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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.

Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia) and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC) and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior and result in phenotypic abnormalities.

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 environment in which individuals develop and mature is critical for their physiological and psychological outcome; in particular, the intrauterine environment has reached far more clinical relevance given its potential influence on shaping brain function and thus mental health. Gestational stress and/or maternal infection during pregnancy has been related with an increased incidence of neuropsychiatric disorders, including depression and schizophrenia. In this framework, the use of animal models has allowed a formal and deep investigation of causal determinants. Despite disruption of circadian clocks often represents a hallmark of several neuropsychiatric disorders, the relationship between disruption of brain development and the circadian system has been scarcely investigated. Nowadays, there is an increasing amount of studies suggesting a link between circadian system malfunction, early-life insults and the appearance of neuropsychiatric diseases at adulthood. Here, we briefly review evidence from clinical literature and animal models suggesting that the exposure to prenatal insults, i.e. severe gestational stress or maternal immune activation, changes the foetal hormonal milieu increasing the circulating levels of both glucocorticoids and pro-inflammatory cytokines. These two biological events have been reported to affect genes expression in experimental models and critically interfere with brain development triggering and/or exacerbating behavioural anomalies in the offspring. Herein, we highlight the importance to unravel the individual components of the body circadian system that might also be altered by prenatal insults and that may be causally associated with the disruption of neural and endocrine developmental programming.

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.

Exposure to methylphenidate (MPH) during adolescence is the elective therapy for attention deficit/hyperactivity disorder (ADHD) children, but raises major concerns for public health, due to possibly persistent neurobehavioral changes. Rats (30- to 44-days old) were administered MPH (2 mg/kg, i.p once daily) or saline (SAL). At the end of the treatment we collected plasma, testicular, liver, and brain (striatum) samples. The testes and liver were used to evaluate conventional reproductive and metabolic endpoints. Testes of MPH-exposed rats weighed more and contained an increased quantity of sperm, whereas testicular levels of testosterone (TST) were markedly decreased. The MPH treatment exerted an inductive effect on enzymatic activity of TST hydroxylases, resulting in increased hepatic TST catabolism. These findings suggest that subchronic MPH exposure in adolescent rats could have a trophic action on testis growth and a negative impact on TST metabolism. We have analyzed striatal gene expression profiles as a consequence of MPH exposure during adolescence, using microarray technology. More than 700 genes were upregulated in the striatum of MPH-treated rats (foldchange1.5). A first group of genes were apparently involved in migration of immature neural/glial cells and/or growth of novel axons. These genes include matrix proteases (ADAM-1, MMP14), their inhibitors (TIMP-2, TIMP-3), the hyaluronan-mediated motility receptor (RHAMM), and growth factors (transforming growth factor-beta3 [TGF-beta3] and fibroblast growth factor 14 [FGF14]). A second group of genes were suggestive of active axonal myelination. These genes mediate survival of immature cells after contact with newly produced axonal matrix (laminin B1, collagens, integrin alpha 6) and stabilization of myelinating glia-axon contacts (RAB13, contactins 3 and 4). A third group indicated the appearance and/or upregulation of mature processes. The latter included genes for: K+ channels (TASK-1, TASK-5), intercellular junctions (connexin30), neurotransmitter receptors (adrenergic alpha 1B, kainate 2, serotonin 7, GABA-A), as well as major proteins responsible for their transport and/or anchoring (Homer 1, MAGUK MPP3, Shank2). All these genes were possibly involved in synaptic plasticity, namely the formation, maturation, and stabilization of new neural connections within the striatum. MPH treatment seems to potentiate synaptic plasticity, which is an age-dependent developmental phenomenon that adolescent rats are very likely to show, compared to adults. Our observations suggest that adolescent MPH exposure causes only transient changes in reproductive and hormonal parameters, and a more enduring enhancement of neurobehavioral plasticity.

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.

