Piera Ghi

Impaired Adult Neurogenesis Associated with Short-Term Memory Defects in NF-κB p50-Deficient Mice

Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecular mechanisms underlying the regulation of stem/progenitor cell proliferation, survival, maturation, and differentiation have not been completely unraveled. We have studied hippocampal neurogenesis in NF-κB p50-deficient mice. Here we demonstrate that in absence of p50, the net rate of neural precursor proliferation does not change, but some of the steps leading to the final neuron differentiation status are hampered, resulting in ∼50% reduction in the number of newly born neurons in the adult mutant hippocampus. Additionally, in p50−/− mice, we observed a selective defect in short-term spatial memory performance without impairment of hippocampal-dependent spatial long-term memory and learning. Our results highlight the role of NF-κB p50 in hippocampal neurogenesis and in short-term spatial memory.

Gene regulation in the frontal cortex of rats exposed to the chronic mild stress paradigm, an animal model of human depression

In the present study, we have coupled the chronic mild stress (CMS) protocol with Affymetrix microarray technology to screen the rat genome for gene changes in the frontal cortex. The aim of our work was to assess whether the CMS protocol could be a useful experimental model to provide insights into the molecular basis of depression. Under our experimental conditions, 59 transcripts changed by more than ±1.5‐fold between naïve and anhedonic rats and showed significantly altered expression levels (P < 0.05). Among these, 18 were upregulated (fold change range +1.509 to +3.161) and 41 were downregulated (fold change range −1.505 to −2.659). To confirm the data obtained with microarrays, we used real‐time reverse transcription polymerase chain reaction (RT‐PCR). The results confirmed the downregulation of Itga6, Camk2a, Plcb1, Cart, Gad1, Homer1 and Th and the upregulation of Egr2 and Ptgs2 observed in the DNA microarray analysis. Moreover, the fold change data of the nine validated transcripts from microarray analysis and real‐time polymerase chain reaction showed a good correlation (r = 0.863, 7 d.f., P < 0.01; slope = 0.976). It is of great interest that prostaglandin‐endoperoxide synthase 2, tyrosine hydroxylase, Cart, Homer1 and glutamate decarboxylase have already been implicated in affective disorders by different approaches in previous reports. In conclusion, our findings indicate that the CMS paradigm is a useful preclinical model with which to investigate the molecular basis of anhedonia and to help in the discovery of novel targets for antidepressant drugs.

Histamine H3-receptor antagonism improves memory retention and reverses the cognitive deficit induced by scopolamine in a two-trial place recognition task

Several reports have indicated that, under different experimental conditions, the administration of histamine H(3)-receptor antagonists exerts procognitive effects by activating central histaminergic transmission. In the present study the action of thioperamide, a H(3)-receptor blocker, is investigated on consolidation and recall mechanisms of the rat place recognition memory. The animals have been tested on a two-trial delayed comparison paradigm in a Y-maze. Thioperamide enhances the memory retention when administered intraperitoneally (i.p.) post-acquisition (0.7 and 5.0 mg/kg are ineffective, whereas the dose of 2.0 mg/kg improves memory) but does not affect the rat performance when injected 45 min prior to the testing trial. The post-acquisition effect of thioperamide is time-dependent since the administration of the drug 30 min after the end of the training trial has no effect on memory. In addition, thioperamide reverses the amnesia induced by the post-acquisition treatment with 0.02 mg/kg i.p. of scopolamine (SCOP). The procognitive effect of thioperamide is not modified by the contemporary administration of pyrilamine, an histamine H(1)-receptor antagonist. On the contrary, the blockade of H(2)-receptors by zolantidine 10 mg/kg reverses both the effect of thioperamide alone and the drug action on the scopolamine-induced memory deficit. The results indicate that the neuronal histamine released in consequence of the post-acquisition thioperamide treatment improves place recognition memory through the activation of postsynaptic H(2)-receptors.

