ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Generation of receptor knockout mice has offered a new approach to study processes underlying anxiety. In this paper, studies focusing on anxiety using 5-HT1Areceptor knockout (1AKO) and 5-HT1Breceptor knockout (1BKO) mice are reviewed. 1AKO mice on different genetic background strains have initially been described as more anxious. In 1AKO mice on the 129/Sv background strain, the initial findings could not always be replicated, although under certain conditions, mild anxiety-like responses were observed in these 1AKO mice. In 1BKO mice, some indications of reduced anxiety have been found, but these observations may be confounded partly with increased motor impulsivity of these mutants. To study whether the putative effects of the null mutations on anxiety were reflected in the autonomic nervous system, basal heart rate and body temperature of 1AKO and 1BKO mice were measured, as well as their autonomic responses to novel cage exposure and to reversal of the light–dark rhythm. 1AKO mice did not differ from wild-type mice in any parameter, neither under non-stress conditions, nor following novel cage exposure. In 1BKO mice, basal heart rate was reduced and body temperature was increased. 1BKO mice showed exaggerated autonomic responses to novel cage stress. Adaptation to the reversal of the light–dark cycle was comparable in the three genotypes. The stress-induced hyperthermia procedure showed no differential responses of the three genotypes to the stressor. Pharmacological responses to various psychotropic drugs in the stress-induced hyperthermia test were also comparable in 1AKO, 1BKO and wild-type mice. The present data illustrate the complexity of studying the behavioural and physiological consequences of deletion of genes coding for important receptors in the CNS.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Clinically effective antidepressant drugs have been available for many years but our understanding of how these drugs bring about their therapeutic effects, and how to develop more diverse, better treatments has progressed little. At a time when informed choices need to be taken early on in drug development programs in order to exploit the opportunities for innovation created through genomics, this article considers the strengths and weaknesses of behavioral pharmacology assays and their various roles in the drug discovery process. In the past, a widespread lack of confidence in animal models of depression, combined with the high failure rate of clinical trials and escalating costs of drug development, has stifled a more entrepreneurial approach to drug discovery. In order to encourage greater confidence in discovery programs, the gap between exploratory preclinical and clinical studies needs to be bridged. Functional pharmacology markers need to be developed in patient populations, and in normal volunteers and preclinical species, so that selection of new drug targets can be made with greater confidence at earlier stages of discovery programs. The use of functional brain imaging to quantify drug actions in the human CNS is developing rapidly and may provide powerful new techniques to filter active new drugs of the future from those that are less promising.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine – a 5-HT2/&agr;2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites – substitute for neither citalopram nor reboxetine, indicating that ‘antidepressant’ effectsper sedo not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2Cantagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the &agr;1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the &agr;2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at &agr;1- and &agr;2-ARs, respectively. These observations indicate that 5-HT2Creceptors and &agr;1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1and neurokinin1) receptors.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Although the advances in molecular genetics have revolutionized many areas of the life sciences, they have, so far, been of limited use in the development of animal models for brain diseases. This is due to the fact that the genetics of most neurological and psychiatric diseases are highly complex, presumably involving multiple genes, most of which are still unknown. Moreover, in many brain diseases, non-genetic factors also play an important role. This leads to a general model in which several genetic factors interact with a number of early and late environmental factors, ultimately culminating in the disease. We have tried to illustrate how the existing genetic and environmental models for schizophrenia fit into this general etiological scheme, and how these models can be further improved by focusing specifically on the interaction between genetic and environmental factors.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Alzheimer's disease (AD) is the most common cause of senile dementia, for which there is presently no disease-based treatment. The identification of genetic factors contributing to this disease, and the intense investigation into the cell biology of amyloid precursor protein (APP) and, to some extent, tau, has led to the development of several transgenic mouse models of this disease. These mice show some of the characteristic AD pathology, such as an age-dependent formation of amyloid plaques consisting of A&bgr; peptides. However, they usually lack both the tau pathology, i.e. neurofibrillary tangle formation, and the neurodegeneration also associated with AD. Importantly, many of these transgenic lines develop age-dependent deficits in some relevant behavioural tests and thus provide an animal model not only for amyloidosis but also for the cognitive deficits of AD patients. Incorporation of additional disease genes may lead to models that show a more complete disease phenotype. This review attempts to summarize much of this work, and describes how the availability of these models should assist in the understanding of AD aetiology and the identification of effective treatments for this disease. The review also considers the role behavioural testing may have in future AD drug discovery research.