βCCM but not physostigmine enhancement of memory retrieval depends on emotional processes in mice

Rationale The effects of methyl beta-carboline-3-carboxylate (CCM, an inverse agonists of GABA/benzodiazepine receptors) or physostigmine (a cholinesterase inhibitor) on retrieval processes and relationships with anxiety have been only marginally studied.Objective This study investigates in mice the effects of acute CCM or physostigmine injections on retrieval of previously acquired discriminations involving distinct contextual cues (serial contextual discrimination; SCD) in a four-hole-board. Animals submitted to SCD were also evaluated for emotional reactivity in an elevated-plus maze.Methods Mice were injected before the learning session began with a saline solution. Twenty-four hours later, mice were replaced on the context of the initial acquisition and a single dose of saline or CCM (0.5 or 1.5 mg/kg) or physostigmine (0.05 and 1.0 mg/kg) was injected 20 min before testing.Results The highest dose of either CCM or physostigmine improved performance of the first discrimination in the SCD task. The higher dose of CCM produced anxiety-like reactivity in the plus maze, and scores of anxiety were significantly correlated with memory scores; in contrast, memory performance of physostigmine-treated subjects were totally independent of emotional reactivity.Conclusion These results show that, as opposed to physostigmine, CCM acts on retrieval processes specifically through its emotional component.     

Anxiolytic effect of wogonin,a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi

The search for novel anxiolytics devoid of undesirable side-effects typical of classical benzodiazepines (BDZs) has been intense, and flavonoids, as a relative new class of ligands, have been shown to possess anxiolytic effects in vivo. The present study evaluated the pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy-8-methoxyflavone or wogonin. The affinity (K(i)) of wogonin for the benzodiazepine site (BZD-S) on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex was 0.92 microM. Using electrophysiological techniques, we showed that wogonin enhanced the GABA-activated current in rat dorsal root ganglion neurons, and in Xenopus laevis oocytes expressing recombinant rat GABA(A) receptors, the enhancement was partially reversed by the co-application of a 1 microM concentration of the BZD-S antagonist anexate (Ro15-1788). Acute toxicity and behavioral effects were examined in mice. Acute lethal activity was low, with an LD(50) of 3.9 g/kg. Oral administration of wogonin (7.5 to 30 mg/kg) elicited an anxiolytic response that was similar to that elicited by diazepam in the elevated plus-maze; a dose-dependent increase in open arm entries and time spent in open arms was observed. More importantly, its anxiolytic effect was blocked by the co-administration of Ro15-1788. In the holeboard test, not only did wogonin-treated mice experience an increased number of head-dips but they also spent more time at it, showing no signs of sedation. Furthermore, wogonin did not cause myorelaxant effects in the horizontal wire test. Taken together, these data suggest that wogonin exerts its anxiolytic effect through positive allosteric modulation of the GABA(A) receptor complex via interaction at the BZD-S. Its anxiolytic effect was not accompanied by sedative and myorelaxant side-effects typical of BDZs.     

The role of the hippocampus and 5-HT/GABA interaction in the central effects of benzodiazepine receptor ligands

Summary. The effects of an intrahippocampal administering of a non-selective full (midazolam), a partial benzodiazepine (BDZ) receptor agonist (bretazenil), and a BDZ₁ selective (zolpidem) receptor ligand were examined in the open field test (OFT) of neophobia and Vogel's test (VT) of conflict behavior in rats. Moreover, the influence of local injections of a non-competitive GABA_A receptor antagonist, picrotoxin, on the anxiolytic-like effect of serotonin (5-HT) depletion (p-chlorophenylalanine, p-CPA) in the Vogel test was studied. It was found that in the OFT only midazolam (0.1 μg/site) given to the hippocampus (HP) disinhibited rat exploratory behavior, whereas all the examined compounds inhibited animal motor activity when injected locally at 10.0 μg/site, the highest dose used in the tests. In the VT, again, only midazolam disinhibited rat conflict behavior on a dose-dependent basis. Picrotoxin administered to the HP produced a tendency to increase locomotor activity in rats, and significantly attenuated the anti-conflict action of serotonin depletion without changing the pain threshold and spontaneous drinking of the animals. p-CPA induced potent, dose-dependent and selective 5-HT and 5-hydroxyindoleacetic acid decrease in the HP after administering the dose used in the behavioral experiment. Thus, the present data provide evidence for the lack of selective anxiolytic activity of a partial non-selective agonist and a full selective agonist at the BDZ₁ receptor after their administration to the HP. The model of intra-HP drug injections appeared effective in discriminating the anxiolytic spectrum of activity of new psychotropic compounds. Moreover, the obtained results indicate that the dorsal HP is one of the central sites important for GABA /5-HT interaction that modulates rat emotional behavior. Received January 12, 1998; accepted September 2, 1998     

