Rats were trained to discriminate tiagabine (30 mg/kg p.o.) from vehicle, and generalisation to drugs that modulate GABA was assessed. RESULTS: Gaboxadol (5-20 mg/kg p.o.), a selective extrasynaptic GABA A agonist, generalised to tiagabine, although the extent of the generalisation was inconclusive. Indiplon (1 mg/kg p.o.), a benzodiazepine-like hypnotic, also partially generalised to tiagabine, although zolpidem and S-zopiclone did not. Baclofen, a GABA B receptor agonist, and gabapentin, which increases synaptic GABA, did not generalise to tiagabine. (+)-Bicuculline (3 mg/kg i.p.), a GABA A receptor antagonist, blocked the tiagabine cue, but the less brain-penetrant salt form, bicuculline methochloride, had no effect. CONCLUSIONS: These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested.
Assuntos
Anticonvulsivantes/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , GABAérgicos/farmacologia , Ácidos Nipecóticos/farmacologia , Administração Oral , Aminas/farmacologia , Animais , Compostos Azabicíclicos/farmacologia , Baclofeno/farmacologia , Benzodiazepinas/farmacologia , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Encéfalo/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA/efeitos dos fármacos , Gabapentina , Generalização do Estímulo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Injeções Intraperitoneais , Isoxazóis/farmacologia , Masculino , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Tiofenos/farmacologia , Tiagabina , Zolpidem , Ácido gama-Aminobutírico/farmacologiaRESUMO
The NMDA receptor co-agonists D-serine and glycine are thought to contribute to glutamatergic dysfunction in schizophrenia. They are removed from the synapse by specific neuronal and glial transporters, the status of which is clearly relevant to theories of D-serine and glycine function in the disorder. D-serine is primarily transported by Asc-1, and glycine by GlyT1 but maybe also by SNAT2. As a first step to addressing this issue, we studied Asc-1, GlyT1 and SNAT2 expression in dorsolateral prefrontal cortex and cerebellum of 18 subjects with schizophrenia and 20 controls, using immunoblotting and in situ hybridization. Asc-1 protein and SNAT2 mRNA were decreased in schizophrenia in both regions. GlyT1 mRNA and protein, and Asc-1 mRNA, were not altered. Antipsychotic administration for 14 days did not alter expression of the genes in rat brain. Unchanged GlyT1 suggests that glycine transport is not markedly affected in schizophrenia, and therefore that increased synaptic removal is not the basis for the putative deficit in glycine modulation of NMDA receptors in the disorder. Lowered Asc-1 in schizophrenia implies that D-serine reuptake is reduced, perhaps as a response to decreased synaptic D-serine availability. However, this interpretation remains speculative. Further investigations will be valuable in the evaluation of these transporters as potential therapeutic targets in psychosis.
Assuntos
Cerebelo/metabolismo , Glutamatos/fisiologia , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Glicina/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/fisiopatologia , Serina/metabolismo , Sistema A de Transporte de Aminoácidos/genética , Sistema A de Transporte de Aminoácidos/metabolismo , Animais , Antipsicóticos/farmacologia , Western Blotting , Grupos Controle , Feminino , Expressão Gênica/efeitos dos fármacos , Glutamatos/genética , Glutamatos/metabolismo , Glicina/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Serina/genética , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
Gaboxadol is a selective extrasynaptic GABA(A) receptor agonist (SEGA) which enhances slow-wave sleep, and may act principally at extrasynaptic GABA(A)alpha4betadelta receptors. Drug discrimination is a very useful approach for exploring in vivo pharmacological similarities and differences between compounds and was therefore used to compare gaboxadol and zolpidem, an established hypnotic drug, against zopiclone, S-zopiclone, indiplon and tiagabine, all of which have been reported to enhance sleep. Gaboxadol generalised to itself, but not to zolpidem, zopiclone, S-zopiclone, R-zopiclone, indiplon or tiagabine. By contrast, zolpidem generalised to itself, zopiclone, S-zopiclone and indiplon, but not to R-zopiclone (the inactive enantiomer of zopiclone), gaboxadol or tiagabine. This suggests that zolpidem, zopiclone, S-zopiclone and indiplon share a discriminative stimulus, which may be mediated by their efficacy at GABA(A)alpha1betagamma receptors. Gaboxadol and tiagabine each have a different discriminative stimulus from all the other drugs tested.