Bisphenol A (BPA) is an environmental estrogen with potentially averse effects on public health. We studied the long-term effects of perinatal exposure to BPA on later behavior in adult rats of both sexes. BPA or vehicle was administered orally to mother rats from mating to pups' weaning, at a concentration (0.040 mg/kg) within the range of human exposure. The offspring of both sexes were tested at adolescence (postnatal days 35-45) for novelty preference (experiment 1). After a 3-day familiarization to one side of a two-chamber apparatus, on day 4 rats were allowed to freely explore the whole apparatus. BPA-exposed females spent significantly less time than did controls in exploration of the novel side (i.e., increased neophobia), whereas no effect was found in the male group. At adulthood, the same animals were food deprived and tested for profiles of impulsive behavior (experiment 2), in operant chambers provided with two nose-poking holes (delivering either five or one food pellet). After the establishment of a baseline preference for the large reinforcer, a delay was introduced before the delivery of the five food pellets, which was progressively increased each day (10, 20, 30, 45, 60, 80, 100 sec). As expected, all animals exhibited a progressive shift toward the immediate but smaller reinforcer. A reduced level of impulsive behavior (i.e., a shift to the right in the intolerance-delay curve) was evidenced in BPA-treated rats. The frequency of inadequate responding (during the length of the delay) also provided a measure of restless behavior. Interestingly, the profile of BPA-treated males was feminized, strongly resembling that of control females. Animals were then tested (experiment 3) for the response to an amphetamine challenge (1 mg/kg, subcutaneously). The drug-induced increment activity was significantly less marked in BPA-treated male rats compared with controls. These findings provide clear indirect evidence of long-term alterations in brain monoaminergic function after perinatal BPA exposure. This may be a cause for concern for public health, confirming that exposure to a weak environmental estrogen in the period of sexual differentiation of the brain can influence adult behavior.

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.

Exposure to psychostimulants, including both abused and therapeutic drugs, can occur first during human adolescence. Animal modeling is useful not only to reproduce adolescent peculiarities but also to study neurobehavioral adaptations to psychostimulant consumption. Human adolescence (generally considered as the period between 9/12 and 18 years old) has been compared with the age window between postnatal days (pnd) 28/35 and 50 in rats and mice. These adolescent rodents display basal hyperlocomotion and higher rates of exploration together with a marked propensity for sensation-seeking and risk-taking behaviors. Moreover, peculiar responses to psychostimulants, including enhanced locomotor sensitization, no drug-induced stereotypy and reduced place conditioning have been described in adolescent rodents. During this age window, forebrain dopamine systems undergo profuse remodeling, thus providing a neuro-biological substrate to explain behavioral peculiarities observed during adolescence, as well as the reported vulnerabilities to several drugs. Further, methylphenidate (MPH, better known as Ritalin®), a psychostimulant extensively prescribed to children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD), raises concerns for its long-term safety. Using magnetic resonance techniques, MPH-induced acute effects appear to be different in adolescent rats compared to adult animals. Moreover, adolescent exposure to MPH seems to provoke persistent neurobehavioral consequences: long-term modulation of self-control abilities, decreased sensitivity to natural and drug reward, enhanced stress-induced emotionality, together with an enhanced cortical control over sub-cortical dopamine systems and an enduring up-regulation of Htr7 gene expression within the nucleus accumbens (NAcc). In summary, additional studies in animal models are necessary to better understand the long-term consequences of adolescent MPH, and to further investigate the safety of the prescription and administration of such pharmacological treatment at early life stages.

We investigated age-related changes in exploratory drive and anxiety in a plus-maze paradigm. We observed the behaviour of outbred CD-1 mice, Mus musculus , of both sexes at three ages: juvenile (35 days), adolescent (48 days) and adult (61 days). Juvenile and adult mice strongly avoided the open arms of the apparatus, suggesting high levels of anxiety. In contrast, adolescents spent similar amounts of time in both open and closed arms. They also entered the open arms more quickly and more often than the other age groups. No age-related differences were found in the frequency of the stretched-attend posture, a behavioural pattern considered to indicate risk assessment. The data can be interpreted in terms of either an increased exploratory drive or reduced environment-related anxiety, or both, during the adolescent period. This is consistent with previous evidence of elevated levels of novelty seeking and reduced behavioural and physiological responses to stressful situations in mice and rats around this age. Copyright 2002 The Association for the Study of Animal Behaviour. Published by Elsevier Science Ltd. All rights reserved .

