Targeting the Stress System During Gestation: Is Early Handling a Protective Strategy for the Offspring?

The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring’s stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14–16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis

Acetaldehyde as a drug of abuse: Involvement of endocannabinoid- and dopamine neurotransmission

Acetaldehyde (ACD), the first metabolite of ethanol, directly enhances dopamine neurotransmission (1) and has rewarding and motivational properties in paradigms tailored for studying addictive-like behaviours (2, 3). The endocannabinoid system affects distinct drug-related behaviours, since it may in turn fine-tune dopamine cell activity (4, 5). In light of this, the present study aimed at investigating the effects of a direct manipulation of the DAergic synapse, and the contribution of the endocannabinoid system on oral ACD self-administration in rats. ACD drinking-behaviour was evaluated in an operant paradigm consisting of acquisition and maintenance; extinction; deprivation and relapse; conflict. D2-receptor agonists, quinpirole (0.03 mg/Kg, i.p.) and ropinirole (0.03 mg/Kg, i.p.), and CB1-receptor antagonist, AM281 (1 mg/Kg, i.p.), were administered during different phases of the experiment. Our results show that oral ACD readily induced the acquisition and maintenance of an operant drinking-behaviour, even during reinstatement and conflict. Quinpirole decreased lever presses for ACD during extinction (p<0.05) and relapse (p<0.01; p<0.001) Ropinirole, administered during abstinence, reduced ACD intake during reinstatement (p<0.001). AM281 significantly decreased lever presses for ACD during extinction (p<0.001), relapse (p<0.001) and conflict (p<0.001). These data suggest that whereas the direct modulation of the dopaminergic synapse influences drug-seeking and relapse behaviour, the endocannabinoid system may also play a role in shock-paired compulsive ACD intake. These findings highlight the mandatory need for further investigation on the therapeutical potential played by the endocannabinoid system taking into account its crucial role in alcohol, and ACD neuropharmacology

BDNF as a Mediator of Antidepressant Response: Recent Advances and Lifestyle Interactions

Conventional antidepressants are widely employed in several psychiatric and neurologic disorders, yet the mechanisms underlying their delayed and partial therapeutic effects are only gradually being understood. This narrative review provides an up-to-date overview of the interplay between antidepressant treatment and Brain-Derived Neurotrophic Factor (BDNF) signaling. In addition, the impact of nutritional, environmental and physiological factors on BDNF and the antidepressant response is outlined. This review underlines the necessity to include information on lifestyle choices in testing and developing antidepressant treatments in the future

Addictive-like behaviour for Acetaldehyde: involvement of D2 receptors

Acetaldehyde (ACD), ethanol's first metabolite, is centrally active and shows rewarding and motivational properties. It is able to activate mesolimbic dopamine system, since it enhances neuronal firing of dopamine cells in ventral tegmental area and exerts dopamine release in the nucleus accumbens (Foddai et al., 2004; Melis et al., 2007; Deehan et al., 2013). ACD motivational properties are demonstrated by self-administration studies in rodents (Rodd et al., 2005), particularly behavioural evidence suggests that ACD could produce positive reinforcing effects in operant-conflict paradigms (Cacace et al., 2012). In order to shed light on neurobiological substrate underpinning ACD-related behaviours, the present study aims at investigating D2-receptor role in the different phases of an operant self-administration paradigm, able to mirror core feature of addictive phenotype. Male Wistar rats underwent ACD (3.2%) oral self-administration, in an operant paradigm which includes Training, Extinction, and repeated cycle of forced abstinence and relapse, as a simple reinstatement model. The effect of two different D2-receptor agonists was evaluated. Quinpirole (0.03 mg/kg, i.p.) was administered during Extinction and Relapse phases. Ropinirole (0.03; 0.05 mg/kg, i.p.) was injected daily during abstinence. Our results show that ACD is able to induce and maintain a drug-taking behaviour, which involves D2-receptor neurotransmission. In particular, Quinpirole administration can decrease the number of lever presses for ACD during Extinction and Relapse phases; Ropinirole daily administration during abstinence, at both dosages, is able to reduce the number of lever presses and ACD intake in the relapse phase. ACD has its own motivational properties, which involve dopamine neurotransmission. Activation of D2-autoreceptors by Quinpirole negatively affects operant behaviour for ACD, likely decreasing ACD-induced dopamine release. The activation of post-synaptical D2-receptor, by Ropinirole treatment during abstinence, could restore dopaminergic tone during withdrawal, leading to a decrease in the motivation to subsequent relapse. These data further strengthen the evidence that ACD may play a crucial role in ethanol's central effects

Narrazione storica e storiografia come strumenti indispensabili per la costruzione di un sistema coloniale di insediamento: il caso sionista israeliano

