Search

Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another’s emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.

Both human and non-human animals frequently deal with risky decisions in a social environment. Nevertheless, the influence of the social context on decision-making has been scarcely investigated. Here, we evaluated for the first time whether the presence of a conspecific influences risk preferences in rats and in tufted capuchin monkeys. Subjects received a series of choices between a constant, safe option and a variable, risky option, both alone (Alone condition) and when paired with a conspecific (Paired condition). The average payoff of the risky option was always lower than that of the safe option. Overall, the two species differed in their attitude towards risk: whereas rats were indifferent between options, capuchins exhibited a preference for the safe option. In both species, risk preferences changed in the Paired condition compared to the Alone condition, although in an opposite way. Whereas rats increased their risk preferences over time when paired with a conspecific, capuchins chose the risky option less in the Paired condition than in the Alone condition. Moreover, whereas anxiety-like behaviours decreased across sessions in rats, these behaviours where more represented in the Paired condition than in the Alone condition in capuchins. Thus, our findings extends to two distantly-related non-human species the evidence, so far available for human beings, that a decrease in anxiety corresponds to an increase in risk preferences, and vice versa. This suggests that the modulation of risk preferences by social influences observed in rats and capuchin monkeys may rely on a common, evolutionarily ancient, mechanism.

Item does not contain fulltext Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 mug/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.

Despite it has not been formally included in DSM-5 as a disorder, 'Internet addiction (IA)' has become a worldwide issue. It can be broadly defined as a non-chemical, behavioral addiction, which involves human-machine interaction. We pinpoint it as an "instrumental" form of social interaction (i.e. mediated by machines), a notion that appears useful for the sake of possible preclinical modeling. The features of Internet use reveals as addictive when this comes at the expense of genuine real-life sociability, with an overlap towards the hikikomori phenomenon (i.e., extreme retreat to one's own room). Due to the specific neuro-developmental plasticity in adolescence, IA poses risks to youths' mental health, and may likely produce negative consequences in everyday life. The thwarted development of adolescents' identity, self-image and adaptive social relationships is discussed: the IA adolescents often suffer loss of control, feelings of anger, symptoms of distress, social withdrawal, and familial conflicts. Further, more severe clinical conditions are also associated to IA, such as dysthymic, bipolar, affective, social-anxiety disorders, as well as major depression. This paper overviews the literature on IA, from neuro-biological, psycho-social and clinical standpoints, taking into account recent debates on diagnostic criteria, nosographic label and assessment tools. Neuroimaging data and neurochemical regulations are illustrated with links to pathogenetic hypotheses, which are amenable to validation through innovative preclinical modeling.

Author(s): Zhang, Dajie; Bedogni, Francesco; Boterberg, Sofie; Camfield, Carol; Camfield, Peter; Charman, Tony; Curfs, Leopold; Einspieler, Christa; Esposito, Gianluca; De Filippis, Bianca; Goin-Kochel, Robin P; Hoglinger, Gunter U; Holzinger, Daniel; Iosif, Ana-Maria; Lancioni, Giulio E; Landsberger, Nicoletta; Laviola, Giovanni; Marco, Eva M; Muller, Michael; Neul, Jeffrey L; Nielsen-Saines, Karin; Nordahl-Hansen, Anders; O'Reilly, Mark F; Ozonoff, Sally; Poustka, Luise; Roeyers, Herbert; Rankovic, Marija; Sigafoos, Jeff; Tammimies, Kristiina; Townend, Gillian S; Zwaigenbaum, Lonnie; Zweckstetter, Markus; Bolte, Sven; Marschik, Peter B

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.

Brain serotonin 7 (5-HT7) receptors play an important functional role in learning and memory, in regulation of mood and motivation, and for circadian rhythms. Recently, we have studied the modulatory effects of a developmental exposure (under subchronic regimen) in rats with LP-211, a brain-penetrant and selective 5-HT7 receptor agonist. We aimed at further deciphering long-term sequelae into adulthood. LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during the adolescent phase (postnatal days 43-45 to 47-49). When adult (postnatal days >70), forebrain areas were obtained for ex vivo immunohistochemistry, whose results prompted us to reconsider the brain connectivity maps presented in our previous study (Canese et al., Psycho-Pharmacol 2015;232:75-89.) Significant elevation in levels of 5-HT7 receptors were evidenced due to adolescent LP-211 exposure, in dorsal striatum (which also shows an increase of dopaminergic D2 auto-receptors) and-unexpectedly-in piriform cortex, with no changes in ventral striatum. We observed that functional connectivity from a seed on the right hippocampus was more extended than reported, also including the piriform cortex. As a whole, the cortical loop rearranged by adolescent LP-211 exposure consisted in a hippocampus receiving connections from piriform cortex and dorsal striatum, the latter both directly and through functional control over the 'extended amygdala'. Such results represent a starting point to explore neurophysiology of 5-HT7 receptors. Further investigation is warranted to develop therapies for sleep disorders, for impaired emotional and motivational regulation, for attentive and executive deficit. The 5-HT7 agonist LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during adolescence (postnatal days 43-45 to 47-49) in rats. When adult (postnatal days >70), a significant elevation in levels of 5-HT7 receptors were evidenced in dorsal striatum and-unexpectedly-in piriform cortex.

Gambling disorder is associated to an increased impulsivity, a high level of novelty-seeking and a dysregulation of the forebrain neurotransmission systems. However, the neurobiological mechanisms of this addictive disorder are not fully understood and no valid pharmacological approach has yet been approved. The present study aimed to investigate the effect of 5-HT7 receptor (5-HT7R) stimulation with a brain penetrant and selective agonist, LP-211 (0.25 and 0.50 mg/kg i.p.) during post-experience consolidation, i) acutely in a novelty-preference test (Exp. 1) or ii) sub-chronically in the Probabilistic-Delivery Task (rPDT, commonly used to measure individual differences in risk proneness of rats; Exp. 2). Results of Exp. 1 showed that 5-HT7R activation improves consolidation of chamber-shape memory in the novelty-preference test, leading to significant novelty-induced hyperactivity and recognition, in conditions where controls displayed a null-preference. These results suggest that 5-HT7Rs may be involved in the consolidation of information inherent to spatial environments, facilitating the recognition of novelty. Furthermore, in the operant rPDT (Exp. 2), 5-HT7R activation shifts the choice towards a larger yet unlikely reward and turns the propensity of rats towards risk-prone behavior. Thus, 5-HT7Rs stimulation apparently strengthens the consideration of future, bigger rewards, also enhancing the seeking of it by operant pokes. These effects may well be explained by LP-211 actions on hippocampal versus prefrontal cortex-mediated regulations, leading to an improved (though suboptimal) strategy formation. However, further experiments are necessary to determine more in depth the serotonergic pathways involved. This article is protected by copyright. All rights reserved.

Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbances like conduct disorder, antisocial and narcissistic personality disorders. Limited sensitivity to punishment, shallow or deficient affect and reduced physiological reactivity to environmental stressors have been often reported to co-occur with limited empathy and contribute to the onset of antisocial phenotypes. Empathy in its simplest form (i.e. emotional contagion) is addressed in preclinical models through the evaluation of the social transmission of emotional states: mice exposed to a painful stimulus display a higher response if in the presence of a familiar individual experiencing a higher degree of discomfort, than in isolation. In the present study, we investigated whether a reduction of emotional contagion can be considered a predictor of reduced sociality, sensitivity to punishment and physiological stress reactivity. To this aim, we first evaluated emotional contagion in a group of Balb/cJ mice and then discretised their values in four quartiles. The upper (i.e. Emotional Contagion Prone, ECP) and the lower (i.e. Emotional Contagion Resistant, ECR) quartiles constituted the experimental groups. Our results indicate that mice in the lower quartile are characterized by reduced sociability, impaired memory of negative events and dampened hypothalamic-pituitary-adrenocortical reactivity to external stressors. Furthermore, in the absence of changes in oxytocin receptor density, we show that these mice exhibit elevated concentrations of oxytocin and vasopressin and reduced density of BDNF receptors in behaviourally-relevant brain areas. Thus, not only do present results translate to the preclinical investigation of psychiatric disturbances, but also they can contribute to the study of emotional contagion in terms of its adaptive significance.

Gambling Disorder (GD) is characterized by excessive gambling despite adverse consequences on individual functioning. In spite of some positive findings, it is difficult to draw any conclusion on the genetics of GD. Indeed, beyond DNA sequence variation, other regulatory mechanisms (like those that engage epigenetics) may explain gene alterations in this addictive disease. Wistar male rats underwent an operant task for the evaluation of individual propensity to gamble. Few rats, after having learnt to prefer nose-poking for a large over a small food reward, were sacrificed to obtain a baseline profile of gene expression at both central and peripheral levels. In the remaining rats, probability of occurrence of large-reward delivery decreased progressively to very low levels. Thus, rats were faced with temptation to “gamble”, i.e. to nose-poke for a binge reward, whose delivery was omitted the majority of times. After 3 weeks of testing, rats showing a clear-cut profile of either gambling proneness or aversion were selected and sacrificed after the last session. A selective down-regulation of i) serotonin transporter in prefrontal cortex, ii) tyrosine hydroxylase in ventral striatum, iii) dopamine transporter in lymphocytes was evidenced in “gambler” vs “non-gambler” rats. The exposure to such operant task (compared to home-cage alone) modulated ventrostriatal but not prefrontal genes. A consistent increase of DNA methylation, in one specific CpG site at serotonin transporter gene, was evident in prefrontal cortex of “gambler” rats. Elucidation of epigenetic changes occurring during GD progression may pave the way to the development of new therapeutic strategies through specific modulation of epigenetic factors.

Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats.

The preclinical study of human disorders associated with comorbidities and for which the aetiology is still unclear may substantially benefit from multi-strain studies conducted in mice. The latter can help isolating experimental populations (strains) exhibiting distinct facets in the parameters isomorphic to the symptoms of a given disorder. Through a reverse-translation approach, multi-strain studies can inform both natural predisposing factors and environmental modulators. Thus, mouse strains selected for a particular trait may be leveraged to generate hypothesis-driven studies aimed at clarifying the potential role played by the environment in modulating the exhibition of the symptoms of interest. Tourette's syndrome (TS) constitutes a paradigmatic example whereby: it is characterized by a core symptom (tics) often associated with comorbidities (attention-deficit-hyperactivity and obsessive-compulsive symptoms); it has a clear genetic origin though specific genes are, as yet, unidentified; its course (exacerbations and remissions) is under the influence of environmental factors. Based on these considerations, we tested four mouse strains (ABH, C57, CD1, and SJL) - varying along a plethora of behavioural, neurochemical, and immunological parameters - on a test battery tailored to address the following domains: tics (through the i.p. administration of the selective 5-HT2 receptor agonist DOI, 5mg/kg); locomotion (spontaneous locomotion in the home-cage); perseverative responding in an attentional set shifting task; and behavioural stereotypies in response to a single amphetamine (10mg/kg, i.p.) injection. Present data demonstrate that while ABH and SJL mice respectively exhibit selective increments in amphetamine-induced sniffing behaviour and DOI-induced tic-like behaviours, C57 and CD1 mice show a distinct phenotype, compared to other strains, in several parameters.

Interest is rising for animal modeling of pathological gambling. Using the operant probabilistic-delivery task (PDT), gambling proneness can be evaluated in laboratory animals. Drawing a comparison with rats, this study evaluated the common marmoset (Callithrix jacchus) using a PDT. By nose- or hand-poking, subjects learnt to prefer a large (LLL, 5-6 pellets) over a small (SS, 1-2 pellets) reward and, subsequently, the probability of occurrence of large-reward delivery was decreased progressively to very low levels (from 100% to 17% and 14%). As probability decreased, subjects showed a great versus little shift in preference from LLL to SS reinforcer. Hence, two distinct subpopulations (“non-gambler” versus “gambler”) were differentiated within each species. A proof of the model validity comes from marmosets’ reaction to reward-delivery omission. Namely, depending on individual temperament (“gambler” versus “non-gambler”), they showed either persistence (i.e., inadequate pokes towards LLL) or restlessness (i.e., inadequate pokes towards SS), respectively. In conclusion, the marmoset could be a suitable model for preclinical gambling studies. Implementation of the PDT to species other than rats may be relevant for determining its external validity/generalizability and improving its face/construct validity.

The central endocannabinoid system (eCB system) sustains the activity of the hypothalamus–pituitary–adrenal (HPA) axis in mediating individual emotional responses. Deviation in maturational trajectories of these two physiological systems, may persistently adjust individual behavioral phenotype. We investigated, in outbred CD1 male mice, whether exposure to prenatal stress may influence short- and long-term emotional and neurochemical responses to a pharmacological stimulation of the eCB system during adolescence. To mimic prenatal stress, pregnant mice were supplemented with corticosterone in the drinking water (33.3 mg/l); their adolescent male offspring received daily injections of the fatty acid amide hydrolase inhibitor, URB597 (0.4 mg/kg), in order to enhance eCB signaling. Mice were then tested for: locomotor activity during adolescence and locomotor activity, anxiogenic, and anhedonic profiles in adulthood. We analyzed the expression of CB1 receptors (CB1Rs) in prefrontal cortex, hippocampus, striatum, and cerebellum in adulthood. Corticosterone administration (PC group) resulted, in adolescence, in a reduction in body weight and locomotion, while in adulthood, in increased anxiety-related behavior and reduced CB1Rs expression in cerebellum. URB597 exposure reduced locomotor activity and increased anhedonia in adulthood. CB1Rs were up-regulated in striatum and hippocampus and down-regulated in the cerebellum. PC-URB597 mice failed to show reductions in locomotion; exhibited increased risk assessment behavior; and showed reduced CB1Rs expression within the prefrontal cortex. Present results provide support to the hypothesis that precocious manipulations mapping onto the HPA axis and eCB system may persistently adjust individual emotional responses and eCB system plasticity.