Assuntos
Aprendizagem por Discriminação/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Generalização Psicológica/efeitos dos fármacos , Isoxazóis/farmacologia , Sono/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Interações Medicamentosas , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Beta3 adrenoceptor agonists show an antidepressant-like profile in preclinical rodent assays and improve mood in clinically-obese patients. These observations suggest a possible antidepressant utility for beta3 adrenoceptor agonists. The present study examined the effects of acute and chronic administration of the beta3 adrenoceptor agonist CL 316243 on two physiological indicators of antidepressant activity in the rat: hypothalamic 5-HT synthesis and suppression of REM sleep. 5-HT synthesis was estimated by the accumulation of 5-hydroxytryptophan (5-HTP) after treatment with the L-aromatic acid decarboxylase inhibitor NSD 1015. Sleep-wake patterns were monitored using electroencephalogram and electromyogram signals collected by radiotelemetry. Rats were administered CL 316243 acutely or once daily for 11 days. Acute administration of CL 316243 significantly increased hypothalamic 5-HT synthesis, as indicated by increased levels of 5-HTP, and reduced the amount of REM sleep. However, chronic administration produced no changes in 5-HTP or REM compared with vehicle treatment. The present observations suggest that acute administration of CL 316243 causes antidepressant-like effects on REM sleep, possibly mediated by increased central 5-HT synthesis. However, these effects are not maintained with repeated dosing.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacologia , Antidepressivos/farmacologia , Dioxóis/farmacologia , Hipotálamo/efeitos dos fármacos , Serotonina/biossíntese , Sono REM/efeitos dos fármacos , 5-Hidroxitriptofano/biossíntese , Animais , Inibidores das Descarboxilases de Aminoácidos Aromáticos , Descarboxilases de Aminoácido-L-Aromático/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Hipotálamo/enzimologia , Hipotálamo/metabolismo , Masculino , Ratos , Receptores Adrenérgicos beta 3/metabolismo , Fatores de Tempo , Vigília/efeitos dos fármacosRESUMO
(2S)-2-{[(3,5-Diflurophenyl)acetyl]amino}-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide (compound E) is a gamma-secretase inhibitor capable of reducing amyloid beta-peptide (1-40) and amyloid beta-peptide (1-42) levels. In this study we investigated the effect of in vivo administration of compound E on guinea-pig plasma, CSF and cortical amyloid beta-peptide (1-40) concentration. Using repeated sampling of CSF, compound E (30 mg/kg p.o.) was shown to cause a time-dependent decrease in CSF amyloid beta-peptide (1-40) levels, which was maximal at 3 h (70% inhibition), compared to baseline controls. After 3 h administration, compound E (3, 10 and 30 mg/kg p.o.), reduced plasma, CSF and DEA-extracted cortical amyloid beta-peptide (1-40) levels by 95, 97 and 99%; 26, 48 and 78%; 32, 33, and 47%, respectively, compared to vehicle control values. In the same animals, compound E (3, 10 and 30 mg/kg p.o.) inhibited cortical gamma-secretase activity, determined ex vivo using the recombinant substrate C100Flag, by 40, 71 and 79% of controls, respectively. These data demonstrate the value of determining not only the extent by which systemic administration of a gamma-secretase inhibitor reduces amyloid beta-peptide, but also the inhibition of brain gamma-secretase activity, as a more direct estimate of enzyme occupancy.
Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Inibidores de Proteases/administração & dosagem , Administração Oral , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/metabolismo , Animais , Arsenicais/administração & dosagem , Bisbenzimidazol/administração & dosagem , Bisbenzimidazol/análogos & derivados , Relação Dose-Resposta a Droga , Endopeptidases , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Cobaias , Masculino , Fragmentos de Peptídeos/metabolismoRESUMO
The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Receptores de Serotonina/genética , Antagonistas da Serotonina/uso terapêutico , Animais , Marcação de Genes/métodos , Imobilização/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Receptores de Serotonina/deficiência , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
The subcutaneous injection of 0.1 mg/kg apomorphine induced a syndrome consisting of yawning, chewing and sexual arousal in male rats. Bilateral lesions of the striatum induced with 6-hydroxydopamine abolished the drug-induced yawning, chewing and sexual arousal and produced a 58% depletion of the concentrations of dopamine in the striatum. These data suggest that apomorphine-induced yawning is mediated by presynaptic dopamine receptors (which may be autoreceptors). Furthermore, it appears that dopaminergic innervation of the striatum may play an important role in the production of yawning elicited by small doses of dopamine agonists.
