LP-211, a selective 5-HT7 receptor agonist, increases novelty-preference and promotes risk-prone behavior in rats.

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-HT7 R) stimulation with a brain penetrant and selective agonist, LP-211 (0.25 and 0.50 mg kg-1 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-HT7 R 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-HT7 Rs 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-HT7 R activation shifts the choice towards a larger yet unlikely reward and turns the propensity of rats towards risk-prone behavior. Thus, 5-HT7 Rs 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 improved (though suboptimal) strategy formation. However, further experiments are necessary to determine more in depth the serotonergic pathways involved.

Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens.

Multiple theories have been proposed for sensation seeking and vulnerability to impulse-control disorders [Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: Common biosocial factors. J Pers 68:999-1029], and many of these rely on a dopamine system deficit. Available animal models reproduce only some behavioral symptoms and seem devoid of construct validity. We used lentivirus tools for over-expressing or silencing the dopamine transporter (DAT) and we evaluated the resulting behavioral profiles in terms of motivation and self-control. Wistar adult rats received stereotaxic inoculation of a lentivirus that allowed localized intra-accumbens delivery of a DAT gene enhancer/silencer, or the green fluorescent protein, GFP. These animals were studied for intolerance to delay, risk proneness and novelty seeking. As expected, controls shifted their demanding from a large reward toward a small one when the delivery of the former was increasingly delayed (or uncertain). Interestingly, in the absence of general locomotor effects, DAT over-expressing rats showed increased impulsivity (i.e. a more marked shift of demanding from the large/delayed toward the small/soon reward), and increased risk proneness (i.e. a less marked shift from the large/uncertain toward the small/sure reward), compared with controls. Rats with enhanced or silenced DAT expression did not show any significant preference for a novel environment. In summary, consistent with literature on comorbidity between attention-deficit/hyperactivity disorder and pathological gambling, we demonstrate that DAT over-expression in rats' nucleus accumbens leads to impulsive and risk prone phenotype. Thus, a reduced dopaminergic tone following altered accumbal DAT function may subserve a sensation-seeker phenotype and the vulnerability to impulse-control disorders.

Home cage testing of delay discounting in rats.

Testing rodents in their home cages has become increasingly popular. Since human intervention, handling, and transport are minimized, behavior can be recorded undisturbed and continuously. Currently existing home cage systems are too complex if only relatively simple operant-learning tests are to be carried out in rats. For that purpose, a new low-cost computer-controlled operant panel was designed, which can be placed inside the home cage. A pilot study was carried out, using an intolerance-to-delay protocol, classically developed for testing behavioral impulsivity. Male adult rats were tested in their home cages, containing the operant panel provided with nose-poking holes. Nose poking in one hole resulted in the immediate delivery of one food pellet (small-soon, SS), whereas nose poking in the other hole delivered five food pellets after a delay (large-late), which was increased progressively each day (0-150 sec). The two daily sessions, spaced 8 h apart, lasted 1 h each, and the time-out after food delivery was 90 sec. A clear-cut shift toward preference for SS, which is considered a classical index of cognitive impulsivity, was shown at the longest delay. It is noteworthy that rats shifted when the delay interval was longer than the mean intertrial interval-that is, when they experienced more than one delay-equivalent odds against discounting (see Adriani & Laviola, 2006). The shortened training (2 days) and testing (5 days) phases, as allowed by prolonged and multiple daily sessions, can be advantageous in testing rodents during selected short phases of development. Current research is focusing on further validation of this and similar protocols.

Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by a developmentally inappropriate, pervasive and persistent pattern of severe inattention, hyperactivity and impulsivity. Despite onset in early childhood, ADHD may continue into adulthood with substantial impairment in social, academic and occupational functioning. A new animal model of this disorder was developed in rats with genetic deletion of the dopamine transporter (DAT) gene (dopamine transporter knockout rats; DAT-KO rats). We analyzed the behavior of DAT-KO rats for a deeper phenotypical characterization of this model. We first tested rats of the 3 genotypes at different ages (preadolescent, adolescent and adult), in a novelty-seeking test using a black/white box (Experiment 1). After that, we tested adult rats in a novelty-preference test using a 3-chamber apparatus with different shapes (Experiment 2). Experiment 1: as evidenced by analysis of time spent in the novel environment, adult DAT heterozygous (DAT-HET) rats show an increased curiosity-driven exploration compared with wild-type (WT) controls while DAT-KO rats did not recognize novelty. The locomotor activity data show a minimal difference between genotypes at adolescent age while the preadolescent and adult DAT-KO rats have significantly increased activity rate compared with WT and DAT-HET subjects. Experiment 2: in this case, due to more clearly evident spatial differences, time spent in novel environment was not significantly different among genotypes. During first 10 minutes, DAT-KO rats showed a decreased hyperactivity, apparently related to curiosity and attention to the new environments. In conclusion, DAT-KO rats may show some inattention while more novelty-seeking traits appear in DAT-HET rats.

Social modulation of risky decision-making in rats (Rattus norvegicus) and tufted capuchin monkeys (Sapajus spp.).

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.

1H MRS-detectable metabolic brain changes and reduced impulsive behavior in adult rats exposed to methylphenidate during adolescence.

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 1H 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.

Internet Addiction in adolescence: Neurobiological, psychosocial and clinical issues.

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.

Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model.

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.

Psychobiological risk factors for vulnerability to psychostimulants in human adolescents and animal models.

Adolescence is associated with an increased risk of developing drug abuse/dependence. During this ontogenetic phase, brain and hormonal systems are still undergoing crucial maturational rearrangements, which take place together with significant modifications in psychosocial development. However, the neurohormonal and behavioral facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants such as MDMA ("Ecstasy") and amphetamine (AMPH). Novelty-seeking, a temperamental/behavioral trait that is typical of this age period, might substantially contribute to both psychological and psychobiological vulnerability. In humans, an elevated score of novelty-sensation seeking and a derangement of monoaminergic function were both associated with late adolescence MDMA users compared to controls. In animal models of periadolescence, the search for novel stimuli and sensations actually shares a common neurobiological substrate (the reward-related brain mesolimbic pathways) with psychostimulants. The present review summarises recent work in mice, which indicates that periadolescent subjects are characterized by an unbalanced and "extremes-oriented" behavior and by elevated novelty-seeking compared to adults. Repeated and intermittent administration of cocaine or AMPH was associated with the development of a prominent locomotor sensitization in periadolescents, which failed to exhibit the marked sensitization of the stereotyped behavioral syndrome--possibly associated with poor welfare--that was typical of adults. A unique profile of integrated behavioral and physiological hyporesponsivity to both forced novelty and acute AMPH administration during periadolescence was also found. As a whole, these results, together with previous work on this topic, suggest that periadolescents may be more "protected" from AMPH-related aversive properties, and perhaps more vulnerable to the experience of internal states of reward, than older animals. Thus, the present animal model of adolescence seems to represent a reliable and useful method for the investigation of vulnerability to a variety of habit-forming agents or emotional experiences whose positive reinforcing properties may rely on common neurobiological substrates. A deeper understanding of psychostimulant effects during adolescence on the complex interaction between genetic, neurobiologic, psychosocial, and environmental factors will lead to earlier and more effective prevention and treatment.

A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice.