We report here the results of studies aimed to investigate the involvement of serotonin receptor 7 subtype (5-HT7-R) in the modulation of emotional response in Naples High-Excitability (NHE) rat, a validated model for hyperactivity and impaired attention. A range of dosages (0.0, 0.125, 0.250, or 0.500 mg/kg) of LP-211, a selective agonist of 5-HT7-Rs, has been evaluated in animals at different age (adolescence and adulthood). Male NHE and random bred (NRB) control rats were tested in an Elevated Zero-Maze (EZM) after LP-211 treatment in two different regimens: at the issue of adolescent, subchronic exposure (14 intraperitoneal [i.p.] injections, once/day, pnd 31–44, tested on pnd 45—Exp. 1) or as adult, acute effect (15 min after i.p. injection—Exp. 2). Adolescent, subchronic LP-211 at 0.500 mg/kg dosage increased the frequency of head-dips only in NHE rats. Drug effect on time spent and entries in open EZM quadrants were revealed with adult, acute administration of 0.125 mg/kg LP-211 (both strains), indicating a tendency toward anxiolytic effects. In conclusion, data demonstrate that subchronic stimulation of 5-HT7-Rs during prepuberal period increases novelty-seeking/risk-taking propensity in NHE adults. These sequels are revealing increased disinhibition and/or motivation to explore in the NHE rats, which are characterized by a hyperactive dopaminergic system. These data may open new perspectives in studying mechanism of risk-seeking behavior. Synapse 68:159–167, 2014. © 2013 Wiley Periodicals, Inc.

Individual differences in behavioural flexibility are a significant issue in human psychopathology as well as in its animal models. We aimed to investigate individual variations of operant-choice behaviour in the common marmoset (Callithrix jacchus), a small New World primate, using a new operant panel with two hand-poking holes.Experimental subjects (N=16) were presented with a choice between a SmallSoon (SS) vs a LargeLate (LL) food reward. After extensive training (31 daily sessions with no delay, during which a basal, large-reward preference developed), the delay before release of LL was progressively increased (from 0 to 60 s, during 16 daily sessions; indifferent point at delay=9 s). Subjects were classified as either "flexible" or "non-flexible", respectively, based on a decrease (or not) in the preference for LL with increasing delays. Each subject was also classified as "maximizer" (or "non-maximizer") based on capacity (or not) to maximize the food payoff as delay increased.Upon delays shorter than the indifferent point (9s), none of the subjects showed a shift from LL to SS, denoting a lack of delay-induced, cognitive impulsivity. Individual differences only emerged upon delays longer than the indifferent point (9 s), when a preference shift could be interpreted as economically-driven. In general, a profile of few unrewarded hand-pokes in reaction to initial delays (i.e., a low motor impulsivity) and of clear-cut basal LL preference seemed to predict elevated flexibility of choices and better food payoff, which was typical of subjects classified as both "flexiblemaximizer".These results provide normative data on the marmosets, which can be used as a model for the investigation of 1) individual differences in behavioural flexibility, as well as 2) biological mechanisms rooted in our evolutionary history.

In the present manuscript we review a substantial body of literature describing several pre-clinical animal models designed and developed with the purpose of investigating the biological determinants of Tourette syndrome (TS). In order to map the animal models onto the theoretical background upon which they have been devised, we first define phenomenological and etiological aspects of TS and then match this information to the available pre-clinical models. Thus, we first describe the characteristic symptoms exhibited by TS patients and then a series of hypotheses attempting to identify the multifactorial causes of TS. With respect to the former, we detail the phenomenology of abnormal repetitive behaviors (tics and stereotypies), obsessive-compulsive behaviors and aberrant sensory-motor gating. With respect to the latter, we describe both potential candidate vulnerability genes and environmental factors (difficult pregnancies, psychosocial stressors and infections). We then discuss how this evidence has been translated in pre-clinical research with respect to both dependent (symptoms) and independent (etiological factors) variables. Thus, while, on the one hand, we detail the methodologies adopted to measure abnormal repetitive and obsessive-compulsive behaviors, and sensory-motor gating, on the other hand, we describe genetic engineering studies and environmental modulations aimed at reproducing the proposed biological determinants in laboratory rodents. A special emphasis is placed upon "programming" events, occurring during critical stages of early development and exerting organizational delayed consequences. In the final section, we outline a heuristic model with the purpose of integrating clinical and pre-clinical evidence in the study of TS.

Pathological gambling is widespread among adolescents (3–8%). Gambling proneness can be evaluated in animals using the Probabilistic Delivery (PD) task. In this operant protocol, rats learn to choose for large over small reward. Subsequently, the probability of large reward-delivery decreases progressively to very low levels. Using a home-cage version of the PD task, we studied (Exp. 1–3) the development of preference for the largest reward in middle (pnd 34–35) and late (pnd 48–49) adolescent rats, using the standard paradigm ( Zoratto et al., 2012 ) and then modifying: (i) probability “p” initially associated with the largest reward; (ii) size difference between rewards; (iii) “removable” or “fixed” partitions (allowing to house animals in couples, separating them only during testing). The standard paradigm (p = 50%, 2 vs 6 pellets; “removable” partitions) does not allow the establishment of preference for the largest reward, at neither adolescent age. Conversely, the modified paradigm (p = 66%; 1 vs 5 pellets; “fixed” partitions) allows the development of such preference, already at pnd 34–35. By using the best combination of these factors, we then investigated (Exp. 4) the characteristics of gambling behaviour in middle adolescent (pnd 36–49) and young adult (pnd 67–80) rats. Gambling proneness appears slightly increased during adolescence when compared to adulthood. Notably, inadequate responses (expressed during post-choice timeout, 30 s) appear markedly reduced, suggesting developing animals to be insensitive to reward-delivery omission. In conclusion, methodological refinement is essential to allow the study of risk-prone behaviour during rat adolescence, thus contributing to a better understanding of psychobiological determinants of gambling.

Recent data indicate that both availability and consumption of synthetic and natural psychoactive substances, marketed under the name of "legal highs", has increased. Among them, the aminoalkylindole-derivative JWH-018 is widely distributed due to its capability of binding the cannabinoid receptors CB1 and CB2 thereby mimicking the effects of classical drug agonists. To address whether the behavioral effects of the synthetic compound JWH-018 are similar to those induced by classical cannabinoid agonists, we investigated, in outbred CD1 mice, the consequences of its acute and sub-chronic administration (0, 0.03, 0.1, or 0.3 mg/kg, IP) at the level of body temperature, pain perception, general locomotion, and anxiety. In order to address whether the exposure to precocious stressors-modified individual reactivity to this psychoactive substance, we also investigated its effects in adult mice previously exposed to prenatal stress in the form of corticosterone supplementation in the maternal drinking water (33 or 100 mg/L). In the absence of major effects on motor coordination, JWH-018-reduced body temperature, locomotion and pain reactivity, and increased indices of anxiety. Prenatal corticosterone administration-reduced individual sensitivity to the effects of JWH-018 administration in all the aforementioned parameters. This altered response is not due to variations in JWH-018 metabolism. Present data support the hypothesis that precocious stress may affect, in the long-term, the functional status, and reactivity of the endocannabinoid system.

Summary The serotonergic system and the hypothalamic-pituitary-adrenal (HPA) axis are crucially involved in the regulation of emotions. Specifically, spontaneous and/or environmentally mediated modulations of the functionality of these systems early in development may favour the onset of depressive- and anxiety-related phenotypes. While the independent contribution of each of these systems to the emergence of abnormal phenotypes has been detailed in clinical and experimental studies, only rarely has their interaction been systematically investigated. Here, we addressed the effects of reduced serotonin and environmental stress during the early stages of postnatal life on emotional regulations in mice. To this aim, we administered, to outbred CD1 mouse dams, during their first week of lactation, a tryptophan deficient diet (T) and corticosterone via drinking water (C; 80 μg/ml). Four groups of dams (animal facility rearing, AFR; T treated, T; C treated, C; T and C treated, TC) and their male offspring were used in the study. Maternal care was scored throughout treatment and adult offspring were tested for: anhedonia (progressive ratio schedule); anxiety-related behaviour (approach-avoidance conflict paradigm); BDNF, dopamine and serotonin concentrations in selected brain areas. T, C and TC treatments reduced active maternal care compared to AFR. Adult TC offspring showed significantly increased anxiety- and anhedonia-related behaviours, reduced striatal and increased hypothalamic BDNF and reduced dopamine and serotonin in the prefrontal cortex and their turnover in the hippocampus. Thus, present findings support the view that neonatal variations in the functionality of the serotonergic system and of HPA axis may jointly contribute to induce emotional disturbances in adulthood.