Individual differences in coping with novelty and in the response to psychoactive drugs have been related to early life events, such as the age of weaning. Outbred CD-1 mice underwent a precocious (postnatal day (pnd) 15, Wean-15 group), regular (pnd 21, Wean-21 group), or delayed (pnd 27, Wean-27 group) weaning, and were tested as adults (pnd > 60). In Experiment 1, animals underwent a treatment history with d-amphetamine (AMPH 0, 1, or 5 mg/kg once/day for three days) in a familiar environment. On testing day, mice were challenged with SAL or a standard 1 mg/kg AMPH dose (to evaluate acute drug effects and sensitization), and placed in the familiar environment. As expected, regular Wean-21 animals showed an AMPH-induced hyperactivity and a profile of conditioned locomotion, whereas the same dosage failed to induce any change in Wean-15 and Wean-27 groups. Levels of spontaneous novelty seeking were particularly elevated for Wean-27 mice, when compared with the other weaning groups. In Experiment 2, pairing of AMPH administration (0, 1, 2, 3.3, or 5 mg/kg once/day for three days) with a distinct environment produced a classical conditioned place preference. The magnitude of the preference profile was significantly more marked for Wean-15 mice, when compared with the other two weaning groups. Both experiments also provided evidence that the development of sensitization was particularly evident in Wean-27 mice. In summary, delayed weaning was associated in adult mice with both elevated levels of novelty seeking and increased sensitization to drug effects. Conversely, animals weaned precociously were much more responsive to AMPH-induced incentive conditioning. These results appear relevant to the issue of early experiences as possible risk factors for a number of psychiatric disorders in humans, including the abuse of drugs.

A "gateway" function toward substance abuse has been suggested for early tobacco smoking. Nicotine actually represents an easily available drug for human adolescents, who are very likely to use a number of different psychoactive agents. Surprisingly, the psychobiological factors involved in this age-related willingness have been poorly investigated. In Experiment 1, nicotine consumption was studied in outbred CD-1 mice during Early (postnatal day (pnd) 24 to 35), Middle (pnd 37 to 48) or Late (pnd 50 to 61) adolescence, in an oral self-administration paradigm. During the drinking session (2 h/day), animals had free choice between either tap water or a nicotine solution (10 mg/l). After a 6-day period, a fading study was carried out, in which nicotine concentration was reduced to 7 mg/l (days 7-9) and 5 mg/l (days 10-12), to assess whether animals would compensate by increasing their intake from the nicotine solution. In Experiment 2, psychopharmacological effects on locomotion induced by the nicotine solution (0, 10, 30 mg/l) during the 1-h drinking session were assessed in Early and Late adolescent mice. In Experiment 1, Early adolescents expressed a marked and stable preference for the nicotine solution, showing a daily nicotine intake of 1.15 +/- 0.04 mg/kg. Middle adolescents did not show any preference for either bottle, whereas a tendency toward avoidance for the nicotine solution was found for Late adolescents. In the fading study, Early adolescents were the only group to show increased consumption from the nicotine bottle as far as nicotine concentration was reduced. A time-course analysis of plasma levels of cotinine (the principal biomarker of nicotine consumption) revealed some pharmacokinetic differences between the three age-groups. In Experiment 2, drinking from a nicotine solution produced a prominent hyperactivity in Early adolescents, whereas a quite opposite profile was associated with older subjects. In summary, even if a role for taste factors cannot be completely ruled out, a peculiar spontaneous drive toward oral nicotine consumption, as well as a nicotine-induced arousal, is specific to Early adolescence in mice. The present animal model might be useful to investigate psychobiological determinants involved in early tobacco smoking in human adolescents

Nicotine (NIC) shares most of the characteristics of other addictive drugs. However, attempts to establish oral self-administration failed under an ad libitum fluid availability. Outbred mice were scheduled to a restricted 2 h/day water access. In Experiment I, such schedule elevated corticosterone blood levels, which were strongly reduced following the drinking session. In two replications of Experiment II, mice had several days of free choice between water or NIC (10 mg/l). A consistent and reliable preference for NIC was found. Mice also progressively increased their drug intake in a fading study. In Experiment III, levels of cotinine (the principal NIC biomarker in the blood) confirmed pharmacologically active drug concentrations after oral intake. In Experiment IV, another set of mice was exposed to a 6-days 'passive' nicotine consumption, by masking the drug taste with 10% sucrose. After sucrose removal, a preference for NIC emerged, which however vanished during the following days. This 'neutral' profile resulted to be the combined performance of a NIC-preferring and a NIC-non-preferring subpopulations. In conclusion, a clear-cut preference for NIC can be easily established when the drug offer is concurrent to a restricted access to water. The present paradigm may be useful to investigate issues of NIC dependence.

LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive or sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats’ forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days), or vehicle, during adolescence (44 to 48 post-natal days); histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e. hippocampus, orbital prefrontal cortex), activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations.

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects.

Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RTT patients. In RTT mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RTT mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases.

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with multifactorial origin characterized by social communication and behavioural perseveration deficits. Several studies showed an association between the reelin gene mutation and increased risk of ASD and a reduced reelin expression in some brain regions of ASD subjects, suggesting a role for reelin deficiency in ASD etiology. Reelin is a large extracellular matrix glycoprotein playing important roles during development of the central nervous system. To deeply investigate the role of reelin dysfunction as vulnerability factor in ASD, we investigated the behavioural, neurochemical and brain morphological features of reeler male mice. We recently reported a genotype-dependent deviation in ultrasonic vocal repertoire and a general delay in motor development in reeler pups. We now report that adult male heterozygous reeler mice did not show social behaviour and communication deficits during male-female social interactions. Wildtype and heterozygous mice also showed a typical light/dark locomotor activity profile, with a peak during the central interval of the dark phase. However, when faced with a mild stressful stimulus (a saline injection) only heterozygous mice showed an over response to stress. At the end of the behavioural studies, we conducted high performance liquid chromatography and magnetic resonance imaging and spectroscopy to investigate whether reelin mutation influences brain monoamine and metabolites levels in regions involved in ASD. Low levels of dopamine in cortex and high levels of glutamate and taurine in hippocampus were detected in heterozygous mice, in line with clinical data collected on ASD children. Altogether, our data detected subtle but relevant neurochemical abnormalities in reeler mice supporting this mutant line, particularly male subjects, as a valid experimental model to estimate the contribution played by reelin deficiency in the global ASD neurobehavioural phenotype.

More than 10 % of children during school years suffer from a transient tic disorder, and 1 % has a particular type of tic disorder known as Tourette syndrome. At present, there is no available treatment that can improve tics without considerable side effects. Recent evidence indicates that tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, reduced in mice the head twitch responses, a tic pharmacologically induced by the selective serotonin 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). THC has some considerable side effects that render its use problematic. In this view, cyclohexyl-carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), an indirect cannabinoid agonist that enhances endogenous anandamide levels, can constitute a valid alternative to the use of direct CB1 receptor agonists. We investigated whether URB597 may reduce the exhibition of DOI-induced head twitch responses in mice. Moreover, to address whether the effects of URB597 on DOI-induced behavioral response constitute a general phenomenon, we evaluated four (ABH, C57BL/6N, SJL/J, CD-1) mouse strains. These strains have been selected in order to represent an ample spectrum of genetic background and phenotypic variation. Predictably, DOI induced consistent tic-like behaviors in all mice. While URB597 exerted slight sedation in C57BN/6L mice, this cannabinoid agonist remarkably mitigated the exhibition of DOI-induced head twitch in all strains. Present data may disclose novel avenues for the pharmacological treatment of tic disorders.

Exposure to Stimulating Environments (SE) during development may improve neuroplasticity in central nervous system, protect against neurotoxic damage, and promote neuronal recovery in adult life. While biochemical mechanisms of SE-promoted neuronal plasticity are well known in the brain, much less is known on the signaling cascade governing plasticity and neuroprotection in the retina. In order to investigate if in the retina signaling molecules involved in neuronal plasticity are affected by SE, neonatal CD-1 mice were exposed to moderate corticosterone levels (NC), supplemented through maternal milk during the first postnatal week, or to environmental enrichment (EE) conditions (physical and social stimuli) from early adolescence. Our results showed that both NC and EE increased the phosphorylation level of Extracellularly Regulated Kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) in the adult retinal tissue. Furthermore, we observed that activated ERK1/2 was restricted to Muller cells, while pCREB was mostly present in the nuclei of retinal neurons. Neither NC, nor EE modified the expression of GFAP, a marker of Muller cells activation. In conclusion our results indicate that both NC and EE activate ERK1/2 and CREB in the retina and provide a biochemical background for the neuroprotective activity exerted by SE against retinal damage. Furthermore, they support the role of Muller glia as a key cell determinant of retinal neuroplasticity.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2–308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.

