RESUMO
The discovery of a novel high-affinity and selective dopamine D4 receptor antagonist, L-745,870, and the results of clinical trials with this compound are reviewed. Despite several lines of evidence which suggest that a selective D4 receptor antagonist may be an effective antipsychotic agent with a lower propensity to induce extrapyramidal side-effects, L-745,870 was ineffective as an antipsychotic in humans.
Assuntos
Antipsicóticos/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2 , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Humanos , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Receptores de Dopamina D4 , Roedores , Esquizofrenia/fisiopatologiaRESUMO
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 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
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 putative D3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D3 receptors in vivo. Given that non-selective D2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 microg kg(-1), s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D3 receptor mediated response, the non-selective D2/3 receptor agonist apomorphine and the D3 preferring agonists 7-OH-DPAT and (-) quinpirole generalised to the cue whilst the D2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D1 selective agonist (+/-)-SKF 81297 and D1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent alpha-methyl-p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D3 receptor. Thus the 10-fold selective D2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists > 40 and > 100-fold selective for D3 receptors, failed to modify the response. These results suggest that presynaptic D2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D3 receptors in vivo.
Assuntos
Benzopiranos/farmacologia , Agonistas de Dopamina/farmacologia , Oxazinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Discriminação Psicológica , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D3RESUMO
Repeated daily administration to female rats of either an electroconvulsive shock (110 V, 1 sec) or desipramine (DMI; 5 mg/kg x 2) caused a progressive decrease in presynaptic alpha 2-adrenoceptor function assessed by the hypoactivity (sedation) response to clonidine (0.5 mg/kg). This reduction was maximal after approximately seven electroshocks or 8-12 days of injection of DMI. Daily administration of oestradiol (100 micrograms s.c.), starting one day prior to the commencement of administration of DMI or treatment with electroshock, markedly accelerated the onset of decreased hypoactivity responses to clonidine, but did not alter the maximum reduction induced by repeated injection of DMI or administration of electroshock. Injection of oestradiol alone had no effect on the responses to clonidine. Administration of DMI for 14 days decreased the number of both alpha 2- and beta-adrenoceptors in the cortex. Cortical beta-, but not alpha 2-adrenoceptors, were also decreased after 4 days of injection of DMI. Two and ten electroshocks moderately increased and decreased cortical alpha 2-adrenoceptors, respectively. beta-Adrenoceptors were also decreased by ten electroshocks, but two were without effect. Simultaneous administration of oestradiol had little influence on the changes in the binding of alpha 2- or beta-adrenoceptors induced by repeated administration of DMI or treatment with electroshock. Oestradiol increased the numbers of cortical alpha 2- and beta-adrenoceptors 3 and 15 days after injection, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Desipramina/farmacologia , Estradiol/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Clonidina/farmacologia , Desipramina/administração & dosagem , Eletroconvulsoterapia , Estradiol/administração & dosagem , Feminino , Injeções Intraperitoneais , Injeções Subcutâneas , RatosRESUMO
Repeated, daily administration of either an electroconvulsive shock (ECS; 110 V, 1 sec) or desipramine (DMI; 5 mg/kg X 2) to rats caused a progressive decrease in the function of presynaptic alpha 2-adrenoceptors, assessed by the hypoactivity (sedation) response to clonidine (0.2 mg/kg). This attenuation required approximately 7 days' administration of either treatment for maximum effect. A single injection of triiodothyronine (T3; 100 micrograms/kg) on day 1 of the treatment markedly accelerated the decreased responses to clonidine induced by DMI or electroconvulsive shock, but did not alter the maximum attenuation. By itself T3 did not affect the hypoactivity responses. alpha 2-Adrenoceptors, measured by the binding of [3H]idazoxan in the cortex, which are believed to be predominantly postsynaptic, were decreased by 14 days of DMI or electroconvulsive shock for 10 days, but not 2 days of either treatment. Triiodothyronine did not influence the decreased number of alpha 2-adrenoceptors induced by DMI or electroconvulsive shock but may have delayed the onset produced by DMI. Binding to beta-adrenoceptors in the cortex was measured using [3H]dihydroalprenolol. This was significantly decreased by 14 days administration of DMI, but not significantly by electroconvulsive shock for 10. Down-regulation of beta-adrenoceptors, induced by DMI was rapid, being observed after 1 day of treatment. Injection of T3 did not influence the final decreases produced by DMI or electroconvulsive shocks but moderately delayed their onset. Triiodothyronine alone caused a 25% reduction in cortical beta-adrenoceptors 24 hr after injection.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Encéfalo/efeitos dos fármacos , Desipramina/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Tri-Iodotironina/farmacologia , Animais , Clonidina/farmacologia , Di-Hidroalprenolol/metabolismo , Dioxanos/metabolismo , Eletrochoque , Idazoxano , Cinética , Masculino , Ratos , Ratos EndogâmicosRESUMO
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.
Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Dopamina/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sistema Límbico/efeitos dos fármacos , Fenciclidina/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Aminopiridinas/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Indóis/farmacologia , Sistema Límbico/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Estimulação QuímicaRESUMO
Studies of neurotransmitter release in guinea pig and human brain indicate that the 5-HT terminal autoreceptor is the 5-HT1D subtype and that it regulates the depolarization evoked release of 5-HT. Thus, blockade of the terminal 5-HT autoreceptor should enhance 5-HT release in vivo. In the present study, we have used the recently described, selective and potent 5-HT1D receptor antagonist, GR127935, to determine if blockade of the terminal 5-HT autoreceptor enhanced 5-HT neurotransmission in the guinea pig. Neurochemical studies showed that GR127935 (0.1, 0.3 and 1.0 mg/kg i.p.) significantly increased 5-HT metabolism in forebrain regions but not in the raphe nucleus of the guinea pig. However, using in vivo dialysis, GR127935 did not significantly increase cortical 5-HT efflux when given either systemically (1 and 5 mg/kg i.p.) or by infusion via the probe directly into the cortex (10, 33 and 100 microM). Fast cyclic voltammetry studies in the guinea pig dorsal raphe slice in vitro failed to observe any significant effects of GR127935 (0.01-1 microM) on electrically evoked 5-HT release. Behavioural studies in the guinea pig were also unable to demonstrate any effects of GR127935 (0.1-3.0 mg/kg i.p.) per se or in combination with the 5-HT precursor 5-hydroxytryptophan. Taken together, results from the present neurochemical and behavioral studies in the guinea pig provide little substantial evidence that blockade of the terminal 5-HT autoreceptor following the acute administration of GR127935 increased brain 5-HT neurotransmission in vivo.
Assuntos
Encéfalo/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Antagonistas da Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Discinesia Induzida por Medicamentos/etiologia , Estimulação Elétrica , Fluoxetina/farmacologia , Cobaias , Humanos , Técnicas In Vitro , Masculino , Metiotepina/farmacologia , Paroxetina/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Triptofano/metabolismoRESUMO
Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3 agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC) induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine. In the present study we examined the effects of the more potent mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine (DA) release in mPFC of male rats. Subjects were implanted with a unilateral microdialysis probe in the mPFC and were tested 12-24 h after implantation. Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA, although the glutamate response was slower in onset compared with DA. Pretreatment with either systemic (3 mg/kg s.c.) or local (1 microM, in the probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe) had no effect on glutamate release but did significantly enhance the release of DA. Application of NMDA (500 microM in the probe), on the other hand, decreased DA while increasing glutamate release. The effect of NMDA on evoking glutamate release was blocked by systemic but not local administration of LY379268. These findings indicate that systemic ketamine increases both glutamate and DA release in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group II mGluR receptors. Local ketamine, on the other hand, does not increase glutamate but does increase DA release. This suggests that ketamine acts outside of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The origin of the ketamine effect on mPFC glutamate is currently not known.
Assuntos
Aminoácidos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dopamina/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Ketamina/farmacologia , N-Metilaspartato/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Anestésicos Locais/farmacologia , Animais , Vias de Administração de Medicamentos , Interações Medicamentosas , Masculino , Microdiálise/métodos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Tetrodotoxina/farmacologia , Fatores de TempoRESUMO
1. The effect of intra-accumbens injection of histamine and related compounds on the spontaneous motor activity of the rat has been investigated. 2. Microinjections of histamine (1-200 micrograms) induced dose-dependent, biphasic changes in rat activity consisting of an initial brief hypoactivity response followed by a marked hyperactivity phase. The histamine metabolite, n-tele-methylhistamine was without effect. 3. Pretreatment with the H1-receptor antagonist mepyramine (10 micrograms) blocked the hypoactivity response and markedly attenuated histamine-induced hyperactivity. In contrast, pretreatment with the H2-receptor antagonist SKF93479 had no effect on histamine-induced behaviour. 4. Microinjection of the H1-receptor agonist 2-thiazolylethylamine induced a marked hyperactivity response, but unlike the response to histamine, there was no initial hypoactivity. The H2-receptor agonist dimaprit had no apparent behavioural effects following intra-accumbens injection. 5. Intra-accumbens injection of the non-selective histamine agonists n alpha-methylhistamine or n alpha, n alpha-dimethylhistamine induced both marked hypoactivity and hyperactivity responses which were comparable with the effects of histamine. 6. The present results demonstrate a histamine, H1-receptor-mediated arousal in the nucleus accumbens which follows transitory hypoactivity, possibly due to activation of presynaptic H3-receptors.