Conduct disorder (CD), a disturbance characterised by excess rates of aggression - often associated with callousness, lack of empathy and shallow/deficient affect - is extremely prevalent (2-10%) in the juvenile population. CD symptoms are quantitative rather than qualitative in nature whereby, rather than exhibiting abnormal behaviours, CD patients indulge in normal behaviours at abnormal rates. Although genetic and environmental factors contribute to CD aetiology, their precise contribution is yet to be determined. Experimental animal models may aid discriminating genetic vs. environmental effects and designing innovative therapeutic approaches. Here we discuss a theoretical framework potentially favouring the design of experimental models of CD. We suggest that the latter shall recapitulate the "norm violation" typical of the human disorder across the core domains involved in CD: aggression, callousness, empathy and emotionality. We first review how these domains have been operationalised in preclinical models; we then suggest that these experimental paradigms shall be combined with appropriate statistical tools to identify a subset of individuals consistently characterised by abnormal values in CD-relevant phenotypes.

The prevalence, age of onset and symptomatology of many neurodevelopmental disorders strongly differ between genders. This review examines sex biases in human neurodevelopmental disorders and in validated animal models. A focus is made on disorders of well-established genetic origin, such as Rett syndrome, CDKL5-associated disorders, Fragile X and Down syndrome. Autism is also addressed, given its paradigmatic role as a sex-biased neurodevelopmental disorder. Reviewed literature confirms that a complex interaction between genetic factors and sex hormones may underlie the differential susceptibility of genders and may impact the severity of symptoms in most of the analyzed neurodevelopmental disorders. Even though further studies addressing the advantages and disadvantages conferred by biological sex in this class of disorders are needed to disentangle the underlying mechanisms, present findings suggest that modulation of sex steroid-related pathways may represent an innovative approach for these diseases. Much effort is now expected to unravel the potential therapeutic efficacy of drugs targeting sex hormones-related signaling pathways in neurodevelopmental disorders of well-established genetic origin.

Psycho-genetic studies have revealed a role for the brain serotonin system in gambling proneness and poor decision-making. We assessed whether manipulation of brain serotonin levels in rats affected performance in operant-based tasks for decision-making and gambling proneness. Male Wistar rats were exposed to an l -tryptophan (TRP) deficient diet (0.0 g/kg; T− group) or to a control, l -tryptophan containing diet (2.8 g/kg; T+ group). The same rats were tested for decision-making performance in the rodent Iowa Gambling Task (rIGT) using home-cage operant panels, and subsequently for gambling proneness in a Probabilistic Delivery Task (rPDT) using classic Skinnerboxes. At sacrifice, monoamines and metabolites were evaluated with HPLC analysis, confirming a drastically reduced serotonin synthesis, as well as altered dopamine turnover in the prefrontal cortex of T− rats. As expected, control rats (T+) progressively chose the option with the best long-term payoff in the rIGT, and also shifted from “Large & Luck-Linked” (LLL) to “Small & Sure” (SS) reinforcers in the rPDT. In contrast, depleted animals (T−) exhibited a weaker improvement of performance in the rIGT and maintained a sub-optimal attraction for LLL reinforcer in the rPDT. Comparing individual performances in both tests, we found a significant correlation between the two tasks in control (T+) but not in depleted (T−) rats. The present study revealed that (1) brain 5-HT depletion leads to poor decision-making and to gambling proneness; (2) the relationship between these two traits, shown in the control group, was disrupted in 5-HT depleted rats. The data are discussed in terms of changes within forebrain loops involved in cognitive and motivational/affective processes.

Serotonin receptor 7, i.e. 5-HT(7) protein coded by Htr7 gene, was discovered in supra-chiasmatic nucleus (SCN) of the hypothalamus but is widespread in the forebrain. Studies have shown that this receptor is involved in learning/memory, regulation of mood and circadian rhythms. The modulatory effects of two novel agonists, LP-211 and LP-378, were assessed in male adult CD-1 mice with a battery of behavioral tests. Exp. 1 (Black/White Boxes, BWB: Adriani et al., 2009) and Exp. 2 (Dark/Light, D/L; Novelty-seeking, N-S) show: a) that LP-211 administration (acutely, at a 0.25 mg/kg dose i.p.) increases locomotion and BWB exploration; b) that the time spent away from an aversive, lit chamber (i.e., stress-induced anxiety) and in a new environment (i.e., novelty-induced curiosity) are both reduced. Sub-chronic LP-211 (at a 2.5 mg/kg dose i.p.) reveals a sensitization of locomotor-stimulant properties over 4–5 days. In Exp. 3 (BWB), a three- to four-fold dosage (acutely, at 0.83 mg/kg i.p.) is needed with LP-378 to increase locomotion and BWB exploration. In Exp. 4, mice under constant-light conditions reveal the expected spontaneous lengthening (1.5 h per day) of circadian rhythms. A significant phase advance is induced by LP-211 (at a 0.25 mg/kg dose i.p., administered around activity offset), with onset of activity taking place 6 h earlier than in controls. In summary, LP-211 is able to act consistently onto exploratory motivation, anxiety-related profiles, and spontaneous circadian rhythm. In the next future, agonist modulation of 5-HT(7) receptors might turn out to be beneficial for sleep and/or anxiety disorders. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Summary Maternal behavior in rodents has been proposed to vary as a function of the external environment and, in turn, adjust offspring’s stress and fear responses. Early handling (brief periods of maternal separation during the first two weeks of life) studies and analyses of spontaneously high-caring rat mothers converge to indicate that increased levels of maternal care may reduce offspring emotionality in adulthood. However, the hypothesis that environmentdependent reduction in maternal care correlates with increased offspring vulnerability to pathology has been scarcely investigated. To test this hypothesis we studied maternal care and offspring development in young, adolescent and young-adult Sprague—Dawley rats reared in a communal nursing situation, characterized by two dams delivering their offspring four days apart and communally caring for them until weaning. We show that dams of the first-born litter show increased aggression towards the pregnant female and that offspring belonging to the second-born litter receive less maternal care compared to older cage-mates. Additionally, second-born rats show increased anxiety-related behavior in a plus-maze test in adolescence and adulthood and abnormal developmental trajectories in terms of social interaction and BDNF levels in the amygdala and hippocampus compared to both the first-born litter and to animal facility reared controls. This is the first indication that adverse environments, not requiring experimenter handling, may reduce maternal care and in turn increase offspring’s emotionality and modify social behavior and BDNF developmental trajectories.