The aim of the research is to analyse the evolution of the official Zionist/Israeli historiography around the year 1948 and the creation of the State of Israel, through the prism of the Settler Colonial paradigm. As a matter of fact, this historiography has been strongly linked to the Zionist and Israeli settler colonial establishment and served it in spreading a compromised version of the historical facts around the Israeli “War of Independence” and, in particular, around the birth of the Palestinian refugee problem. What is new in settler colonial contexts compared to other types of colonialism is the so-called logic of elimination of the natives, that means that the aim of the settler is to eliminate the native, both physically and discursively. This logic has been largely used in this research to demonstrate the Israeli responsibility in creating the Palestinian refugee problem. In historiographical terms, the logic of elimination of the natives has been translated into what has been called as the “narrative transfer”, a narrative expedient to literally transfer the natives away from history and from historiography

Manipulation of the DA signal on the onset of relapse of ACD

It's widely known that all addictive drugs show analogous pathological behaviours consisting in compulsive drug seeking,loss of self –control and propensity to relapse. This evidence is suggestive of a common brain mechanism involving the Ventral Tegmental Area and Nucleus Accumbens whereby mesocorticolimbimc dopamine pathway. Dfferent and apparently anthitetic classes of drugs of abuse manage to increase DA release, in the aforementioned areas (Di Chiara, 1988; 1995). Reductions in activity of the mesolimbic dopamine system in the nucleus accumbes occur during drug withdrawal in animal studies (Weiss F et al. 1992; 1996). Experimental evidences have proven D2 receptor involvement in drug seeking and reinstatement behaviours. In that, according to the hypo-dopaminergic hypothesis of drug abuse, striatal D2-receptors significantly decrease during forced abstinence (Thanos, 2008). These premises suggest that D2 receptor manipulations might represent a valid strategy for alcohol dependence. Ropinirole, a D2-D3 receptors agonist, apparently acting on post-synaptical terminal and thus previously administered in methamphetamine withdrawal (Hoefer, 2006), could reduce drug intake in the reinstatement by means of its presumable properties in compensating DA reduction during abstinence. Acetaldehyde, alcohol first metabolite, is able to induce and maintain an operantdrinking behaviour, because of its addictive properties (Cacace, 2012). This research pointed at evaluating Ropinirole protective effect on ACD relapse as a possible therapeutic tool, together with a dose-response investigation. Rats were trained to self-administer ACD 3,2% solution along 30 days. Then, animals underwent three cycles, each one consisting of withdrawal (7days) followed by relapse phase (5 days). The first withdrawal-relapse cycle provided basal information of animal responses for ACD. During the second withdrawal phase, rats were treated i.p. daily with Ropinirole under the dosage of 0.03mg/kg. A third cycle of withdrawal and relapse was performed so as to correlate the drug potency to a higher dosage of 0.05mg/kg. Preliminary data convey that the aforementioned DA agonist is able to reduce animal responses for ACD also at the latter dosage, which is proved by a lower frequency of lever presses during the third relapse phase. An open field test was used to exclude a not specific Ropinirole effect on reducing locomotor activity and to assess dopaminergic activation by measuring the number of episodes of stereotypes, such as grooming and rearing. Our results indicated that this DA agonist, administered during withdrawal phase, is able to limit ACD reinstatement with responses dose-related. Such studies may be implemented in order to assess Ropinirole efficacy in other drug addictions, starting with alcoholism investigation

Drinking pattern matters: effects on maternal care and offspring vulnerability to alcohol in rats