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We investigated the social behavioural effects of a single exposure to either social defeat or electric shocks, using the recently developed social avoidance test in rats. The testing apparatus consisted of two connected chambers, one of which contained an unfamiliar male confined in a sub-chamber by a perforated Plexiglas wall. The subjects were placed in the empty chamber and, after 3 min of habituation, were allowed to explore the apparatus for 5 min. The latency, frequency and duration of visits made to the opponent-containing chamber were recorded. Both stressors reduced the exploration of the opponent-containing chamber for more than 5 days. The effects of electric shocks were not affected by housing conditions, whereas group housing protected rats from the long-term effects of defeat. In addition, the effects of social defeat in isolated rats lasted longer than the effects of electric shocks. These differences suggest that the two stressors have qualitatively different effects and may model different behavioural states in humans. In a second experiment, social avoidance induced by electric shocks was readily abolished by both chlordiazepoxide and buspirone. We suggest that the shock-induced social avoidance paradigm may become a useful model of stress-induced anxiety.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Convergent data suggest that SP, through the activation of neurokinin1receptors (NK1-R), may be involved in anxiety. In particular, NK1-R antagonists have been reported to exert anxiolytic-like effects in a variety of animal procedures in which anxiety-related behaviour is induced by novelty. The present study investigated the effects of acute blockade of NK1-R in conflict paradigms, another category of anxiety-related procedures, in which positively reinforced responses are suppressed by contingent punishment. For this purpose, three selective antagonists with nanomolar affinity for rat NK1-R, GR205171, RP67580 and [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine (Compound L), were tested in the safety signal withdrawal operant paradigm. In this procedure, suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety, with no presentation of a conditioned signal for punishment, and no punishment. Compound L was also tested in the punished drinking test, which consists of the contingent delivery of electric footshocks upon water drinking. As expected, the reference compound, diazepam (2 mg/kg s.c.), induced an anxiolytic-like effect, as indicated by significant increases of the number of responses emitted during conflict period in the operant procedure, and footshocks received in the drinking test. In contrast, GR205171 (10 mg/kg s.c.), RP67580 (0.25–8 mg/kg s.c.) and Compound L (10 and 30 mg/kg s.c.) failed to release lever pressing during the operant conflict period. In addition, punished drinking was not affected by Compound L (3–30 mg/kg s.c.). These data show that NK1-R blockade has no anxiolytic-like effects in conflict paradigms, thereby suggesting that the anxiolytic properties of NK1-R antagonists are less broad than those reported for benzodiazepines.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Investigation of the antidepressant-like actions of substance P (NK1receptor) antagonists has been hindered by the few available compounds that bind with high affinity to the rat and mouse NK1receptor, as these are the most commonly used preclinical species. The best available compounds for such studies are SR140333 and GR205171. However, SR140333 does not penetrate the central nervous system (CNS) after systemic administration, and GR205171 is active only at high doses, where unspecific pharmacological effects occur, so that changes in behaviour cannot be attributed to selective NK1receptor blockade. These compounds may be substrates for P-glycoprotein (P-gp) and hence are actively excluded from the brain. The present studies used mdr1a−/− mice, a spontaneously occurring mutant that is deficient in P-gp, to examine the CNS penetration of SR140333 and GR205171. Following systemic administration of SR140333 and GR205171 (0.01–10 mg/kg i.v.), considerably higher drug concentrations were achieved in the brains of mdr1a−/− than in mdr1a+/+ mice, and this corresponded with a greater ability to inhibit NK1-agonist-induced behaviours in the mdr1a−/− mutants. Moreover, an NK1-receptor-specific inhibition of aggressive behaviour by GR205171 (10 mg/kg) could be demonstrated in mdr1a−/−, but not mdr1a+/+, mice. These findings suggest that P-gp deficient mice may have useful applications in behavioural pharmacology studies, especially when highly brain-penetrant compounds are not yet available.

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers,S-(+)-citalopram (escitalopram) andR-(−)-citalopram (R-citalopram).R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction betweenR-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8 mg/kg per day),R-citalopram (7.8 mg/kg per day) and escitalopram 3.9  mg/kg per day plusR-citalopram 7.8 mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine andR-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8 mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 forR-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/kg per day).R-citalopram (7.8 mg/kg per day) and escitalopram (3.9 mg/kg per day) plusR-citalopram (7.8 mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting thanR-fluoxetine and imipramine.R-citalopram counteracted the effect of escitalopram. The mechanism of action ofR-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs).

ISSN:0955-8810    

出版商:OVID    

年代:2003

数据来源: OVID