Early life experiences have been shown to adjust cognitive abilities, stress reactivity, fear responses and immune activity in adult mammals of many species. However, whereas severe stressors have been generally associated with the emergence of hypothalamic pituitary adreno-cortical (HPA)-mediated pathology, mild neonatal stressful experiences have been traditionally associated with 'positive' effects or resilience. External stressors stimulate the HPA axis to induce a corticosterone secretion in mouse dams, which, in turn is directly transmitted to the progeny through lactation. Such corticosteroid transfer may offer a unitary mechanism whereby early low corticosterone exposure may favor resilience in the offspring and high corticosterone increase vulnerability to pathology. In this study we further investigated this hypothesis by evaluating the long-term effects of a neonatal exposure to low (33 mg/l) and high (100 mg/l) doses of corticosterone during the first 10 days of life in outbred CD-1 mice through supplementation in the maternal drinking water. Offspring attentional set-shifting abilities, central neurotrophic regulation and levels of natural auto-antibodies (na-Abs) directed to serotonin (SERT) and dopamine (DAT) transporters were assessed in adulthood. While low levels of neonatal corticosterone improved adult cognitive abilities and increased na-Abs levels directed to SERT, high doses of neonatal corticosterone reduced hippocampal BDNF levels and na-Abs directed to DAT. These findings confirm and extend our previous findings, supporting the view that both adaptive plasticity and pathological outcomes in adulthood may depend on circulating neonatal corticosterone levels and that these effects follow a U-shaped profile.

Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.

Environmental rearing conditions during the neonatal period are critical for the establishment of neurobiological factors controlling behavior and stress responsiveness. Early maternal deprivation (MD), consisting of a single 24-h maternal deprivation episode during early neonatal life, has been proposed as an animal model for certain psychopathologies including anxiety, depression and schizophrenic-related disorders. Despite first onset of mental disorders usually occur during adolescence, characterization of MD has been mostly developed in adult animals. We review here a series of experiments that were conducted on rats and mice, in which we analyzed the psychoimmunoendocrine outcomes of MD at both adolescence and adulthood. As a whole our results indicate that MD might promote a depressive-like trait that may be present from adolescence to maturity. Maternally deprived adolescent animals also displayed altered locomotor responses, a reduced interest for social investigation and seemed prone for impulsive behavior. Therefore, MD in rodents is further confirmed as a suitable animal model for the study of neuropsychiatric disorders that might become evident during adolescence. Given the increasing consumption of cannabis derivatives among the juvenile population and the reported comorbidity of neuropsychiatric symptoms with cannabis abuse, we also discuss our results indicating altered responses of maternally deprived adolescent animals to cannabinoid compounds.

Mental disorders are increasingly recognized to be chronic and disabling, belonging to a group of serious medical illnesses including heart disease, cancer and diabetes (Insel and Scolnick, 2006; Mathers and Loncar, 2006). The Global Burden of Disease report has revealed that neuropsychiatric conditions account for a quarter of all disability-adjusted life years (Prince et al., 2007). Furthermore, the burden of mental disorders is likely to be underestimated because of inadequate appreciation of the link between mental illness and other health conditions. Several health conditions increase the risk for mental disorder and co-morbidity complicates help-seeking, diagnosis and treatment and can affect prognosis. An often underestimated risk factor for mental health has to do with exposure to maternal or nutritional perinatal conditions, as well as exposure to early stress. For the most common major illnesses, we now have medical and psychosocial interventions of proven efficacy in randomized, controlled trials. Many patients with mood disorders will respond to treatment and some will recover completely. However, the available treatments appear still insufficient, thus urging a more effective bridge between basic research discoveries and the development of novel therapeutic strategies for the cure and prevention of mental illnesses. One the limiting factors for developing appropriate therapeutic strategies could derive from the notion that researchers have so far approached mental illnesses as fundamentally different from all other medical diseases (Insel and Scolnick, 2006). These considerations have prompted us to deal with these issues by soliciting a number of contributions from researchers involved in basic research in mental health. The aim of this Special Issue of Neuroscience and Biobehavioral Reviews is to give an overview of how different approaches can be used in translational neuroscience in order to facilitate the identification of vulnerability factors, novel diagnostic markers as well as pharmacological targets to be exploited by the pharmaceutical industry for the development of innovative preventive approaches and treatment strategies. Within this issue studies performed in humans (Gerra et al., 2007; Andersen and Teicher, 2008) provide a clear evidence that exposure to adverse events during the course of development predispose an individual to substance abuse. Understanding the role that development plays in the expression of these risk factors is often overlooked, but definitively needs more attention to fully understand the impact of early life events on the complex neurobiological derangement, including HPA axis and dopamine system dysfunctions, playing a crucial role in addictive and affective disorders - and possibly metabolic -susceptibility. Despite the important information provided by human studies, these have a limited capacity to explain basic mechanisms of disease. In this issue we included a number of papers demonstrating how, in recent years, there has been a growing emphasis on developing complex models that incorporate a number of variables which can be manipulated by the experimenter thus providing new opportunities for translation from basic to clinical research. We will provide examples of studies performed with the common aim of understanding the role of environmental/nutritional factors in shaping brain development and functioning. While studies performed using rodents (Alleva and Francia, 2008; Andersen and Teicher, 2008; Cirulli et al., 2008) offer a great opportunity to ask questions that can be answered in a short-time scale and allow for the analysis of neurobiological substrates, (Coccurello et al., 2008; Laviola et al., 2008; Marco et al., 2008; Nag et al., 2008; Scattoni et al., 2008) those using non-human primates offer a great opportunity to ask questions that can be answered in a short-time scale and allow for the analysis of neurobiological substrates, those using non-human primates provide the closest match to humans in terms of genetic, behavioral, biological and social similarity (Cirulli et al., 2008). In addition, non-human primates’ relatively long lifespan, extended infancy, and socio-affective behavior parallel many aspects of human development. The challenge that basic science needs to meet is to make use of a comparative approach to benefit the most from what each model, notwithstanding its constraints, can tell us about the mechanisms underlying an increased risk for mental health.

Despite the alarming increment in the use and abuse of cannabis preparations among young people, little is known about possible long-term consequences of targeting the endocannabinoid system during the critical developmental period of adolescence. Therefore, we aimed to analyze possible long-lasting neurobiological consequences of enhancing endocannabinoid signalling during adolescence, by means of blocking anandamide (AEA) hydrolysis. Adolescent Wistar male rats were administered an inhibitor of AEA hydrolysis, i.e. URB597 (0, 0.1 or 0.5 mg/kg/day from postnatal days 38 to 43). The expression of brain cannabinoid receptor type 1 (CB1R) was then analyzed by [3H]CP-55,940 auto-radiographic binding at adulthood. Repeated URB597 administration during adolescence persistently modified CB1R binding in a region-dependent manner. A long-lasting decrease of CB1R binding levels was found in caudate-putamen, nucleus accumbens, ventral tegmental area and hippocampus, while an opposite increment was observed in the locus coeruleus. Present results provide evidence for long-lasting effects of adolescent URB597 administration. Activation of endocannabinoid transmission during the still plastic phase of adolescence may have implications for the maturational end-point of the endocannabinoid system itself, which could lead to permanent alterations in neuronal brain circuits and behavioural responses. Insights into the developmental trajectories of this neuromodulatory system may help us to better understand and prevent outcomes of neonatal and adolescent cannabis exposure.

Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, ‘paradoxical’ responses to psychostimulants have been reported at this age. Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague–Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min. Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters. The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy.

