Interactions of anxiolytic and antidepressant drugs with hormones of the hypothalamic-pituitary-adrenal axis

Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from anxiety and depressive disorders are reviewed, and the changes that occur when animals are exposed to test situations used preclinically to model anxiety or depression. The effects of exogenous administration of HPA hormones both clinically and in animal tests is discussed and the effects of clinically used anxiolytics and antidepressants on hormones of the HPA axis. The final section discusses stress-induced changes in the CNS.     

Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs

Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) were identified in the mid 90s as a novel peptidergic system structurally related to opioids. A growing body of preclinical evidence suggests that blockade of NOP receptors evokes antidepressant-like actions. These have been explored using a range of compounds (peptide and non peptide antagonists), across different species (rat and mouse) and assays (behavioral despair and chronic mild stress) suggesting a robust and consistent antidepressant-like effect. Moreover, rats and mice knockout for the NOP receptor gene display an antidepressant-like phenotype in behavioral despair assays. Electrophysiological, immunohistochemical and neurochemical studies point to an important role played by monoaminergic systems, particularly 5-HTergic, in mediating the antidepressant-like properties of NOP antagonists. However other putative mechanisms of action, including modulation of the CRF system, circadian rhythm and a possible neuroendocrine-immune control might be involved. A close relationship between the N/OFQ-NOP receptor system and stress responses is well described in the literature. Stressful situations also alter endocrine, behavioral and neurochemical parameters in rats and chronic administration of a NOP antagonist restored these alterations. Interestingly, clinical findings showed that plasma N/OFQ levels were significantly altered in major and post-partum depression, and bipolar disease patients. Collectively, data in the literature support the notion that blockade of NOP receptor signaling could be a novel and interesting strategy for the development of innovative antidepressants.     

Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice

Antidepressant-like effects of metabotropic glutamate (mGlu)5 receptor antagonists have been reported previously. We now provide definitive identification of mGlu5 receptors as a target for these effects through the combined use of selective antagonists and mice with targeted deletion of the mGlu5 protein. In these experiments, the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the more selective and metabolically stable analog 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) decreased immobility in the mouse forced swim test, a test predictive of antidepressant efficacy in humans. mGlu5 receptor knockout mice had a phenotype in the forced swim test that was congruent with the effects of receptor blockade; mGlu5 receptor knockout mice were significantly less immobile than their wild-type counterparts. Consistent with mGlu5 receptor mediation of the antidepressant-like effects of MPEP, the effects of MPEP were not observed in mGlu5 receptor knockout mice, whereas comparable effects of the tricyclic antidepressant imiprimine remained active in the mutant mice. MPEP and imiprimine resulted in a synergistic antidepressant-like effect in the forced swim test. The drug interaction was not likely because of increased levels of drugs in the brain, suggesting a pharmacodynamic interaction of mGlu5 and monoaminergic systems in this effect. Thus, the present findings substantiate the hypothesis that mGlu5 receptor antagonism is associated with antidepressant-like effects. This mechanism may not only provide a novel approach to the therapeutic management of depressive disorders but also may be useful in the augmentation of effects of traditional antidepressant agents.     

Pharmacogenomics and antidepressant drugs

While antidepressant pharmacotherapy is an effective treatment of depression, it still is hampered by a delayed time of onset of clinical improvement and a series of side effects. Moreover, a substantial group of patients has only limited response or fails to respond at all. One source accounting for these variations are genetic differences as currently analysed by single nucleotide polymorphisms (SNP) mapping. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. So far they mostly focused on metabolizing enzymes of the cytochrome P450 (CYP) families and genes within the monoaminergic system with compelling evidence for an effect of CYP2D6 polymorphisms on antidepressant drug plasma levels and of a serotonin transporter promoter polymorphism on clinical response to a specific class of antidepressants, the selective serotonin reuptake inhibitors. It is clear, however, that other candidate systems have to be considered in the pharmacogenetics of antidepressant drugs, such as neuropeptidergic systems, the hypothalamus-pituitary adrenal (HPA) axis and neurotrophic systems. There is recent evidence that polymorphisms in genes regulating the HPA axis have an important impact on response to antidepressants. These studies mark the beginning of an emerging standard SNP profiling system that ultimately allows identifying the right drug for the right patient at the right time.     