Sex Differences in Memory Performance in the Object Recognition Test. Possible Role of Histamine Receptors

The mnemonic performances of male and female rats were compared in an object recognition test. Females were still able to recognize a previously identified object after a 90-min between-trial interval, compared with only 60 min in the males. Because histamine (HA) involvement in memory processes has been strongly suggested, the effect of H3-HA autoreceptor antagonist thioperamide was investigated. This drug was found to produce a dose-dependent promnestic effect in both sexes, but it did not influence the time course of memory retrieval. These behavioral data were compared to the density of H1-HA, H2-HA, and H3-HA receptors in cortical membranes. The densities of H1-HA and H2-HA receptors were greater in the females, whereas that of H3-HA was substantially the same in both sexes. The behavioral effect of thioperamide was very similar in both sexes, and this agrees with a similar H3-HA receptor density; however a better memory performance might have been expected in the female after thioperamide treatment (in view of different H1-HA and H2-HA receptor density), but this was not found. Because thioperamide has also been demonstrated to influence the acetylcholine release, its possible role in regulating the cholinergic memory effect was investigated. The scopolamine-reduced visual retrieval was antagonized by thioperamide in a similar way in both sexes. In conclusion, these data have shown a better performance of the female in a visual memory test, but this behavioral difference could not be affected by an H3-HA receptor-dependent manipulation of histaminergic and cholinergic systems.

Biochemical and behaviour changes induced by acute stress in a chronic variate stress model of depression : the effect of amitriptyline

This paper examines the biochemical and behaviour changes induced by an acute stress (five 10-s, 1-mA foot-shocks) in three groups of rats: (1) never stressed, (2) subjected to chronic variate stress for 20 days, (3) subjected to the same chronic stress and treated with 5 mg/kg per day amitriptyline. After 15 min, acute stress led to a marked reduction in cortical beta-adrenoceptor and 5-HT2 receptor density, whereas the density of the 5-HT1A receptors was unchanged. Chronic stress also increased beta-adrenoceptor and 5-HT2 receptor density and had no effect on 5-HT1A. Acute stress diminished the density of beta-adrenoceptors in chronically stressed animals, but did not alter that of the two 5-HT populations. Amitriptyline alone reduced beta-adrenoceptor and 5-HT2 receptor densities only. Acute stress applied to animals treated with amitriptyline reduced 5-HT1A receptors, and caused a further beta-adrenoceptor decrease, but had no further effect on the 5-HT2 receptors. On behaviour, chronic stress diminished reactivity to the acute stress. This reduction was fully abolished by amitriptyline. An open-field study showed that acute stress reduced motor activity, increased latency times and diminished rearing in the controls, whereas chronic stress reduced motor activity only. No significant changes in behaviour were induced by the acute stress in animals subjected to chronic stress. The combination of chronic stress with amitriptyline was accompanied by a diminution of exploratory activity that persisted after the acute stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Quetiapine prevents anhedonia induced by acute or chronic stress.

The role of atypical antipsychotics as add-on treatments and as primary mood stabilizers in different phases of bipolar disorder is an important current research area. Although in bipolar patients the main therapeutic indication of quetiapine (QTP) is the management of acute mania, several observations suggest that this agent may exert antidepressant as well as antimanic effects. However, in our knowledge, there are no preclinical studies supporting this hypothesis. Thus, the main goal of the present work was to evaluate the putative antidepressant effect of QTP (0.4, 2.0, or 10 mg/kg/day), in comparison to amitriptyline (AMI) (2 or 5 mg/kg/day), in rats exposed to acute or chronic stress. The administration of QTP, 2 mg/kg/day, prevents the onset of anhedonia in rats exposed to a 6-week chronic mild stress (CMS) protocol. The effect of QTP has a slow onset, beginning at week 5, and causes a complete recovery from anhedonia. In this respect, the effect of QTP is similar to that obtained after chronic administration of AMI 2 or 5 mg/kg/day. Our findings also indicate that a 6-week administration of QTP, 2 or 10 mg/kg/day, has protective effects against the onset of anhedonia caused by the exposure to an acute subthreshold stressful event in rats that have previously experienced the CMS procedure. The results suggest that QTP is able to prevent both the transient mood depression caused by acute stress and the long-lasting anhedonic state induced by exposure, over a period of weeks, to a variety of unpredictable mild stressors.

Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats.