The search for neuronal and psychological underpinnings of pathological gambling in humans would benefit from investigating related phenomena also outside of our species. In this paper, we present a survey of studies in three widely different populations of agents, namely rodents, non-human primates, and robots. Each of these populations offers valuable and complementary insights on the topic, as the literature demonstrates. In addition, we highlight the deep and complex connections between relevant results across these different areas of research (i.e., cognitive and computational neuroscience, neuroethology, cognitive primatology, neuropsychiatry, evolutionary robotics), to make the case for a greater degree of methodological integration in future studies on pathological gambling.

The serotonin receptor 7 (5-HT7-R), is very abundant in the thalamus, hypothalamus, dorsal raphe nucleus and hippocampus; at lower levels it is found also in the cortex, striatum and amygdala. This neurochemical receptor system plays important functional roles in learning and memory, in regulation of mood and circadian rhythmicity. Recently, many agonist drugs selective for this receptor have been developed and their effects reported. Presently, we review some recent studies we have conducted aimed to evaluate the modulatory effect of a subchronic regimen with LP-211, a new selective agonist compound belonging to 1-arylpiperazine category, on behavioural and molecular parameters. At low dose (0.25 mg/kg, i.p.), LP-211 induced in adult mice a six-hour anticipated wake up with no temporal landmark (constant light) acting as non-photic stimulus for “internal clock” resetting. In standard 12:12h L/D cycle, we observed a subchronic effect (5-6 days at 0.25 mg/kg, once/day), on delay of wake up associated with a reduction of peak locomotor activity and any evidence for a real cellular proliferation after ex vivo analysis. The other studies, conduct on rats, were aimed to investigate long-term effects of subchronic LP-211 administration into adulthood development. Subchronic LP-211 (0.125 mg/kg, i.p. once/day) during the prepuberal phase reduced L-Glutamate, NMDAR1 and DAT, within the ventral striatum. Moreover, we observed a clear reduction of the immunoreactivity of serotonin transporter (SERT) and dopaminergic D2 receptors at dorsal striatum. These results represent a starting point to explore the neurophysiology of 5-HT7-R: subchronic LP-211 in rats and mice appears a suitable tool for studying the role of 5-HT7-R in sleep disorders, emotional and motivational regulations, attentive processes and executive functions.

We have recently reported nicotine-induced stimulation of reelin and glutamic acid decarboxylase 67 (GAD67) mRNA expression levels in the brain of heterozygous reeler mice (HRM), a putative animal model for the study of symptoms relevant to major behavioral disorders.We aimed to evaluate long-term behavioral effects and brain molecular changes as a result of adaptations to nicotine exposure in the developing HRM males.Adolescent mice (pnd 37-42) were exposed to oral nicotine (10 mg/l) in a 6-day free-choice drinking schedule. As expected, no differences in total nicotine intake between WT (wild-type) mice and HRM were found.Long-term behavioral effects and brain molecular changes, as a consequence of nicotine exposure during adolescence, were only evidenced in HRM. Indeed, HRM perseverative exploratory behavior and poor cognitive performance were modulated to WT levels by subchronic exposure to nicotine during development. Furthermore, the expected reduction in the expression of mRNA of reelin and GAD67 in behaviorally relevant brain areas of HRM appeared persistently restored by nicotine. For brain-derived neurotrophic factor (BDNF) mRNA expression, no genotype-dependent changes appeared. However, expression levels were increased by previous nicotine in brains from both genotypes. The mRNA encoding for nicotine receptor subunits (α7, β2 and α4) did not differ between genotypes and as a result of previous nicotine exposure.These findings support the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative short- and long-term effects associated with nicotine modulation.

In rodents, beside basic sex differences, a certain degree of within-gender phenotypic variation can also be provided in utero by hormones from adjacent fetuses. We investigated novelty-seeking behavior in two groups of male and female mice from know intrauterine position: 2M (between males) and 0M (between females). Subjects were assessed during periadolescence (postnatal days 33–43), an ontogenetic phase, which is characterized by an elevated expression of this novelty-seeking behavior. Periadolescent mice underwent a familiarization session for 3 consecutive training days with one side of a two-chamber apparatus. On testing day 4, the opening of a partition, which allowed mice to freely move from the familiar compartment to a novel one, produced an increased behavioral arousal in all animals. Marked sex differences were found, with females being in general more active than males, whereas the latter showed significantly higher levels of novelty seeking than females. Uterine position failed to affect the profile of novelty preference in females, whereas within the male group 2M subjects expressed a marked profile of novelty seeking. The differential titers of sex hormones reported to characterize the 0M and 2M condition early in fetal development are suggested to account for the individual variability in the seeking for novelty within the male group during puberty.