Metabotropic glutamate receptor mGlu5 is a mediator of appetite and energy balance in rats and mice

The metabotropic glutamate receptor subtype mGlu5 modulates central reward pathways. Many transmitter systems within reward pathways affect feeding. We examined the potential role of mGlu5 in body weight regulation using genetic and pharmacological approaches. Adult mice lacking mGlu5, mGluR5-/-, weighed significantly less than littermate controls (mGluR5+/+, despite no difference in ad libitum food intake. After overnight food deprivation, mGluR5-/- mice ate significantly less than their mGluR5+/+ controls when refeeding. When on a high fat diet, mGluR5-/- mice weighed less and had decreased plasma insulin and leptin concentrations. The selective mGlu5 antagonist MTEP [3-[(2-methyl-1,3-thiazol-4-yl)-ethynyl]-pyridine; 15 mg/kg s.c.] reduced refeeding after overnight food deprivation in mGluR5+/+, but not mGluR5-/- mice, demonstrating that feeding suppression is mediated via a mGlu5 mechanism. MTEP (1-10 mg/kg) decreased night-time food intake in rats in a dose-related manner. At 10 mg/kg, MTEP injected at 8.5, 4.5, or 0.5 h before refeeding reduced overnight food intake by approximately approximately 30%. Diet-induced obese (DIO) and age-matched lean rats were treated for 12 days with MTEP (3 or 10 mg/kg/day s.c.), dexfenfluramine (3 mg/kg/day s.c.), or vehicle. Daily and cumulative food intakes were reduced in DIO rats by MTEP and dexfenfluramine. Weight gain was prevented with MTEP (3 mg/kg), and weight and adiposity loss was seen with MTEP (10 mg/kg) and dexfenfluramine. Caloric efficiency was decreased, suggesting increased energy expenditure. In lean rats, similar, although smaller, effects were observed. In conclusion, using genetic and pharmacological approaches, we have shown that mGlu5 modulates food intake and energy balance in rodents.     

Metabotropic glutamatergic receptors and their ligands in drug addiction

Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction.     

Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes

The effects of drugs that bind selectively to different serotonin (5-HT) receptor subtypes were assessed in pigeons. Keypecking was maintained by a multiple fixed-ratio schedule of reinforcement in which responding also was punished during one component. The greatest increases in punished responding were produced by the buspirone analogs BMY 7378 and ipsapirone, which act at the 5-HT1A receptor. RU 24969, with high affinity for both 5-HT1A and 5-HT1B receptors, and 1-(2-methoxyphenyl)piperazine, a 5-HT1 compound, increased punished responding to a lesser extent, as did the 5-HT2 antagonists ketanserin and ritanserin. The 5-HT3 antagonists GR 38032F, ICS 205930 and MDL 72222 showed little systematic effect, and the mixed 5-HT1B/5-HT1C compound 1-(3-chlorophenyl)piperazine produced only decreases in punished responding. Levels of neurotransmitter metabolites in cerebrospinal fluid were assessed across a wide dose range of representative drugs used in the behavioral studies. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were decreased significantly by BMY 7378 and ipsapirone, were not changed by ritanserin and were increased at one dose by MDL 72222. The results are consistent with suggestions that decreased 5-HT neurotransmission is involved in the effects of novel nonbenzodiazepine anxiolytics such as buspirone. Behavioral and neurochemical data also indicate that the effects of these drugs on other neurotransmitter systems do not play a significant role in their anxiolytic actions.     

Use of conditioned taste aversion as a conflict model: effects of anxiolytic drugs

Moderate taste aversions were induced by pairing the initial consumption of 0.25% sodium saccharin (SACC) with either 25 mg/kg i.p. l-5-hydroxytryptophan or 30 mg/kg i.p. LiCl. The expression of these moderate conditioned SACC aversions was antagonized by pretreatments (i.p. or p.o.) with benzodiazepine and non-benzodiazepine anxiolytic drugs (lorazepam, diazepam, chlordiazepoxide, oxazepam, phenobarbital, meprobamate, and chlormezanone). Chlordiazepoxide produced less or no antagonism of the expression of stronger SACC aversions induced by 50 or 75 mg/kg l-5-hydroxytryptophan or by 60 or 90 mg/kg LiCl. Nonanxiolytic drugs, including dipsogenic compounds that increased the water intake of hydrated rats (2 M NaCl i.p.; isoproterenol HCl s.c.; and histamine diphosphate s.c.), and even additional 24 hr of fluid deprivation did not antagonize the expression of moderate conditioned taste aversions, indicating that anxiolytic drugs have a very selective effect and that they do not appear to act through homeostatic drinking mechanisms. An essential feature of the taste aversion conflict model is that thirsty rats encounter only SACC. When water was conspicuously available in addition to SACC in two-bottle tests, neither chlordiazepoxide nor phenobarbital antagonized the expression of conditioned taste aversion. Thus, anxiolytic drugs do not produce amnesia for the conditioned aversion, but attenuate the ability of conditioned SACC aversion to suppress SACC consumption in one-bottle tests. The antagonism of the expression of conditioned taste aversion measured with a one-bottle testing method offers a simple, sensitive, and selective screen for anxiolytic drugs. A possible mechanism by which anxiolytics increase both suppressed as well as unsuppressed fluid consumption is discussed.     

Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents

Use-dependent N-methyl-d-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients, suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. To further elucidate the role of mGluR5, the present study examined the effects of mGluR5 antagonist administration, with and without coadministration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition (PPI) of the acoustic startle response in rodents. We further examined PPI in mGluR5 knockout mice. Finally, we examined PPI after administration of the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine has no effect on locomotor activity or PPI by itself but does potentiate both PCP-induced locomotor activity and disruption of PPI. We further found that mGluR5 knockout mice display consistent deficits in PPI relative to their wild-type controls. Finally, the data indicate that CHPG has no effect on PPI by itself, but ameliorates amphetamine-induced disruption of PPI. Collectively, these data suggest that mGlu5 receptors play a modulatory role on rodent PPI and locomotor behaviors and are consistent with the hypothesis that mGlu5 agonist/potentiators may represent a novel approach for antipsychotic drug development.     

Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of structure-based in silico screening and high-capacity functional assays in recombinant and neuronal cells, we identified a low-molecular weight TrkB ligand (ANA-12) that prevented activation of the receptor by BDNF with a high potency. ANA-12 showed direct and selective binding to TrkB and inhibited processes downstream of TrkB without altering TrkA and TrkC functions. KIRA-ELISA analysis demonstrated that systemic administration of ANA-12 to adult mice decreased TrkB activity in the brain without affecting neuronal survival. Mice administered ANA-12 demonstrated reduced anxiety- and depression-related behaviors on a variety of tests predictive of anxiolytic and antidepressant properties in humans. This study demonstrates that structure-based virtual screening strategy can be an efficient method for discovering potent TrkB-selective ligands that are active in vivo. We further propose that ANA-12 may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders.     

代谢性谷氨酸受体配体参与大鼠海马脑缺血耐受诱导机制的研究

背景代谢型谷氨酸受体是G蛋白偶联的膜受体,参与脑内多种生理、病理过程,但其参与脑缺血耐受的诱导机制尚不清楚.目的探讨代谢型谷氨酸受体2/3、代谢型谷氨酸受体1/5在脑缺血耐受诱导中的作用.设计以动物为研究对象,随机对照实验.单位一所省级医院的神经科和一所大学的基础研究所病理生理学研究室.材料实验于2002-05/2003-05在河北医科大学基础医学研究所病理生理研究室完成.健康雄性Sprague Dawley大鼠64只由河北医科大学实验动物中心提供.试剂胶质纤维酸性蛋白抗体、MTPG和(s)-4C3HPG均购自Sigma公司.干预采用大鼠四血管闭塞全脑缺血模型,应用硫堇染色和胶质纤维酸性蛋白免疫组化法.64只大鼠椎动脉凝闭后分为假手术组、单纯预处理组、单纯缺血组、脑缺血耐受组,MTPG+假手术组、MTPG+脑缺血耐受组、MTPG+缺血组和(s)-4C3HPG+脑缺血耐受组,所有动物均在手术后或末次缺血后7 d处死取材,行脑组织切片,硫堇染色和胶质纤维酸性蛋白免疫组化染色.主要观察指标观察海马锥体细胞形态学变化及星形胶质细胞胶质纤维酸性蛋白表达的变化.结果①单纯8 min缺血可使海马CA1区组织学分级升高、锥体神经元密度降低和胶质纤维酸性蛋白阳性表达增加(P＜0.05).②脑缺血耐受组未见单纯缺血组的上述变化,表明脑缺血预处理可防止后续8 min缺血造成的神经元损伤.③脑缺血预处理的这种保护作用可被MTPG或(s)-4C3HPG阻断,表现为海马CA1区组织学分级升高和锥体神经元密度降低(P＜0.05).结论MTPG或(s)-4C3HPG可阻断脑缺血预处理诱导脑缺血耐受的作用,提示代谢型谷氨酸受体2/3,代谢型谷氨酸受体1/5参与脑缺血耐受的诱导,揭示了其对神经损伤保护作用的机制.     

gp130 receptor ligands as potential therapeutic targets for obesity

Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world's population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity.     