Assuntos
Apomorfina/antagonistas & inibidores , Corpo Estriado/fisiologia , Hidroxidopaminas/farmacologia , Reflexo/efeitos dos fármacos , Animais , Desipramina/farmacologia , Masculino , Oxidopamina , Ratos , Ratos EndogâmicosRESUMO
Intracerebral dialysis was used to monitor the change of extracellular concentration of striatal cAMP in rats anaesthetised with chloral hydrate. Forskolin (1-10 microM), an activator of adenylate cyclase, caused a concentration-dependent increase in efflux of cAMP, which was decreased by (+)PHNO (10 microM), an effect probably mediated by D2 sites, since (-)-sulpiride, a D2 receptor antagonist prevented these effects. Dopamine (1-100 microM) also increased the efflux of cAMP but only when the activity of monoamine oxidase and reuptake of dopamine were concomitantly blocked. The D1 receptor agonist SKF 38393 (1-100 microM) caused a concentration-dependent increase in efflux of cAMP, which was blocked by the D1 receptor antagonist SCH 23390 (1-100 microM), but was unaffected by the D2 receptor antagonist sulpiride (10 microM) or by depletion of the concentration of striatal dopamine after pretreatment with 6-hydroxydopamine. Taken together, these results indicate that intracerebral dialysis may be used to monitor the interaction of drugs with post-synaptic dopamine receptors in vivo.
Assuntos
Colforsina/farmacologia , Corpo Estriado/metabolismo , AMP Cíclico/metabolismo , Receptores Dopaminérgicos/metabolismo , Animais , Benzazepinas/farmacologia , Desipramina/farmacologia , Dopaminérgicos/farmacologia , Hidroxidopaminas/farmacologia , Cinética , Masculino , Oxazinas/farmacologia , Oxidopamina , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/efeitos dos fármacos , Sulpirida/farmacologia , Sinapses/fisiologiaRESUMO
Exposure to footshock (1 mA) for 30 sec induced a marked analgesia that was enhanced by pretreatment with the 5HT synthesis inhibitor, p-chlorophenylalanine, and attenuated by the 5HT releasing drugs p-chloroamphetamine and fenfluramine, by the 5HT re-uptake inhibitor, fluoxetine and by the 5HT agonists, 5-methoxy-N,N-dimethyltryptamine and MK212. However, agonists, quipazine and trifluoromethylphenylpiperazine, with greater reported affinities for 5HT binding sites on rat brain membranes than MK212 were without effect as were the antagonists metergoline, methysergide, cyproheptadine, mianserine and methiothepin. The specific opioid antagonist naloxone was also without effect. The results in general indicate that analgesia induced by brief footshock (1 mA, 30 sec) is inversely related to 5HT availability but there is little evidence of involvement of known 5HT receptors.
Assuntos
Analgesia , Naloxona/farmacologia , Dor/fisiopatologia , Antagonistas da Serotonina/farmacologia , Serotonina/farmacologia , Animais , Eletrochoque , Masculino , Nociceptores/efeitos dos fármacos , Dor/tratamento farmacológico , Ratos , Ratos Endogâmicos , Receptores de Serotonina/efeitos dos fármacosRESUMO
Analgesia was determined in rats by a standard procedure in which the time taken to withdraw the tail from water at 51 degrees C was noted. The analgesic responses resulting from footshock applied for 30 sec and 30 min showed marked differences in pharmacological profile and in the dependence on experimental conditions. Thus, analgesia induced by footshock applied for 30 sec was enhanced when 5-HT in the brain was decreased by injection of p-chlorophenylalanine (PCPA), was unaffected by naloxone and was dependent on pre-exposure to the test-procedure for analgesia. In contrast analgesia induced by footshock applied for 30 min was attenuated by injection of PCPA and naloxone but was not dependent on pre-exposure to the analgesia test. It is suggested that the analgesia induced by footshock applied for 30 sec and 30 min reflects distinct mechanisms and that, in the former case, the animal behaves as if the shock occurred as a consequence of its motor response to the noxious heat applied during the pre-shock determination of analgesia.
Assuntos
Analgesia , Fenclonina/farmacologia , Naloxona/farmacologia , Serotonina/fisiologia , Animais , Eletrochoque , Masculino , Ratos , Ratos Endogâmicos , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
The present study has examined the glycine/N-methyl-D-aspartate (NMDA) receptor antagonist, R-(+)-3-amino-1-hydroxypyrrolid-2-one (R-(+)-HA-966) and the competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) on the behavioural syndrome and increased hipppocampal acetylcholine efflux induced during morphine-withdrawal in the rat. Subcutaneous naltrexone (1 mg/kg) injection, 48 hr after implantation of a 75 mg morphine pellet, induced a robust withdrawal syndrome consisting of wet dog shakes, ejaculations, mouth movement, ptosis, irritability to touch and diarrhoea. Pretreatment with the alpha2-adrenoceptor agonist, clonidine (0.1-0.4 mg/kg), R-(+)-HA-966 (10-60 mg/kg) or CGS 19755 (5 or 10 mg/kg) significantly reduced the incidence of withdrawal behaviours. In addition, all three compounds significantly attenuated the increase in hippocampal acetylcholine efflux induced following naltrexone (1 mg/kg, s.c.) injection in morphine-dependent rats. These results provide further evidence demonstrating that NMDA receptor antagonists attenuate both the behavioural and neurochemical effects observed during morphine withdrawal in the rat.