The functions of the central alpha-adrenergic, serotoninergic and dopaminergic systems were investigated in 28 heroin-dependent subjects 6-8 weeks after detoxification, and in 22 healthy control subjects (group C). Fourteen heroin-dependent subjects with depressive comorbidity (group A), and 14 heroin-dependent subjects without other Axis I and II pathologies (group B) were included among abstinent substance abusers. Norepinephrine (NE) function was evaluated by growth hormone (GH) responses to acute stimulation with clonidine (clon); serotonin (5-HT) function by prolactin (PRL) and cortisol (CORT) responses to acute stimulation with D-fenfluramine (D-fen) and dopamine (DA) function by GH and PRL responses to acute administration of bromocriptine (brom). Central NE activity, as measured by the GH-clon test, seems to be well preserved both in A and B subjects. PRL and CORT responses to D-fen were significantly blunted both in A subjects and in B subjects, in comparison with control subjects (C); the PRL response in A subjects was significantly lower than in B subjects. The DA system of B subjects was found unimpaired; in contrast, a significantly higher GH response to brom in A subjects (depressed) could express D2 post-synaptic receptor hypersensitivity and, therefore, decreased pre-synaptic DA release. In sum, the study of central monoamine function revealed an alteration only of the 5-HT system in detoxified heroin-dependent subjects without psychiatric comorbidity, which might be a trait character of these subjects, possibly involved in the pathogenesis of the disorder. A more significant impairment of 5-HT function and the hypersensitivity of post-synaptic DA receptors in A subjects suggests that specific biological correlates of psychiatric comorbidity may characterize substance abuser subtypes.

In periadolescent rats, social interactions are typically characterized by elevated levels of playful and affiliative behavior. Aim of the present study was to assess the behavioral and hormonal effects of partner familiarity upon the separation and reunion in a novel environment of established pairs of periadolescent subjects. At weaning (post-natal day, PND 21), Sprague–Dawley rats were pair housed with a non-sibling subject of the same age and sex. On PND 35, the members of each pair were separated for a 24-h period, and randomly assigned to different experimental groups: (1) sacrificed before separation; (2) sacrificed immediately after the isolation period; (3–4) placed individually in a novel cage for 30 min either in low-light or in high-light conditions; (5–6) reunited for 30 min in a novel cage either with their previous cagemate (familiar, FAM); or (7–8) with an unfamiliar rat (UNF) of the same age and sex, in either light conditions. During reunion, the occurrence of social and non-social behaviors was scored. Blood samples were collected at the end of the session from all groups and assayed for corticosterone (CORT). The separation of the two members of an established pair did not affect baseline CORT levels. Upon reunion, the presence of a conspecific exerted a significant buffering effect on the novelty-induced increase in CORT levels. Such an effect of the social companion appeared more marked in males than in females, and in FAM compared to UNF pairs. Interestingly, FAM rats also expressed a significantly higher amount of social investigation and play-soliciting behavior compared to UNF animals. Behavioral results, together with previous data, suggest that periadolescent rats housed in established pairs develop a sort of amicable relationship. The overall CORT output measured at the end of the session is also in line with this interpretation. As a whole, these findings indicate that periadolescence is a time period during rat development, during which social variables play a very important role in modulating both behavioral and physiological responses to novelty in a fashion that does not completely overlap with data on adult subjects.