Antistress properties of antidepressant drugs and their clinical implications

Stress, in its different forms, represents a major environmental component for increased susceptibility to mental illness and, indeed, stressful life events serve as significant predictors of depression. With this respect, since antidepressant drugs may be effective in a variety of conditions that are triggered by, or associated with, exposure to stress, it is important to establish to what extent drug treatment can interfere with behavioral, functional and molecular alterations induced by stress exposure.The aim of this article is to examine the evidence supporting the ability of antidepressant treatment to reverse or modulate stress-induced alterations in humans and animals. Biologically, there is accumulating evidence that antidepressants can modify not only the neuroendocrine response to stress, but also mechanisms that regulate neuronal plasticity and that may play a key role in structural and functional changes associated with major depression.We believe that a detailed analysis of pharmacotherapy effects on stress-induced alterations may be important to define the ability and potency of different antidepressants to ‘normalize’ alterations that are central to the disease, in order to differentiate them with respect to the pathologic phenotype. This may lead to the identification of new pharmacological targets and contribute to the development of novel and more effective agents, which may eventually achieve higher rates of remission.     

A beta-blocker as anxiolytic and haemostatic in tonsillectomy

Administration of a beta-blocker, pindolol, was utilized in the premedication of patients selected for tonsillectomies (dissection), to study anxiolytic effects. A curious result observed was that bleeding during and after operation in patients on pindolol was remarkably reduced compared to those not on beta-blocker treatment. This effect was further explored in a small controlled study. Nineteen patients were given pindolol, 5 mg the evening before and on the morning, an hour prior to surgery. Seventeen controls were on placebos. The amount of bleeding was measured in both groups. Patients on pindolol show significantly reduced bleeding when compared to controls (1.77 +/- 1.15 ml versus 7.30 +/- 6.05 ml; p less than 0.005). Coagulation and fibrinolytic profiles were studied in a number of patients in both groups attempting to clarify the cause of the reduced bleeding. The results will be reported. This preliminary study shows that pindolol is a useful drug for controlling bleeding in tonsillectomies. To our knowledge the haemostatic properties of pindolol have been reported before.     

Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands

Yohimbine is a potent and relatively nonselective alpha(2)-adrenergic receptor (AR) antagonist. In an earlier report, we demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human alpha(2C)-AR ligands. Little work has been done to examine the role of the tether group or the absence of the second yohimbine pharmacophore on selectivity for human alpha(2)-AR subtypes. The goal of our study was to determine the binding affinities and functional subtype selectivities of a series of tethered yohimbine ligands in the absence of the second pharmacophore. The profiles of pharmacological activity for the yohimbine analogs on the three human alpha(2)-AR subtypes expressed in Chinese hamster ovary cells were examined using receptor binding and cAMP inhibition assays. All of the tethered yohimbine analogs exhibited higher binding affinities at the alpha(2C)- versus alpha(2A)- and alpha(2B)-AR subtypes. Notably, the benzyl carboxy alkyl amine and the carboxy alkyl amine analogs exhibited 43- and 1995-fold and 295- and 54-fold selectivities in binding to the alpha(2C)- versus alpha(2A)- and alpha(2B)-ARs, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities and selectivity profiles of selected compounds from the tethered series. The data demonstrate that the second pharmacophore may not be essential to obtain alpha(2C)-AR subtype selectivity, previously observed with the dimers. Further changes in the nature of the tether will help in optimization of the structure-activity relationship to obtain potent and selective alpha(2C)-AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.     

beta 3-adrenergic receptor agonists as anti-obese and anti-diabetic drugs]

Beta 3-adrenergic receptors are expressed mainly in adipose tissues and play an important role in lipolysis and thermogenesis. Chronic administration of beta 3-adrenergic receptor agonists into obese rodents reduce the size of adipocytes by the breakdown of triglyceride and ameliorate insulin resistance associated with the normalization of the expression of adipocytokines, such as leptin and tumor necrosis factor-alpha. However, acute administration of the drugs induce remarkable insulin secretion, the mechanism of which is still unclear. Although the effect of beta 3-adrenergic receptor agonists may be different between rodents and human, these drugs are promising as anti-obese or anti-diabetic agents, and several clinical studies are underway.