Assuntos
Acetilcolina/metabolismo , Hipocampo/metabolismo , Dependência de Morfina/metabolismo , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Clonidina/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Microdiálise , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ácidos Pipecólicos/farmacologia , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
This study examined the long-term change in serotonergic (5-hydroxytryptamine, 5-HT) neuronal function and 5-HT(2C) receptor agonist-induced behaviour following treatment of young rats with 3,4-methylenedioxymethamphetamine (MDMA). On post-natal day (PND) 28, Lister-hooded rats received either MDMA (15 mg/kg i.p.) or saline (1 ml/kg i.p.) twice daily for 3 days. On PND 50 social interaction was assessed between treatment-matched pairs of rats derived from separate litters. The effect of either the 5-HT(2C) receptor agonist, m-chlorophenylpiperazine (m-CPP, 2.5 or 1 mg/kg i.p., respectively) or saline was examined on open-field exploration (PND 52) and elevated plus-maze behaviour (PND 56). Acutely, MDMA produced hyperlocomotion and hypothermia compared with saline injection (p<0.001). Following 20 days abstinence, social interaction was decreased by 26% (p<0.05) in MDMA pre-treated rats compared with saline controls, without any change in locomotion. There was no difference in open-field or elevated plus-maze behaviour between pre-treatment groups. m-CPP caused hypolocomotion in the open-field and decreased both the percentage entries into, and time spent in, the open arms of the elevated plus-maze to a comparable extent in MDMA and saline pre-treated rats. Hippocampal and frontal cortical 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were significantly reduced in MDMA pre-treated rats, without any change in [(3)H]paroxetine binding or plasma corticosterone levels. These data suggest that the MDMA-induced reduction in social interaction is not mediated via alteration of 5-HT(2C) receptor function.
Assuntos
N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Receptores de Serotonina/efeitos dos fármacos , Serotoninérgicos/efeitos adversos , Comportamento Social , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corticosterona/sangue , Comportamento Exploratório/efeitos dos fármacos , Ácido Hidroxi-Indolacético/metabolismo , Hipotermia/induzido quimicamente , Técnicas In Vitro , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Paroxetina/metabolismo , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT2C de Serotonina , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
As cerebrospinal fluid (CSF) possesses unique characteristics in order to explore concentration-pharmacological response relationships of drugs active in the CNS, the practicability of serial sampling of CSF was tested in a study with heptabarbital. Concentrations in CSF and plasma were measured simultaneously in individual rats during and after an intravenous infusion for 30 min. At the end of the infusion, the distribution equilibrium was attained with a CSF/plasma concentration ratio of 0.38, roughly equal to the fraction unbound to protein. When concentrations in blood and CSF were determined at the onset and offset of loss of righting reflex concentrations in blood were significantly greater at onset (146 +/- 19 mg/l) than at offset (108 +/- 16 mg/l, n = 6), whereas concentrations in CSF were identical (39 +/- 5 and 38 +/- 5 mg/l, respectively). This confirmed the earlier observation that the CSF is pharmacokinetically indistinguishable from the site of action. When the duration of the loss of righting reflex was varied, concentrations of heptabarbital in CSF at onset and offset were similar, independent of the duration of the loss of righting reflex (1-5 hr). These findings demonstrate the absence of the development of acute tolerance and confirmed that no (inter)active metabolites interfered with the pharmacological response. In a total number of 26 rats the concentrations in CSF at onset and offset of loss of the righting reflex were compared. The interindividual variation was 13-15% and the intra-individual variation was only 4-6%. The results demonstrate the usefulness of serial sampling of CSF in pharmacodynamic studies with centrally acting drugs.