Small perturbations of young animals' sensory experience or hormonal milieu have been shown to alter ontogenetic pathways and to potentially produce huge effects on CNS functioning and behaviour later in life. From a social point of view, variables such as the expression of affiliative bonding and of playful interactions among littermates, the quantity/quality of maternal care, or episodes of maternal or sibling deprivation during critical phases in development, seem to interfere as epigenetic factors with the rigidly ordered temporal sequences of events that occur during the ontogenesis of CNS. This leads to the onset of adaptive neurodevelopmental changes, which are observable within a continuum that encompasses both “normal” individual variability and potential behavioural disorganisation, which in turn will probably be related to profound alteration in the establishment of adult social competence. The present review summarises the more recent work in mice dealing with short-term, as well as long-term modifications, in naturally occurring species-typical social and non-social responses as a function of the early manipulation of social characteristics of the family unit (such as litter gender composition and time of weaning). These analyses were carried out on infant animals, i.e. during the ontogenetic stage of the establishment of social bonding, as well as on pre-pubertal and adult mice and on lactating adult females. Critical issues, such as the respective roles of sibling–sibling and dam–offspring interactions in the shaping of “sibling effects”, are also addressed. Overall, these studies indicate that, within their natural range of variation, early patterns of social stimulation are powerful determinants of subsequent behaviour of developing altricial rodents, and confirm that early social life events warrant attention because they can strongly affect neurobehavioural development. Evidence of a relationship between social events occurring during early rearing (i.e. when dramatic transitions in neuroendocrine and neurochemical CNS systems occur) and individual behavioural variability in the infant and adult response to the effects of psychostimulants abused by humans is presented. A better understanding of the mechanisms that mediate such remarkable plasticity might have great psychobiological as well as clinical importance, especially when considering the issue of vulnerability to drug abuse.

Following repeated association between psychostimulant drugs and a distinct environment, contextual cues acquire the ability to elicit a conditioned approach response. Further, both rats and mice have a natural drive to seek for the experience of novelty, and a previously unknown environment is able to elicit an unconditioned approach response. Both the experience of novelty and amphetamine (AMPH)-conditioned effects have been associated in rodents with the activation of brain meso-limbic dopaminergic pathways. This study assessed the relative strenght of AMPH-conditioned and novelty-induced unconditioned motivations in mice. During the pretreatment period, mice were randomly assigned to three different treatment history groups, and received d-AMPH (0, 2, or 10 mg/kg IP once/day) injections for 3 days in the presence of a familiar environment. Following a 48-h washout from the last drug injection, animals were placed in the familiar and pretreatment-paired environment and challenged with either SAL (to evaluate conditioning) or a standard AMPH dose (2 mg/kg, to assess either acute drug effects or carryover influences of each animal’s treatment history with the same drug). Following the opening of a partition, animals showed both a clear-cut preference for a novel environment as well as a marked novelty-induced hyperactivity. Interestingly, when mice were tested in a drug-free state in this free-choice paradigm, they expressed neither conditioning to the drug-associated environment nor carry-over effects on the novelty-induced hyperactivity profile. On the other hand, mice injected with AMPH showed a mixed profile, with AMPH 2 treatment history mice showing a conditioned preference for the familiar and drug-paired environment, whereas AMPH 10 animals preferred to spend more time in the novel compartment. Both AMPH doses were associated with an increased locomotion, whereas only the AMPH 10 dose resulted in a stereotyped behavioral syndrome, possibly reminescent of an aversive “poor welfare” condition. Thus, as a function of the drug dosage, differential positive or negative incentive properties are suggested to be evoked by the AMPH-conditioned environment. In conclusion, a reliable and useful experimental paradigm has been developed to investigate the issue of vulnerability to a variety of habit-forming agents or emotional experiences whose positive reinforcing properties may rely on a common neurobiological mechanism.

The development of agonistic behavior was characterized in outbred Swiss CD-1 male Mus domesticus. At weaning (postnatal day [PND] 21), mice were housed either individually or as male pairs. Social encounters were carried out between dyads of initially unfamiliar same-age and same-housing subjects every 3rd day, from PND 23 to 47. The majority of both offensive and defensive elements had their onset around PND 29. Overall, their expression increased around puberty (i.e., on PND 35), which also represented the peak of an inverted U-shaped profile for the frequency of the "ambivalent" tail rattling behavior. A stability of dominance-submission relationships over development appeared, and early short latencies to display either the first crouched posture (subordinate) or the first attack (dominant) turned out to be possible predictors of adult social status. Ongoing individual housing was associated with a greater expression and an earlier onset of fighting behavior.