Assuntos
Histamina/farmacologia , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacos , Animais , Masculino , Metilistaminas/farmacologia , Atividade Motora/fisiologia , Núcleo Accumbens/fisiologia , Pirilamina/farmacologia , Ratos , Ratos Endogâmicos , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos/fisiologia , Tiazóis/farmacologiaRESUMO
1. The present study has investigated the effect of chronic intra-accumbens administration of the thyrotrophin-releasing hormone (TRH) analogue, CG3509, on CG3509- and histamine-induced spontaneous motor activity and brain TRH-like immunoreactive (TRH-LI) levels in the rat. 2. Chronic intra-accumbens administration of CG3509 (5 x 5 micrograms over 3 days) induced: (a) a significant (P less than 0.05) reduction in intra-accumbens CG3509 (0.5 micrograms)-induced hyperactivity, (b) reduced levels of TRH-LI in the nucleus accumbens but not other brain regions, (c) a marked increase (107%, P less than 0.01) in histamine-induced non-locomotor hyperactivity. 3. The present results demonstrate that alteration of central TRH function following treatment with a TRH analogue enhances the effect of intra-accumbens histamine on behavioural hyperactivity, possibly via changes in H1 receptors and suggest that the neuropeptide, TRH and histamine interact in behavioural arousal mechanisms in rat brain.
Assuntos
Comportamento Animal/efeitos dos fármacos , Histamina/farmacologia , Hormônio Liberador de Tireotropina/análogos & derivados , Animais , Química Encefálica/efeitos dos fármacos , Injeções , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens , Ratos , Ratos Endogâmicos , Hormônio Liberador de Tireotropina/administração & dosagem , Hormônio Liberador de Tireotropina/farmacologiaRESUMO
1. The effects of the glycine/NMDA receptor antagonist, (+)-HA-966 on the neurochemical and behavioural responses to amphetamine have been determined in the mouse and rat. 2. In vehicle-treated control mice, (+)-HA-966 (30-100 mg kg-1) did not affect dopamine synthesis in either the nucleus accumbens or striatum and was without marked effect on spontaneous locomotor activity. 3. In the mouse, (+)-HA-966 (30 and 100 mg kg-1) dose-dependently blocked the enhancement of dopamine synthesis induced in the nucleus accumbens by amphetamine, but was without effect on the increase in dopamine synthesis in the striatum. 4. Intracerebroventricular administration of the glycine/NMDA receptor antagonist, 5,7-dichlorokynurenic acid, in the mouse (10 micrograms) also significantly attenuated amphetamine-enhanced DOPA accumulation in the nucleus accumbens, but not in the striatum. 5. The decrease of dopamine synthesis in striatum and nucleus accumbens induced by the dopamine receptor agonist, apomorphine, was unaffected by (+)-HA-966 (100 mg kg-1). 6. (+)-HA-966 (30 mg kg-1) failed to attenuate the hyperactivity induced by the systemic administration of amphetamine in the mouse, but totally prevented the hyperlocomotion following infusion of amphetamine into the rat nucleus accumbens. In contrast, stereotyped behaviour induced by infusion of amphetamine into the rat striatum was not altered following pretreatment with (+)-HA-966 (30 mg kg-1). 7. The results are consistent with a selective facilitatory role of glycine/NMDA receptors on mesolimbic dopaminergic neurones.