Alcohol drinking during pregnancy and post-partum period is a major concern because of the persistent neurobehavioral deficits in the offspring, which include increased vulnerability to substance abuse (1). The intermittent pattern of alcohol consumption induces higher drinking levels and deeper neurobiological changes in addiction-related brain regions, with respect to traditional free-access paradigms in male rats (2, 3). Nevertheless, no studies investigated on the effects of the drinking pattern on female subjects during pregnancy and perinatal time. To this aim, this study explored the consequences of continuous vs. intermittent drinking pattern on maternal behaviour and on offspring vulnerability to alcohol, during adulthood. Dams were given two-bottle choice to water and 20% alcohol with either continuous- or intermittent access (CA vs IA), along a 12-week period. They suspended alcohol drinking during breeding and resumed alcohol self-administration from late gestation throughout lactation, when they were assessed for home-cage undisturbed maternal behaviour. In the adulthood, alcohol-exposed offspring were assessed for alcohol drinking behaviour in a free-choice paradigm and tested for the deprivation effect. Our results show that alcohol consumption and preference significantly decreased in IA group during pregnancy, returning to baseline during lactation. Alcohol drinking was able to disrupt spontaneous maternal behaviour, especially in IA exposed dams. On the other hand, perinatal CA exposure did not increase alcohol-drinking behaviour in the offspring with respect to controls, while rats perinatally exposed to IA displayed a high vulnerability to alcohol, in terms of drinking behaviour and deprivation effect. In conclusion, this study indicates for the first time that the pattern of alcohol consumption can be responsible for different extents of maternal behaviour disruption and detrimental consequences in the offspring. Therefore gender- but also pattern-related differences should be taken into account for contrasting alcohol abuse and dependence, especially during perinatal time.   1. McMurray MS, Williams SK, Jarrett TM, Cox ET, Fay EE, Overstreet DH, Walker CH, Johns JM. Neurotoxicol Teratol. 2008;30(6):475-86. 2. Stuber GD, Hopf FW, Hahn J, Cho SL, Guillory A, Bonci A. Alcohol Clin Exp Res. 2008 Oct;32(10):1714-20 3. George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, Crawford E, Mandyam CD, Koob GF. Proc Natl Acad Sci U S A. 2012;109(44):18156-6

Effect of acetaldehyde intoxication and withdrawal on NPY expression: focus on endocannabinoidergic system involvement

Acetaldehyde (ACD), the first alcohol metabolite, plays a pivotal role in the rewarding, motivational, and addictive properties of the parental compound. Many studies have investigated the role of ACD in mediating neurochemical and behavioral effects induced by alcohol administration, but very little is known about the modulation of neuropeptide systems following ACD intoxication and withdrawal. Indeed, the neuropeptideY (NPY) system is altered during alcohol withdrawal in key regions for cerebrocortical excitability and neuroplasticity.The primary goal of this research was to investigate the effects of ACD intoxication and withdrawal by recording rat behavior and by measuring NPY immunoreactivity in hippocampus and NAcc, two brain regions mainly involved in processes which encompass neuroplasticity in alcohol dependence. Furthermore, on the basis of the involvement of endocannabinoidergic system in alcohol and ACD reinforcing effects, the role of the selective CB1 receptor antagonist AM281 in modulating NPY expression during withdrawal was assessed. Our results indicate that (i) ACD intoxication induced a reduction in NPY expression in hippocampus and NAcc; (ii) symptoms of physical dependence, similar to alcohol’s,were scored at 12 h from the last administration of ACD; and (iii) NPY levels increased in early and prolonged acute withdrawal in both brain regions examined. The administration of AM281 was able to blunt signs of ACD-induced physical dependence, to modulate NPY levels, and to further increase NPY expression during ACD withdrawal both in hippocampus and NAcc. In conclusion, the present study shows that complex plastic changes take place in NPY system during ACD intoxication and subsequent withdrawal in rat hippocampal formation and NAcc. The pharmacological inhibition of CB1 signaling could counteract the neurochemical imbalance associated with ACD, and alcohol withdrawal, likely boosting the setting up of homeostatic functional recover

Pregnenolone sulphate improves memory processing in early-handled female rats

Early life experiences lead to sex-specific behavioural and neurochemical changes in adulthood. Indeed, early handling enhances learning and memory in male rats (Cannizzaro et al., 2005), whereas it impairs learning performance in female adult rats, a finding that has been correlated to decreased nitric oxide (NO) production in the hippocampus (Noschang et al., 2010). Pregnenolone sulfate (PREGS) is considered as one of the most potent memory-enhancing neurosteroids, since its activity as a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of gamma-aminobutyric acid(A) receptors (GABA(A)Rs) (Vallée et al., 2001). Given these premises, this study aims at characterizing the effect of PREGS on cognitive processes in adult female rats, subject to early handling protocol, by using an object-place association learning task, the ''Can test'', a motivated, non-aversive, spatial/object discrimination test (Popovic´ et al., 2001). Female Wistar rats underwent daily, brief, maternal separation from postnatal day 2 until 21. Once in adulthood, the effect of PREGS administration (10 mg/kg, s.c.) on correct responses, reference memory and working memory was assessed. Results show that PREGS was able to significantly increase the number of correct responses, and consistently, to decrease reference and working memory errors, compared with vehicle. No statistically significant effect of PREGS administration was observed in non-handled, control group. These findings sustain the impact of neurosteroids in learning and memory processing, and suggest a particular role for PREGS in reversing conditions of altered functionality, likely due to the modulation of the glutamate-NO-cGMP pathway (Cauli et al., 2011), and thus neurobiological mechanisms underlying learning and memory. As a consequence, PREGS may represent an important therapeutic tool as memory-enhancer, in order to tackle cognitive deficit caused by stress in early lif