The present study evaluated the behavioral repertoire of lactating CD-1 mouse dams when tested in an environment associated with cocaine in the pre-mating period. Virgin females were randomly assigned for conditioning (8-day long schedule with four cocaine or saline injections administered every other day) to three experimental groups: i) Coc-Test females received one injection of cocaine (5 or 20 mg/kg IP) in the testing chamber and saline 24 h later in the home cage, ii) Coc-Home females received one injection of the same doses of cocaine in the home cage and saline 24 h later in the testing chamber, and iii) Sal-Sal control females received one saline injection in both environments. All females underwent a 25-day long wash out period during which they were mated. Their behavior was subsequently scored in the testing chamber on postpartum day 2 (drug-free state) in the presence of 3 pups from their own litter (single 15-min session). As a whole, Coc-Test dams appeared to be more involved in pup-directed activities such as pup-nosing and nest-building when compared with the Coc-Home group. In addition, non-pup directed behaviors, such as crossing, self-grooming, and rearing were higher in Coc-Test group than in other groups. The opposite was true for stereotyped gnawing activity. A measure of females' body weight gain revealed that Coc-Test 20 group was significantly higher than other groups particularly during the postpartum phase. On postpartum day 6, lactating dams were injected with the low cocaine dose (5mg/kg) and their response to a male intruder was assessed in the testing chamber (single 5-min session). A higher number of Coc-Test 5 dams showed the on nest and the upright offensive postures compared to the corresponding Coc-Home 5 group, whereas a significant higher number of Sal-Sal females showed the on top posture with respect to the Coc-Test 20 group. Oxytocin levels measured after the behavioral test showed a tendency, even if not significant, to be higher in the hypothalamus of Coc-Test dams. As a whole, the present results suggest that the alterations in maternal behavior here observed as well as the trend underlined by oxytocin values, cannot be ascribed to carry-over effects of cocaine administration in the pre-mating phase per se; rather, they seem to represent a conditioned response to the distinct environment previously associated with the drug experience.

Tourette Syndrome (TS) is a neurological disorder characterized by motor and phonic tics affecting approximately 1% of the pediatric population. Behavioral comorbidities often include obsessive-compulsive behavior and impaired attention. The neurobiological substrates associated with TS generally entail abnormalities in neurotransmitter circuitry regulating basal ganglia activity. The neurotransmitters most often associated with TS are dopamine, serotonin, and GABA. TS origin roots in genetic predisposing factors, and environmental variables favoring tic onset and exacerbation. Among the latter, repeated infections with group A beta-hemolytic Streptococcus and psychosocial stressors encountered during development have been proposed to constitute likely susceptibility factors. In this chapter, we describe how this clinical/epidemiological knowledge has been translated into animal models of TS. Specifically, we review several studies attempting to reproduce TS-like symptoms (tics and behavioral stereotypies) and comorbidities (impaired attention, increased locomotion, and perseverative responding) in laboratory rodents. Additionally, we discuss studies in which the genetic and environmental predisposing factors have been modeled in experimental subjects. Ultimately, we propose a unifying perspective recapitulating dependent and independent variables in the preclinical study of TS and discuss its potential theoretical and heuristic implications.

Rho GTPases are key intracellular signaling molecules that coordinate dynamic changes in the actin cytoskeleton, thereby stimulating a variety of processes, including morphogenesis, migration, neuronal development, cell division and adhesion. Deviations from normal Rho GTPases activation state have been proposed to disrupt cognition and synaptic plasticity. This review focuses on the functional consequences of genetic ablation of upstream and downstream Rho GTPases molecules on cognitive function and neuronal morphology and connectivity. Available information on this issue is described and compared to that gained from mice carrying mutations in the most studied Rho GTPases and from pharmacological in vivo studies in which brain Rho GTPases signaling was modulated. Results from reviewed literature provide definitive evidence of a compelling link between Rho GTPases signaling and cognitive function, thus supporting the notion that Rho GTPases and their downstream effectors may represent important therapeutic targets for disorders associated with cognitive dysfunction.

The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKII alpha, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates.

Here we report the synthesis, pharmacological and pharmacokinetic evaluation of a pilot set of compounds structurally related to the potent and selective 5-HT7 ligand LP-211. Among the studied compounds, N-pyridin-3-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (4b) showed high affinity for 5-HT7 receptors (Ki = 23.8 nM), selectivity over 5-HT1A receptors (>50-fold), in vitro metabolic stability (82%) and weak interaction with P-glycoprotein (BA/AB = 3.3). Compound 4b was injected ip in mice to preliminarily evaluate its distribution between blood and brain.