Assuntos
Anfetamina/farmacologia , Dopamina/análise , Glicina/metabolismo , Pirrolidinonas/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de Neurotransmissores/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Di-Hidroxifenilalanina/análise , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de GlicinaRESUMO
1. The effects of the glycine/N-methyl-D-aspartate (NMDA) receptor antagonist, R-(+)-HA-966 on the neurochemical and behavioural responses to phencyclidine (PCP) and dizocilpine (MK-801) have been determined in rodents. 2. In rats, pretreatment with PCP (5 and 10 mg kg-1) or MK-801 (0.25 and 0.5 mg kg-1) dose-dependently stimulated dopamine turnover in nucleus accumbens, amygdala and medial prefrontal cortex, but had no effect in striatum. In contrast, pretreatment with (+)-HA-966 (10 and 30 mg kg-1) did not affect dopamine turnover in any brain region investigated. 3. Pretreatment with (+)-HA-966 (10 and 30 mg kg-1) significantly antagonized the stimulation of dopamine turnover induced by both PCP (10 mg kg-1) and MK-801 (0.5 mg kg-1) in rat nucleus accumbens, amygdala and medial prefrontal cortex. 4. Intracerebral dialysis studies in conscious rats demonstrated that systemic injection of PCP (10 mg kg-1) markedly stimulated dopamine release from the nucleus accumbens, an effect that was abolished by pretreatment with (+)-HA-966 (30 mg kg-1). 5. Pretreatment with PCP (3-30 mg kg-1) or MK-801 (0.1-1.6 mg kg-1) significantly increased locomotor activity in mice. In contrast, subcutaneous injection of (+)-HA-966 (10-100 mg kg-1) failed to stimulate activity. 6. Pretreatment with (+)-HA-966 (10 and 30 mg kg-1) dose-dependently antagonized both PCP (10 mg kg-1) and MK-801 (0.4 mg kg-1) induced hyperactivity in mice. 7. Blockade of PCP-induced hyperactivity by (+)-HA-966 is unlikely to be explained by the induction or potentiation of sedation/ataxia since PCP-induced rotarod deficits were not significantly different in mice pretreated with (+)-HA-966 (30 mg kg-1) or saline.8. The results demonstrate that (+ )-HA-966 antagonizes both the neurochemical and behavioural effects of PCP and MK-801, possibly through interactions at the glycine/NMDA receptor.
Assuntos
Maleato de Dizocilpina/antagonistas & inibidores , Dopamina/fisiologia , Sistema Límbico/efeitos dos fármacos , Fenciclidina/antagonistas & inibidores , Pirrolidinonas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Química Encefálica/efeitos dos fármacos , Diálise , Maleato de Dizocilpina/farmacologia , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Fenciclidina/farmacologia , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
1. The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L-687,414 (R(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one) have been investigated in rodents. 2. L-687,414 dose-dependently antagonized seizures induced by N-methyl-D,L- aspartic acid (NMDLA, ED50 = 19.7 mg kg-1), pentylenetetrazol (PTZ, ED50 = 13.0 mg kg-1) and electroshock (ED50 = 26.1 mg kg-1) when given intravenously 15 min before test, in male Swiss Webster mice but was most potent against audiogenic seizures induced by a 120 dB bell in DBA/2 mice (ED50 = 5.1 mg kg-1, i.p., 30 min before test). 3. L-687,414 also induced impairments of performance in a rotarod test in both Swiss Webster and DBA/2 mice and the ratio [rotarod MED:anticonvulsant ED50] varied between 0.9 and 5, depending on the convulsant used. 4. Similar behaviours to those seen after administration of the non-competitive NMDA receptor antagonist, MK-801 (head weaving, body rolling, hyperlocomotion) were seen in the mouse after giving L-687,414, although the peak effect occurred at a dose (100 mg kg-1) which was 5-20 times the anticonvulsant ED50S, depending on the convulsant used. Unlike MK-801, however, doses of L-687,414 that were behaviourally stimulant did not increase dopamine turnover in the nucleus accumbens. 5. Consistent with the interaction of L-687,414 with the glycine/NMDA receptor, the anticonvulsant, ataxic and motor stimulant effects of the compound were significantly attenuated by the glycine/NMDA receptor agonist, D-serine (10-100 micrograms per mouse, i.c.v.). 6. The results show that L-687,414 is a potent, orally active anticonvulsant with a more benign pharmacological profile than antagonists acting at the ion channel of the NMDA receptor complex. The compound is a useful tool with which to probe the functional role of the glycine co-agonist site in vivo.
Assuntos
Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Pirrolidinonas/farmacologia , Receptores de Glicina/agonistas , Receptores de N-Metil-D-Aspartato/agonistas , Animais , Maleato de Dizocilpina/farmacologia , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Atividade Motora/efeitos dos fármacos , Fenciclidina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Previous studies have demonstrated that the glycine/NMDA receptor antagonist, L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinolone) blocks the activation of mesolimbic dopamine systems induced following psychostimulant administration in the rat (Bristow et al. 1994). In the present study, pretreatment with L-701,324 also reversed the deficit in prepulse inhibition (PPI) observed in rats reared in social isolation after weaning. Given that PPI is also attenuated in schizophrenic patients and that isolation rearing induces both neurochemical and behavioural abnormalities suggestive of a physiologically induced state of dopaminergic hyperactivity, these results suggest that blockade of the glycine/NMDA receptor may offer a new strategy for the development of novel antipsychotic agents.