Assuntos
Barbitúricos/líquido cefalorraquidiano , Reflexo/efeitos dos fármacos , Animais , Barbitúricos/farmacologia , Feminino , Meia-Vida , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
Both pre-clinical and clinical studies suggest that additional treatment with 5-HT(1A) receptor antagonists may accelerate the antidepressant efficacy/onset of selective serotonin re-uptake inhibitors (SSRIs). Given that chronic SSRI treatment has been shown to desensitise 5-HT(2C) receptor mediated responses, we have used the rat social interaction test to determine if combined treatment with WAY 100,635, a selective 5-HT(1A) receptor antagonist, will accelerate this effect. In pairs of unfamiliar rats, acute administration of the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP) or fluoxetine decreased the time spent in social interaction, responses which were reversed by the 5-HT(2C/2B) receptor antagonists SB 200646A and SB 221284. Similar reductions in social interaction were observed in rats treated with fluoxetine (10 mg/kg, i.p. daily) for 4, 7 and 14 days but was no longer apparent after 28 days of treatment. In contrast, only 7 days of combined treatment with WAY 100,635 (1 mg/kg/s.c./day) and fluoxetine were needed to reverse this response. The decrease in social interaction induced by an acute challenge of mCPP (1 mg/kg, i. p.) was also reduced after 6 days co-treatment with WAY 100,635 and fluoxetine. Thus, WAY 100,635 accelerates SSRI-induced desensitisation of 5-HT(2C) receptors, suggesting that this response might contribute towards the therapeutic effects of SSRIs in man.
Assuntos
Fluoxetina/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Indóis/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina , Receptores 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Comportamento Social , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
The functional relevance of the dopamine D3 receptor is still unresolved, largely because of the absence of selective D3 receptor ligands. In the present study we have examined the in vivo profile of (+)-PD 128907, a potent and functionally selective D3 receptor agonist. Low doses of (+)-PD 128907 reduced spontaneous locomotor activity in the rat (ED50 = 13 +/- 3 micrograms/kg, s.c.) a response which was comparable with the non-selective D2,3 receptor agonist apomorphine (ED50 = 13 +/- 1.6 micrograms/kg, s.c.). In addition (+)-PD 128907 impaired prepulse inhibition of the acoustic startle response, with significant effects observed at doses of 30 micrograms/kg when appropriate prepulse intensities were used. Higher doses reversed gamma-butyrolactone-induced catecholamine synthesis (ED50 = 95 +/- 22 and 207 +/- 37 micrograms/kg in accumbens and striatum respectively) and induced yawning (100-300 micrograms/kg), penile grooming (30-1000 micrograms/kg) and sniffing (> or = 300 micrograms/kg) although doses 3- to 10-fold greater than apomorphine were required to produce maximal effects. In contrast to apomorphine, however, (+)-PD 128907 failed to induce intense stereotyped licking and biting in the rat. In view of the potency and selectivity of (+)-PD 128907 for the D3 receptor, a role in the control of locomotor activity is suggested. In addition, the observation that (+)-PD 128907 disrupts prepulse inhibition, a phenomenon which is also impaired in schizophrenic subjects, may indicate the pathological importance of this receptor subtype.
Assuntos
Comportamento Animal/efeitos dos fármacos , Benzopiranos/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Di-Hidroxifenilalanina/metabolismo , Agonistas de Dopamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Oxazinas/farmacologia , 4-Butirolactona/farmacologia , Animais , Apomorfina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Administration of the non-competitive NMDA receptor antagonists phencyclidine (PCP) (0.6-5 mg/kg s.c.) and MK-801 (0.1-0.8 mg/kg s.c. ) dose-dependently increased locomotor activity in the rat. Pre-treatment of rats with SB 221284 (0.1-1 mg/kg, i.p.) a 5-HT(2C/2B) receptor antagonist or SB 242084 (1 mg/kg, i.p.) a selective 5-HT(2C) receptor antagonist, doses shown to block mCPP induced hypolocomotion, significantly enhanced the hyperactivity induced by PCP or MK-801. Neither compound altered locomotor activity when administered alone. Furthermore, systemic administration of PCP (5 mg/kg s.c.) increased nucleus accumbens dopamine efflux in the rat to a maximum of approximately 220% of basal, 40-60 min after administration. Pre-treatment with the 5-HT(2C/2B) receptor antagonist SB 221284 (1 mg/kg, i.p.) and the 5-HT(2C) receptor antagonist SB 242084 (1 mg/kg i.p.) failed to affect nucleus accumbens dopamine efflux per se but significantly enhanced the magnitude and duration of the increase induced by PCP. However, the time course of the neurochemical and behavioural effects were qualitatively and quantitatively different, suggesting the potential involvement of other neurotransmitter pathways. Nevertheless, the present results provide behavioural and neurochemical evidence which demonstrate that, in the absence of effects per se, blockade of 5-HT(2C) receptors enhanced the activation of mesolimbic dopamine neuronal function by the non-competitive NMDA receptor antagonists PCP and MK-801.