Objective and methods The reeler heterozygous (HZ) mice have provided a model for studying the relationship between reelin (a protein of extracellular matrix) haploinsufficiency and the emergence of neuropsychiatric diseases. In a neurodevelopmental framework, the enduring consequences of early maternal separation (5 h/day during the first postnatal week, or handling controls, H) were studied in reeler HZ and wild type (WT) mice at adulthood. The modulatory effects of a chronic treatment with the atypical antipsychotic olanzapine (OLZ, 1.5 mg/kg for 40 days) were also investigated. Results Early maternal separation had long-term effects on brain plasticity, with a reduction of brain- and glial- derived neurotrophic factor (BDNF and GDNF) in several brain areas of mice, but such a consequence was less marked in the HZ genotype. On the other hand, treatment with OLZ did not affect at all the GDNF but led to an increase of BDNF levels in maternally separated (SEP) mice, an effect which was far more marked in the HZ genotype. Brain levels of serotonin (5-HT) were markedly increased, striatal dopamine (DA) was increased, whereas metabolites and turnover were decreased, in SEP mice of both genotypes. The spontaneous home-cage activity was generally lower in HZ than WT mice, and OLZ treatment contrasted this hypoactivity profile. Maternal separation also decreased the interest toward an unknown mouse proposed as a social stimulus, but only in WT mice. Conclusion We investigated the interplay between genetic vulnerability (reelin haploinsufficiency), the outcome of early stressful experiences, and the efficacy of the antipsychotic drug therapy. The reeler HZ genotype exhibited a slightly lower sensitivity to the environmental insult as well as an enhanced response to the atypical antipsychotic treatment.

There is evidence for the existence of functional interactions between nicotine and cannabinoids and opioid compounds in adult experimental animals. However, there is scarce information about these relationships in young animals. In the present study we evaluated short and long-term effects of a subchronic nicotine treatment [0.4 mg/kg daily i.p. injections from postnatal day (PND) 34 to PND 43], upon hippocampal and striatal cannabinoid-CB(1) and mu-opioid receptors in Wistar rats of both genders. Rats were sacrificed 2 h after the last nicotine injection (short-term effects, PND 43) or one month later (long-term effects, PND 75). Hippocampal and striatal cannabinoid CB(1) and mu-opioid receptors were quantified by Western blotting. The subchronic nicotine treatment induced a region-dependent long-lasting effect in cannabinoid CB(1) receptor: a significant increase in hippocampal cannabinoid CB(1) receptors and a significant decrease in striatal cannabinoid CB(1) receptors, with these effects being similar in males and females. With respect to mu-opioid receptors, subchronic nicotine induced a significant down-regulation in hippocampal and striatal mu-opioid receptors in the long-term, and within the striatum the effects were more marked in adult males than in females. The present results indicate that juvenile nicotine taking may have implications for the endocannabinoid and endogenous opioid function and for the behaviors served by those systems, this includes possible modification of the response of adults to different psychotropic drugs, i.e. cannabis and morphine/heroin when taken later in life.

Pharmacological modulation of the endocannabinoid system is a novel but poorly explored field for potential therapy. Early maternal deprivation represents an animal model for specific aspects of neuropsychiatric disorders. This study explored whether a pharmacological manipulation of the endocannabinoid system at adolescence may restore altered phenotypes resulting from early maternal deprivation. Wistar male rats, maternally deprived for 24 h on postnatal day (PND) 9, were administered the fatty-acid amide hydrolase (FAAH) inhibitor URB597 (0, 0.1 or 0.5 mg/kg/day) for six days during adolescence (PND 31–43), while tested in the intolerance-to-delay task. Deprived (DEP) adolescent rats showed a trend for higher impulsivity levels and an increased locomotor response to novelty when compared to non-deprived (NDEP) controls. The low dose of URB597 effectively decreased impulsive behaviour specifically in DEP subjects. Moreover, long-term metabolic brain changes, induced by drug treatment during adolescence, were detected in DEP animals using proton magnetic resonance spectroscopy ( 1 H MRS). Significant changes were only found within the hippocampus: N -acetyl-aspartate and total creatine were up-regulated by the low dose; glutamate and glutamate plus glutamine were conversely down-regulated by the higher dose. In summary, administration of URB597 during adolescence increased self-control behaviour and produced enduring brain biochemical modifications, in a model for neuropsychiatric disorders.

Studies on heterozygous (HZ) reeler mice suggest a relationship between reelin (a protein of extra cellular matrix) haploinsufficiency and the presence of altered neural networks and behaviour. Neonatal adverse and/or stimulating experiences might interfere with the emergence of this genetic-dependent phenotype. Repeated episodes of maternal separation early in ontogeny result in enduring neuroendocrine, neurochemical and behavioural alterations in the offspring. Therefore, in order to investigate whether developmental indexes of neurobehavioural disorders can be studied in the infant reeler mouse model, and whether ontogenetic adverse experiences may question or improve its suitability, homozygous reeler (RL), heterozygous (HZ) and wild-type (WT) mouse pups underwent maternal separation (SEP, 5 h/day) or handling (H, 3 min/day) on PND 2–6. As expected, a sex difference appeared, for measure of emotional and communicative behaviour in infant mice. On PND 7, compared to other genotypes, RL mouse pups from the H control group, showed reduced levels of ultrasound (USV) production and of locomotion. Surprisingly, this deficit in RL mice was fully reverted by maternal separation. Maternal separation per se reduced social motivation in the homing test at PND 9 in WT mice, with no effects on HZ and RL ones. Additionally, female pups emitted much lower levels of ultrasound production than males within the H control group. Such a baseline sex difference, however, disappeared in the SEP group. The present results provide evidence that unusual stress and related hormonal stimulation early in development may (i) independently shape individual phenotype and (ii) interact with a genetic make-up to substantially modify its “natural” developmental trajectories.

Administration of methylphenidate (MPH, Ritalin®) to children affected by attention deficit hyperactivity disorder (ADHD) is an elective therapy, which however raises concerns for public health, due to possible persistent neuro-behavioral alterations. We investigated potential long-term consequences at adulthood of MPH exposure during adolescence, by means of behavioral and brain MRS assessment in drug-free state. Wistar adolescent rats (30- to 44-day-old) were treated with MPH (0 or 2 mg/kg once/day for 14 days) and then left undisturbed until adulthood. Levels of impulsive behavior were assessed in the intolerance-to-delay task: Food-restricted rats were tested in operant chambers with two nose-poking holes, delivering one food pellet immediately, or five pellets after a delay whose length was increased over days. MPH-exposed animals showed a less marked shifting profile from the large/late to the small/soon reward, suggesting reduced basal levels of impulsivity, compared to controls. In vivo MRI-guided 1 H MRS examinations at 4.7 T in anaesthetised animals revealed long-term biochemical changes in the dorsal striatum (STR), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of MPH-exposed rats. Notably, total creatine and taurine, metabolites respectively involved in bioenergetics and synaptic efficiency, were up-regulated in the STR and conversely down-regulated in the NAcc of MPH-exposed rats. A strong correlation was evident between non-phosphorylated creatine in the STR and behavioral impulsivity. Moreover, unaltered total creatine and increased phospho-creatine/creatine ratio were detected in the PFC, suggesting improved cortical energetic performance. Because of this enduring rearrangement in the forebrain function, MPH-exposed animals may be more efficient when faced with delay of reinforcement. In summary, MPH exposure during adolescence produced enduring MRS-detectable biochemical modifications in brain reward-related circuits, which may account for increased self-control capacity of adult rats.

