New and Emerging Therapies for Anxiety
Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen in Handbook of Depression and Anxiety, 2003
In essence, the glutamate theory of anxiety suggests that the embedding of anxiety is a consequence of glutamate-mediated learning. In addition, some authorities believe that simply increasing brain glutamate concentrations will cause anxiety [1]. It is possible to block glutamate transmission at the key receptor involved in learning and memory (the NMDA receptor) by postsynaptic antagonists such as dizocilpine (MK801). These drugs, though, tend to produce problematic alterations in consciousness so they cannot be used as long-term therapy but they can be contemplated as a short-term/immediate intervention. Other antagonists with less problematic side effects have now been discovered and one, memantine, has been used in humans for other indications. It could perhaps be used to test the glutamate theory of anxiety [43].
Metabolic Mapping with Deoxyglucose Autoradiography as an Approach for Assessing Drug Action in the Central Nervous System
Edythe D. London in Imaging Drug Action in the Brain, 2017
The effects on glucose use of nonselective, noncompetitive NMDA antagonists, such as ketamine (Crosby et al., 1982; Oguchi et al., 1982) and phencyclidine (Meibach et al., 1979; Tamminga et al., 1987; Weissman et al., 1987), bear considerable similarity to those elicited by dizocilpine particularly the activation of anatomical components within the limbic system. For example, both phencyclidine and dizocilpine produce massive elevations of glucose use in the entorhinal cortex (Figure 7), anterior thalmus, posterior cingulate cortex, hippocampus (molecular layer), mamillary body; both agents reduce glucose use in rostral dorsolateral neocortex and inferior colliculus (see Weissman et al., 1987; Kurumaji et al., 1989). However, there are a number of distinct differences between phencyclidine and dizocilpine. In the anterior cingulate cortex (Figure 7), nucleus accumbens, amygdala, subthalamic nucleus and globus pallidus, glucose use is increased by phencyclidine but is unaltered after dizocilpine, while in the habenula, glucose use is reduced after phencyclidine, but unaltered after dizocilpine. Finally, in the olfactory cortex, glucose metabolism is unaltered by phencyclidine, but is increased by dizocilpine. Phencyclidine interacts with the σ receptor, for which dizocilpine has little affinity, and it displays dopaminergic agonist effects. Differences in the functional response to dizocilpine and phencyclidine may be due to the actions of the latter compound on a-opiate and dopaminergic systems, particularly as selective agonists for these systems display similar effects to phencyclidine (McCulloch et al., 1979, 1980, 1982c; Kozlowski, 1986).
New Strategies for Brain Protection Including NMDA Receptor Antagonists
Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin in Brain Injury and Pediatric Cardiac Surgery, 2019
Our laboratory has studied the effect of dizocilpine in a perinatal rat model.2,5 In the model, one carotid artery of a 7-day-old rat is ligated, and the pup is exposed to hypoxia (8% oxygen) for two hours. Over an hour, areas of low flow appear in the periventricular white matter. A 70% reduction in blood flow combined with the hypoxemia leads to a substantial loss of brain tissue in the ipsilateral hemisphere with preservation of the other hemisphere. The fine lamellar organization of the corpus striatum is disrupted in the basal ganglia, and large infarcted areas can often be seen within the smaller hemisphere.10
Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders
Published in Expert Opinion on Drug Discovery, 2021
Tangui Maurice
At the behavioral level, S1R agonists are potent antidepressant and anti-amnesic drugs. In particular, in line with the potentiating effect on [Ca2+]i mobilization and on NMDA-evoked responses in the hippocampus, the effects of the ligands on the learning impairments provoked by the NDMAR noncompetitive antagonist dizocilpine (MK-801) were extensively examined. DTG, [2S-(2α, 6α,11 R*)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (Alazocine, (+)-N-allylnormetazocine hydrochloride, (+)-SKF-10,047; Figure 1), PRE-084 (Figure 2f), cutamesine, or blarcamesine attenuated dizocilpine-induced spontaneous alternation or passive avoidance deficits with a bi-phasic dose response [57,104–107]. Furthermore, S1R ligands attenuated the learning deficits induced by cholinergic blockade. (+)-Pentazocine, cutamesine, or ANAVEX1-41 prevented the learning deficits induced by the mAChR antagonist scopolamine in a haloperidol-, NE-100-, or BD10,047-sensitive manner and with a bell-shaped dose-response curve [108,109]. Similar bi-phasic effects were observed in pathological models of amnesia, including pathological aging as observed in senescence-accelerated mice (SAM) [110], basal forebrain lesions [108,111] or the pharmacological AD model induced by intracerebroventricular injection of oligomerized Aß25-35 amyloid peptide [57,112].
Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies
Published in Expert Opinion on Drug Discovery, 2018
Bence Szilágyi, György G. Ferenczy, György M. Keserű
D-serine is a co-agonist of the NMDA receptor whose hypofunction contributes to the pathophysiology of schizophrenia [76]. D-serine oxidative deamination is catalyzed by DAAO and thus the involvement of DAAO in schizophrenia is widely hypothesized. This possibility is supported by association between schizophrenia and single nucleotide polymorphisms in DAAO and its regulator (G72) [16,17] and by increased DAAO expression and enzyme activity in schizophrenia [18]. Indeed, several experiments showed that administration of DAAO inhibitors alone or together with D-serine to rodents significantly increases D-serine levels in the plasma [56,58–60,64,67,77] and in the brain [56,58,59,67,77]. DAAO inhibitors were also evaluated in animal behavior assays and several experiments suggested that they have the potential to improve psychosis or cognitive deficits associated with schizophrenia. Notably, acute and oral administration of mice with 4 was reported to normalize phencyclidine (PCP)-induced prepulse inhibition [56] and oral chronic treatment with 4 normalized the locomotor activity in PCP treated mice [56]. It was also shown that 18 ameliorated the cognitive deficit induced by MK-801 [67] and the co-administration of 9 with D-serine significantly reduced dizocilpine-induced prepulse inhibition deficits [64]. These results show that DAAO inhibitors are effective in rodent models predictive of antipsychotic activity.
Beneficial effects of atypical antipsychotics on object recognition deficits after adolescent toluene exposure in mice: involvement of 5-HT1A receptors
Published in The American Journal of Drug and Alcohol Abuse, 2022
Mei-Yi Lee, Chung-Pin Hsieh, Ming-Huan Chan, Hwei-Hsien Chen
To test whether activation of 5-HT1A receptors is involved in the beneficial effects of aripiprazole, clozapine, and buspirone to restore the toluene-induced recognition memory deficits, 3 separate experiments were performed. WAY-100635, a 5-HT1A receptor antagonist, was administered 30 min prior to aripiprazole, clozapine, or buspirone in toluene-exposed mice for subsequent NORT. Each experiment included at least 4 groups (oil+vehicle+vehicle, toluene+vehicle+vehicle, toluene+ vehicle+drug, toluene+WAY-100635+drug). WAY-100635 has been reported to alleviate cognitive impairments induced by a fornix lesion (18) or dizocilpine (19). Therefore, the toluene+WAY-100635+vehicle group was included in the experiment of aripiprazole to determine if WAY-100635 alone could restore the detrimental effect of toluene. The numbers of mice used in each experiment were 34 (aripiprazole), 32 (clozapine), and 26 (buspirone).