Aging, diazepam exposure and benzodiazepine receptors in rat cortex

Densities of two benzodiazepine receptor subtypes (BDZ₁ and BDZ₂) in the frontal cortex of 10- and 27-month-old male Fischer-344 rats were nearly identical. Acute diazepam pretreatment produced a 73% increase in receptor density in the aged rats, mainly in the BDZ₂ sites, whereas with the normal adult rat the density increased 42%, primarily due to stimulation of BDZ₁ sites. Chronic exposure elicited similar increases of 28–29% in both normal and aged rats but there were subtle differences in the distribution of specific receptors. This study demonstrates a definite effect of age on the response of benzodiazepine receptors to diazepam pretreatment.     

Effects of MK 801 and Diazepam on the EEG of P and NP Rats

The selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats have been shown to possess a number of behavioral and electrophysiological differences in response to alcohol. We sought to evaluate whether or not P and NP rats would respond differently to other sedative-hypnotic drugs related to ethanol. EEG recordings were conducted following systemic administration of the NMDA receptor antagonist MK 801 (0.1 mg/kg, ip) and the GABA/benzodiazepine receptor complex agonist diazepam (1.5 mg/kg, ip). Nine P and nine NP rats were implanted with bipolar stainless steel electrodes in the frontal cortex, the dorsal hippocampus, the ventral thalamus, and the anterior amygdala. In the vehicle condition, P rats showed significantly greater power of the EEG in the slow frequencies as compared with NP rats in the frontal cortex. Furthermore, P rats were found to have lower peak θ frequency (6–8 Hz) than NP rats in the frontal cortex, the dorsal hippocampus, and the ventral thalamus. MK 801 produced a significantly greater increase in the mean power of the EEG in NP rats in the 8–16 Hz than in P rats, whereas diazepam was found to decrease θ peak frequency (6–8 Hz), but more so in NP rats that in P rats. These data suggest that, in addition to differential responsiveness to alcohol, P and NP rats also differ in response to drugs that modify GABA and glutamate neurotransmission.     

Where and what is the paralaminar nucleus? A review on a unique and frequently overlooked area of the primate amygdala

The primate amygdala is composed of multiple subnuclei that play distinct roles in amygdala function. While some nuclei have been areas of focused investigation, others remain virtually unknown. One of the more obscure regions of the amygdala is the paralaminar nucleus (PL). The PL in humans and non-human primates is relatively expanded compared to lower species. Long considered to be part of the basal nucleus, the PL has several interesting features that make it unique. These features include a dense concentration of small cells, high concentrations of receptors for corticotropin releasing hormone and benzodiazepines, and dense innervation of serotonergic fibers. More recently, high concentrations of immature-appearing cells have been noted in the primate PL, suggesting special mechanisms of neural plasticity. Following a brief overview of amygdala structure and function, this review will provide an introduction to the history, embryology, anatomical connectivity, immunohistochemical and cytoarchitectural properties of the PL. Our conclusion is that the PL is a unique subregion of the amygdala that may yield important clues about the normal growth and function of the amygdala, particularly in higher species.     