Early experiences have profound influences on individual developmental trajectories. For example alcohol exposure during central nervous system development relates to a number of pathological consequences in adulthood. An increased risk of developing psychiatric disorders, like major depression and impulse-control-related pathologies is associated with alcohol exposure during fetal life and/or during adolescence. Additionally, adverse life experiences occurring early in development may exacerbate these consequences, while impinging on the same neural systems affected by precocious alcohol exposure. Conversely, a protective and/or stimulating environment may mitigate these alcohol-related negative outcomes. Experimental research in animal models constitutes a primary source of information in understanding both functional and dysfunctional human adaptations to these events. In this review, a selection of rodent and primate studies shows that developmental ethanol exposure on the one hand, and environmental treatments aimed at modifying the mother-offspring interaction on the other hand, independently modulate similar neuro-endocrine systems. In particular, we discuss the effects that the above-mentioned independent variables exert on the hypothalamic-pituitary-adrenal (HPA)-axis and on brain serotonergic pathways. Experimental evidence indicates that pathological adaptations of these systems are valuable predictors of human neuro-behavioral abnormalities like depression, impaired impulse control and alcohol abuse. Finally, a working hypothesis is proposed, which combines primate and rodent studies aimed: (i) at studying functional and pathological individual development following early ethanol consumption, and (ii) at heading towards a better definition of potential intervention strategies.

This review analyses the most relevant studies in which ethanol intake was measured after prenatal exposure to the drug. Despite the variety in methodology, in most such studies this prenatal experience induced a higher consumption of ethanol. Several variables that may affect the expression of this phenomenon are discussed, such as gender, age at testing, period of ethanol exposure, ethanol dose and conditions during the test. The mechanisms proposed in all these studies to explain the increased ethanol intake effect are also discussed. Some of these mechanisms are related to the teratological effects of the drug on the neurochemical systems involved in the reinforcing effects of abuse drugs, as well as on the regulatory systems of stress response. Another explanation of this phenomenon is also proposed in terms of associative learning. Specifically, the increased ethanol intake effect may be the result of a conditioned preference for ethanol acquired by the fetus when exposed to the drug during the last days of gestation.

Interest is rising for animal modelling of Gambling disorder (GD), which is rapidly emerging as a mental health concern. In the present study, we assessed gambling proneness in male Wistar-Han rats using the "Probabilistic Delivery Task" (PDT). This operant protocol is based on choice between either certain, small amounts of food (SS) or larger amounts of food (LLL) delivered (or not) depending on a given (and progressively decreasing) probability. Here, we manipulated the ratio between large and small reward size to assess the impact of different magnitudes on rats' performance. Specifically, we drew a comparison between threefold (2 vs 6 pellets) and fivefold (1 vs 5 pellets) sizes. As a consequence, the "indifferent point" (IP, at which either choice is mathematically equivalent in terms of total foraging) was at 33% and 20% probability of delivery, respectively. Animals tested with the sharper contrast (i.e. fivefold ratio) exhibited sustained preference for LLL far beyond the IP, despite high uncertainty and low payoff, which rendered LLL a sub-optimal option. By contrast, animals facing a slighter contrast (i.e. threefold ratio) were increasingly disturbed by progressive rarefaction of rewards, as expressed by enhanced inadequate nose-poking: this was in accordance with their prompt shift in preference to SS, already shown around the IP. In conclusion, a five-folded LLL-to-SS ratio was not only more attractive, but also less frustrating than a three-folded one. Thus, a profile of gambling proneness in the PDT is more effectively induced by marked contrast between alternative options.

Interest is rising for auto-immune contribution in neuro-psychiatry. We evaluated the auto-antibodies against dopamine transporter (DAT aAbs) in 61 children (46 ADHD who met DSM-IV-TR criteria, 15 healthy controls). Methods ADHD patients were assigned, according to severity, either to a non-pharmacological therapy (NPT, N = 32) or to a pharmacological treatment (PT, N = 14) with methylphenidate (MPH). In ADHD children, blood samples were withdrawn twice, at recruitment (T0 basal) and after 6 weeks (T1); following 16 excluded subjects, DAT genotype was characterized (9-repeat or 10-repeat alleles; N = 15 each). After 18 months of NPT or PT, some patients (carrying at least one 9-repeat allele) were blood sampled again (T2), for comparison with healthy controls (final n = 8) Results Compared to NPT, basal DAT aAbs titers were higher within most severe patients (then assigned to PT), specifically if carrying a DAT 10/10 genotype. DAT aAbs levels of NPT group resulted highly correlated with distinct subscales of Conners' Parent/Teacher Scales (Rs > 0.34), especially within DAT 10/10 genotype (Rs > 0.53). While T1 titers were elevated over T0 baseline for NPT children, such an increase was not observed in PT patients carrying at least one 9-repeat allele, who also showed behavioral response to subchronic MPH. After 12-24 months of MPH exposure, DAT aAbs titers in PT subjects were comparable to those of healthy controls, while titers remained significantly elevated in NPT patients. Data warrant further research on serum DAT aAbs, which could be used to confirm ADHD diagnosis and/or to monitor therapeutic efficacy of MPH.

The serotonin 7 receptor (5-HT7-R) is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive or sleep regulation.We investigated long-term consequences of sub-chronic treatment, during adolescence (43-45 to 47-49 days old) in rats, with a novel 5-HT7-R agonist (LP-211, 0 or 0.250 mg/kg/day).We evaluated behavioural changes as well as forebrain structural/functional modifications by in vivo magnetic resonance (MR) in a 4.7 T system, followed by ex vivo histology.Adult rats pre-treated during adolescence showed reduced anxiety-related behaviour, in terms of reduced avoidance in the light/dark test and a less fragmented pattern of exploration in the novel object recognition test. Diffusion tensor imaging (DTI) revealed decreased mean diffusivity (MD) in the amygdala, increased fractional anisotropy (FA) in the hippocampus (Hip) and reduced axial (D||) together with increased radial (D⊥) diffusivity in the nucleus accumbens (NAcc). An increased neural dendritic arborization was confirmed in the NAcc by ex vivo histology. Seed-based functional MR imaging (fMRI) identified increased strength of connectivity within and between "limbic" and "cortical" loops, with affected cross-correlations between amygdala, NAcc and Hip. The latter displayed enhanced connections through the dorsal striatum (dStr) to dorso-lateral prefrontal cortex (dl-PFC) and cerebellum. Functional connection also increased between amygdala and limbic elements such as NAcc, orbito-frontal cortex (OFC) and hypothalamus. MR spectroscopy (1H-MRS) indicated that adolescent LP-211 exposure increased glutamate and total creatine in the adult Hip.Persistent MR-detectable modifications indicate a rearrangement within forebrain networks, accounting for long-lasting behavioural changes as a function of developmental 5-HT7-R stimulation.