In the present study we have investigated the effects of a chronic administration of olanzapine (Ola) on visual and spatial memory in normal and anhedonic rats. The effects of Ola have been compared to those of the typical antipsychotic Hal, the tricyclic antidepressant amitriptyline (Ami), and the mood stabilizer VPA. Anhedonia (assessed by reduction of sucrose preference) was induced by administration of a chronic mild stress (CMS) protocol, in which rats were exposed sequentially, over a period of 4 wk, to a variety of unpredictable mild stressors. The spatial memory was evaluated by testing the ability of the rats to discriminate a familiar vs. a novel environment, while the visual memory was assessed by testing the ability of the rats to discriminate familiar vs. novel objects. In CMS-free rats, VPA (5 or 30 mg/kg.d), Ola (0.02 or 0.1 mg/kg.d), Ami (2 mg/kg.d) and Hal (0.2 mg/kg.d) caused no detectable modifications of visual memory, whereas VPA (5 mg/kg.d), Ami (2 mg/kg.d) and Ola (0.02 mg/kg.d) did not modify spatial memory performance. In our experimental conditions, the administration of the CMS protocol caused an impairment of both visual and spatial memory. The chronic treatment of anhedonic rats with Ola (0.02 mg/kg.d) or Ami (2 mg/kg.d) prevented, at least in part, the stress-induced impairment of visuospatial performance. In conclusion, the results of the present preclinical study seem to indicate that the chronic administration of low doses of Ola or Ami has the potential to lead to substantial cognitive benefits in depressed patients.

Some molecular effectors of antidepressant action of quetiapine revealed by DNA microarray in the frontal cortex of anhedonic rats.

Objectives and methods We have previously demonstrated that quetiapine (QTP) had antidepressant-like action by using the chronic mild stress (CMS) paradigm, an animal model of human depression. The aim of this study was to investigate the molecular mechanism(s) of QTP antidepressant effect by coupling the CMS protocol with Affymetrix microarray technology to screen the entire rat genome for gene changes in the frontal cortex. Results The genes regulated by the administration of CMS whose transcription was reversed by chronic QTP treatment (2 mg/kg/day) were 42 (23 upregulated and 19 downregulated). The transcripts that showed no significant altered expression levels in anhedonic rats but were regulated by the administration of QTP were 19 (nine upregulated and 10 downregulated). On the whole, the action of QTP prevented the stress-induced impairment of some processes involved in central nervous system development or having a crucial role for viability of neural cells and cell–cell communications, like regulation of signal transduction, inorganic cation transport, membrane organization, and neurite morphogenesis. For 11 genes (Ptgs2, Gad1, Plcb1, Camk2a, Homer1, Senp2, Junb, Nfib, Hes5, Capon, and Marcks), significant differential expressions were confirmed by real-time reverse-transcriptase polymerase chain reaction. Conclusion We have shown that chronic QTP treatment prevented anhedonia and reversed, at least in part, the changes of gene expression induced by CMS in the rat frontal cortex. We have also identified and confirmed by two different methods that 11 genes, representing molecular targets of QTP, are presumably the effectors of its clinical efficacy.

Effect of R-(-)-α-methylhistamine and thioperamide on in vivo release of norepinephrine in the rat hippocampus

1. The modifications of hippocampal release of norepinephrine following the administration of R-(-)-alpha-methylhistamine and thioperamide, respectively agonist and antagonist of histamine H3 receptors, were assessed in freely moving rats by microdialysis. 2. Both the systemic (2 mg/kg i.p.) and local (100 microM via the probe) administration of thioperamide caused no modifications of basal release, indicating that the histaminergic system is not tonically involved in regulating the hippocampal noradrenergic activity. 3. R-(-)-alpha-methylhistamine (1 and 100 microM) produced a slight, short-lasting and dose-dependent reduction of norepinephrine release antagonized by local perfusion (100 microM) and prevented by systemic administration of thioperamide 2 mg/kg. 4. The results seem to indicate that the modulation of norepinephrine release through presynaptic H3-receptors in the rat hippocampus plays a minor role in the memory-enhancing effects of thioperamide.

Effects of estradiol on the ontogenesis of striatal dopamine D1 and D2 receptor sites in male and female rats

Since estradiol (E2) either increases or reduces the number of dopamine receptors in the corpus striatum of adult rats, depending on the dose and length of administration, the sensitivity of the two receptor subpopulations (D1 and D2) to E2 during ontogenesis was investigated. Rats of both sexes received either 10 micrograms/kg E2 for 3 days or 50 micrograms/kg for 6 days, and were sacrificed at the age of 15, 21, 40 and 120 days. D1 receptors (identified by [3H]SCH 23390 binding) displayed no changes in density and affinity in function of age, sex or E2 dose, whereas the D2 receptors (identified by [3H]spiperone binding) fell after the lower dose in all groups, and the higher dose resulted in supersensitivity in males of all ages, but only in the 15-day-old females. These findings show that the effect of E2 is bivalent on D2 density only. The effect of its brief administration at a low dose is not sex-dependent, whereas at higher doses administered for longer periods it appears to involve mechanisms linked to sexual differentiation after birth.