Assuntos
Quinolonas/farmacologia , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Isolamento SocialRESUMO
The in vivo pharmacological profiles of the selective tachykinin NK1 receptor agonists, [Sar9,Met(O2)11]substance P and GR 73632, were examined in gerbils. Both agonists induced a pronounced chromodacryorrhea following intravenous injection which was stereoselectively antagonised by the tachykinin NK1 receptor antagonist, CP-99,994, but not by its inactive enantiomer, CP-100,263, or the rat-selective tachykinin NK1 receptor antagonist, RP 67,580. In contrast, chromodacryorrhea was not observed following intravenous injection of the selective tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10), or the selective tachykinin NK3 receptor agonist, senktide. These results suggest that [Sar9,Met(O2)11]substance P-induced chromodacryorrhea results from activation of peripheral tachykinin NK1 receptors. Repetitive hind paw tapping was also observed in gerbils but only following intracerebroventricular injection of [Sar9,Met(O2)11]substance P or GR 73632. Furthermore, GR 73632-induced hind paw tapping was significantly attenuated by co-administration of the peptide tachykinin NK1 receptor antagonist, GR 82334, or intravenous injection of CP-99,994. Thus, in contrast to chromodacryorrhea, repetitive hind paw tapping may result from activation of central tachykinin NK1 receptors.
Assuntos
Comportamento Animal/efeitos dos fármacos , Glândula de Harder/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores da Neurocinina-1/efeitos dos fármacos , Substância P/análogos & derivados , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Gerbillinae , Glândula de Harder/metabolismo , Indóis/farmacologia , Injeções Intravenosas , Injeções Intraventriculares , Isoindóis , Masculino , Neurocinina A/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Piperidinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Substância P/administração & dosagem , Substância P/antagonistas & inibidores , Substância P/farmacologiaRESUMO
We have previously reported that the glycine/NMDA receptor antagonist, R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one), attenuates amphetamine-induced activation of mesocorticolimbic dopamine neurones. In the present study, the effects of the competitive NMDA receptor antagonists, CGS 19755 (cis-4-(phosphonomethyl)piperidine-2-carboxylic acid) and (+/-)-CPP ((+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) were examined in mice. In the absence of any neurochemical effects per se, both compounds (2 or 5 mg/kg) significantly attenuated amphetamine-induced 3,4-dihydroxyphenylalanine (DOPA) accumulation in the nucleus accumbens and striatum. Furthermore, amphetamine-induced hyperlocomotion was also antagonised following pretreatment with CGS 19755 (ED50 = 2.4 mg/kg) or (+/-)-CPP (ED50 = 5.8 mg/kg) at doses which did not impair spontaneous locomotor activity. Thus, in addition to blockade of the glycine modulatory site, competitive antagonism at the NMDA receptor also attenuates psychostimulant-induced activation of forebrain dopamine neurones.
Assuntos
Anfetamina/toxicidade , Atividade Motora/efeitos dos fármacos , Ácidos Pipecólicos/farmacologia , Piperazinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Ligação Competitiva , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Di-Hidroxifenilalanina/metabolismo , Interações Medicamentosas , Glicina/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismoRESUMO
The behavioural and biochemical profile of the sigma ligand and putative antipsychotic agent, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol) has been determined in the mouse and rat. In mice, pretreatment with BMY 14802 attenuated both amphetamine-induced hyperactivity and conditioned avoidance responding, consistent with its previously reported antipsychotic potential. In common with 5-HT1A receptor agonists or partial agonists, BMY 14802 induced (a) a dose-dependent hypothermia in mice; (b) aspects of the 5-HT behavioural syndrome in rats, (c) antagonised mescaline-induced head twitches in mice and (d) generalised to the 8-hydroxy-2-(di-n-propylamino)tetralin discriminative stimulus over the dose range of 3-15 mg/kg. BMY 14802 had appreciable affinity for the 5-HT1A receptor (pIC50 = 6.7 compared to 7.3 for sigma binding) and antagonised forskolin-stimulated adenylate cyclase activity with a pEC50 of 6.2, consistent with an agonist action at this receptor. The results support the involvement of 5-HT1A receptors, but not the sigma binding site, in the behavioural profile of BMY 14802.