Among transgenic mouse models of Alzheimer's disease, APP-SWE mice have been shown to develop beta-amyloid plaques and to exhibit progressive impairment of cognitive function. Human Alzheimer's disease, however, also includes secondary clinical manifestations, spanning from hyperactivity to agitation. The aim of this study was a better characterization of motor impulsivity in APP-SWE mice, observed at 12 months of age, when levels of soluble beta-amyloid are elevated and beta-amyloid neuritic plaques start to appear. Mice were tested for spatial learning abilities in the Morris water maze (seven daily sessions, four trials per day). The distance traveled to reach the hidden platform showed a learning curve in both groups. This profile, however, was somewhat delayed in APP-SWE mice, thus confirming slightly impaired spatial capacities. To evaluate motor impulsivity, animals were trained to nose-poke for a food reward, which was delivered after a waiting interval that increased over days (15-60 s). Further nose-poking during this signaled waiting interval resulted in food-reward loss and electric-shock punishment. APP-SWE mice received an increased quantity of punishment and were able to earn fewer food rewards, suggesting inability to wait already at the lowest delay. After the animals were killed, prefrontal cortex samples were assessed for neurochemical parameters. Serotonin turnover was elevated in the prefrontal cortex of APP-SWE mice compared with controls. The results clearly confirm cognitive deficits, and are consistent with the hypothesis of reduced behavioral-inhibition abilities. Together with recent findings, APP-SWE mice emerge as a suitable animal model, characterized by a number of specific behavioral alterations, resembling primary and secondary symptoms of human Alzheimer's disease.

Perinatal asphyxia is a concern for public health and may promote subtle and long-lasting neuropsychiatric disorders. In the present study, newborn Wistar rat pups underwent a repeated 20-min exposure to a 100% N2 atmosphere (or air) on postnatal days (pnd) 1, 3, 5, and 7. Half of the animals were housed during adolescence (pnd 21–35) in an enriched environment. The consequences on behavior were assessed throughout adolescence to adulthood. When scored for social performance, adolescent rats exposed to neonatal asphyxia exhibited exaggerated levels of anogenital sniffing behavior, which was normalized by enriched living. In air-exposed controls, enriched living increased the expression of affiliative and novelty-seeking behaviors, as compared to standard housing. However, this enrichment-induced behavioral plasticity was not found in rats neonatally exposed to asphyxia. At adulthood, levels of impulsivity and 5-HT(2A) receptors in the striatum were markedly increased in neonatal-asphyxia rats kept in standard-housing conditions. Interestingly, impulsivity and receptor density were normalized by enriched rearing during adolescence. These findings indicate profound long-lasting behavioral alterations as a consequence of repeated neonatal asphyxia in rats. Beneficial effects of stimulation by an enriched environment during the still-plastic window of adolescence are suggested in these animals.

Anoxia in the first week of life can induce neuronal death in vulnerable brain regions usually associated with an impairment of cognitive function that can be detected later in life. We set-up a model of subneurotoxic anoxia based on repeated exposures to 100% nitrogen during the first 7 days of post-natal life. This mild post-natal exposure to anoxia specifically modified the behaviour of the male adult rats, which showed an attention deficit and an increase in anxiety, without any impairment in spatial learning and any detectable brain damage (magnetic resonance imaging and histological analysis). Post-anoxic rats showed a reduction in the expression of group-I metabotropic glutamate receptors (i.e. mGlu1 and mGlu5 receptors) in the hippocampus and cerebral cortex, whereas expression of the mGlu 2/3 receptors, the NR1 subunit of NMDA receptors, and the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors was unchanged. mGlu1 and mGlu5 receptor signalling was also impaired in postanoxic rats, as revealed by a reduced efficacy of the agonist (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) to stimulate polyphosphoinositide hydrolysis in hippocampal slices. We conclude that rats subjected to subneurotoxic doses of anoxia during the early post-natal life develop behavioural symptoms that are frequently encountered in the inattentive subtype of the attention deficit hyperactivity disorder, and that group-I mGlu receptors may be involved in the pathophysiology of these symptoms.

Neuropeptide Y (NPY) is primarily synthesised and released by neurones, it is co-localised with noradrenaline and is involved in the regulation of cardiovascular function. In a mouse model lacking NPY Y1 receptor (KO), the ability of NPY to potentiate noradrenaline-induced vasoconstriction is abolished during stress but normal in baseline conditions, locomotor activity and metabolic rate are lowered, blood insulin levels and glucose storage activity are increased. The present study was aimed at further characterising NPY Y1 mutants, with special emphasis on: behavioural responses to novelty seeking and open-field with objects tests, heart rate responsiveness during acute social defeat, alpha2-adrenoceptor (alpha2-ARs) function in brain areas involved in cardiovascular regulation, and cardiac structure. As compared to wild-type controls (n=9), NPY Y1 KOs (n=9) showed: reduced somatomotor activation during non-social challenges, lower heart rate in baseline conditions, larger heart rate responsiveness during social defeat, increased number of alpha2-ARs in the dorsal motor nucleus of the vagus (nX) and the locus coeruleus (LC), moderately larger volume fraction of myocardial fibrosis. The remarkable increment of alpha2-adrenoceptor density in the nX and LC allows to view KO mice behavioural and anatomo-physiological peripheral characteristics as 'adaptations' to central adrenergic rearrangement due to NPY Y1 receptor deletion.

Human adolescents may have experience with easily available psychoactive drugs. Impulsivity and/or peculiarities in reward systems may play a role. These variables were studied in adolescent (Postnatal Day [PND] 30-49) and adult (PND > 60) CD-1 mice. In Experiment 1 (impulsivity), food-restricted mice were tested in operant chambers with 2 nose-poking holes that delivered 1 food pellet immediately or 5 pellets after a delay, respectively. Delay length was increased over days (0-100 s). Adolescent mice showed a shift to the left in the intolerance-delay curve, as well as enhanced demanding when nose-poking was not reinforced. In Experiment 2 (place conditioning with d-amphetamine at 0.0. 1.0, 2.0, 3.3, or 5.0 mg/kg for 3 days), adolescent mice showed no reliable evidence of place conditioning when compared with adults. Hence, 2 main features of adolescence were elevated impulsivity and restlessness, and low (or absent) rewarding efficacy of amphetamine.

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a “critical” ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.

The present review deals mainly with the ontogenesis of two important phenomena involved in vulnerability to several neuropsychiatric disorders, namely with drug-induced sensitization (both contextual and non-contextual) and with conditioned place preference. The term 'infancy' covers the first three postnatal weeks during development in rats and mice. Conversely, the term 'adolescence' may cover the whole postnatal period ranging from weaning (PND 21) to adulthood (at least PND 60) or specifically the period around the onset of puberty (animals aged 33-44 days). Recent studies in rats demonstrated that the establishment of a context-dependent sensitization appears during the first (for repeated drug administration) or during the second (for a single drug administration) postnatal week. However, the memory of drug-context association is transient in developing pups (lasting one or two days following the drug pretreatment). The long-term retention of drug-context associations matures progressively, and is complete by the third week of postnatal life. Finally, those mechanisms responsible for an adult-like profile of context-independent pharmacological sensitization appear later during ontogenesis, being mature by the fourth week of postnatal life. Another set of experiments extended this ontogenetic characterization by comparing adolescent and adult mice. When compared to the latter, the former subjects exhibit a greater amphetamine-induced locomotor sensitization, almost no sensitization of aversive stereotyped behaviors, and a less marked place conditioning. The strength of the drug-induced place conditioning was also directly compared with the unconditioned novelty-seeking drive. In conclusion, neonatal rats are able to show a relatively short-lasting retention of sensitized drug effects (short-term sensitization), whereas the ability to exhibit relatively long-lasting sensitized effects matures progressively during infancy (long-term sensitization). On the other hand, adolescent mice show a reduced sensitization of drug-induced psychotic symptoms, together with a more marked sensitization of arousing and euphorigenic properties of the drug and a reduced incentive memory of its hedonic effects. These age-related changes do imply very different degrees of vulnerability to drug addiction and several other neuropsychiatric disorders.