Effect of sertraline treatment on benzodiazepine receptors in the rat brain

Summary In this paper we describe the modification of benzodiazepine (BDZ) binding sites in the rat brain after different times of treatment with the 5-hydroxytryptamine-(5HT) uptake blocker sertraline. We investigated the effect of 8, 15 and 30 days sertraline treatment (10 mg/kg/day, i.p.) on³H-flunitrazepam binding sites. In order to describe the anatomical site of action of the drug, the experiment has been carried out by means of quantitative receptor autoradiography. After 8 days of sertraline treatment, an increase of BDZ receptor density is found in the olfactory tubercle. This effect is reversed at 15 and 30 days. At 15 days of treatment, an increase is found in the anterior cingulate cortex. This increase is still present after 30 days of treatment. At 30 days of treatment, we also found an increase of BDZ receptor density in the frontoparietal motor cortex and in the septal nuclei. The Scatchard plots obtained from the saturation experiments indicate that this increase of the receptor density is due to an increase of both the receptor number and affinity. All the other investigated areas are unaffected by the sertraline treatment. The possible neurochemical basis of these BDZ receptor regulation by sertraline and its influence in the therapeutical profile are discussed.     

Attaining in vivo selectivity of positive modulation of α3βγ2 GABAA receptors in rats: A hard task!

It is unclear whether GABA_A receptors (GABA_ARs) that contain the α3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for α3βγ2 GABA_ARs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2?mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10?mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and βCCt, the non-selective and α1βγ2 GABA_AR affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the α1γ2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the α1γ2 over other BDZ-sensitive sites, and at lower doses (1–2?mg/kg) was devoid of potentiation at α1βγ2 GABA_ARs. The approximation approach revealed a modest selectivity of YT-III-31 for α3γ2- in comparison to α2γ2 and α5γ2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at α3βγ2 GABA_ARs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.     

Oral risperidone, olanzapine and quetiapine versus haloperidol in psychotic agitation

PURPOSE: Acute agitation is a common presentation in emergency departments and is often secondary to an underlying psychotic condition. The aim of this study was to compare the effectiveness of three second generation antipsychotics (risperidone, olanzapine, quetiapine) versus haloperidol in the treatment of psychotic agitation for up to 72 h. GENERAL METHODS: We recruited 101 patients with acute psychosis who were admitted at the Mental Health Department 1 South of Turin, Psychiatric Emergency Service of San Giovanni Battista Hospital, from June 2004 to June 2005. FINDINGS: Aggressive behavior, as measured by Modified Overt Aggression Scale and Hostility-suspiciousness factor derived from the Brief Psychiatric Rating Scale, significantly improved in all groups, with no significant between-group differences. Extrapyramidal symptoms were more common in haloperidol treated patients compared with patients receiving risperidone, olanzapine or quetiapine. CONCLUSIONS: Our results show that in the clinical practice setting of emergency psychiatry olanzapine, risperidone, quetiapine are as effective as haloperidol and better tolerated.     

镇静催眠药物在门诊使用情况的调查分析

目的：了解镇静催眠药在精神科门诊的使用情况。方法：对精神科门诊服用镇静催眠药589例患者的信息资料进行统计，分析其在性别、年龄、病种、病程、所服药物种类，依赖性等方面的临床分布特点。结果：服用镇静催眠药患者589例，占全年门诊总数1997例的29．49％；女性360例（61．12％），男性229例（38．88％）；年龄以40～69岁者居多392例（66．55％）；病种以原发性失眠症最多，其次是精神分裂症、抑郁症，分别为：157例（26．66％）、138例（23．43％）、131例（22．24％）；病程最短的2个月，最长的41年；所服药物均为苯二氮[艹卓]类镇静催眠药，各种安定药物均有不同程度依赖性，药物依赖者共计174例（29．54％）；依赖者服药时间至少连续2年以上。结论：精神科门诊镇静催眠药物使用十分普遍，尤其是中老年人群，易形成药物依赖。应加强认知行为治疗或给予依赖性小的非苯二氮草类药物。