The identification of critical ontogenetic periods of increased vulnerability to the effects of drugs of abuse could have a great psychobiological and clinical-therapeutical importance. Potential age-related differences in the response of the hypothalamic-pituitary-adrenal (HPA) axis to both stress and psychostimulants has been tested here in an animal model of adolescence. Periadolescent (PND 33-43) and Adult (PND>60) mice of both sexes were injected with d-amphetamine (AMPH, 0, 2, or 10 mg/kg i.p.) and immediately faced with a mild psychological stress experience, i.e. placement in a novel environment. A detailed time-course analysis of both hormonal and behavioral profiles was performed, with animals being sacrificed for trunk-blood collection at different time-points during the test (before the injection, NT group; 15, 30, or 120 min after the injection). Basal corticosterone (CORT) levels (NT group) were consistently higher in periadolescents than in adults. As a whole, a marked increment of blood CORT levels was found in mice of both ages exposed to forced novelty. However, important age-related differences were also observed, with Saline-injected periadolescents still exhibiting elevated levels of locomotion at the end of the 120-min test session and failing to show the increasing profile of CORT release over the baseline that was typical of adults. Upon an AMPH 2 administration, periadolescents exhibited a much lower profile of locomotor hyperactivity than adults, and also failed to show an increase across the course of the session in CORT release, that was observed in adults. When treated with the high AMPH 10 dose, a marked locomotor hyperactivity was found in periadolescents, which however showed much lower levels of the stereotyped licking and gnawing behavior, that was typical of adults. The present results suggest a unique profile of integrated behavioral and physiological hyporesponsivity in mice during periadolescence. The latter also represents a very useful model for the study of the issue of psychobiological risk factors involved in vulnerability to drugs of abuse in human adolescents.

Elevated novelty seeking and peculiar d-amphetamine sensitization in periadolescent mice compared with adult mice.

Novelty seeking as well as amphetamine sensitization were studied in adult (postnatal day "PND" > 60) and periadolescent (PND 3343) mice treated with saline or amphetamine (2 or 10 mg/kg once per day) for 3 days in a familiar environment. After a 48-hr wash-out period, mice were challenged with either saline or amphetamine (2 mg/kg) in the same environment. When given a choice, animals showed a preference for a novel environment, an effect more marked in periadolescents. Acute amphetamine strongly increased novelty seeking in adults, whereas it had an opposite effect in periadolescents. Adult mice in the chronic amphetamine 2 group showed a conditioned preference for the drug-paired compartment, whereas an aversion characterized adult mice in the amphetamine 10 group. Periadolescents in the latter group exhibited a greater sensitization of the locomotor response, but did not show the compulsive licking typical of adults. This appears to be a useful model to study psychobiological risk factors involved in vulnerability to addiction during human adolescence.

Sexual segregation in infant mice: behavioural and neuroendocrine responses to d-amphetamine administration.

Individual differences arise from both genetic and epigenetic factors. The aim of this study was to test whether pups raised in distinct socio-sexual conditions would show different behavioural and neuroendocrine responses to d-amphetamine (AMPH) administration upon placement in a novel environment. This issue was addressed by testing infant CD-1 mouse pups of both sexes at three different developmental ages [3, 8, or 18 postnatal (PND) days]. These pups were raised from birth in all-male, all-female, or mixed-sex litters. AMPH effects were assessed as a function of the hypothalamic-pituitary-adrenal (HPA) axis activational state using litters that were either maternally deprived for 24 h (DEP) or normally kept with the dam (NDEP). A concomitant maternal behaviour score carried out on selected postpartum days showed that mothers taking care of all-male litters were more often involved in Active nursing than those rearing the mixed-sex ones, whereas the latter were found more often Laying still out of the nest. Basal and stress-induced corticosterone (CORT) secretion was increased in unisexually reared pups following maternal deprivation, an effect limited to PND 3. In general, neuroendocrine and behavioural responses to AMPH were found to be dissociated and were affected by sexual segregation only in conjunction with maternal deprivation. On PND 3, AMPH injection (1 or 3 mg/kg, i.p.) decreased CORT secretion in deprived unisexually reared subjects without affecting their behaviour. As a whole, behavioural changes due to unisexual rearing were limited to female subjects. On PND 8, unisexually reared females showed, upon maternal deprivation, a generalized shift to the left in the dose-response curve to AMPH for Crossing behaviour, while on PND 18 AMPH-induced stereotypies were considerably reduced in sexually segregated females, especially following maternal deprivation. Thus, maternal deprivation appeared to "sensitize" the monoaminergic system to an AMPH challenge. The individual behavioural and neuroendocrine profiles shown in response to a stressful challenge suggest that changes in social stimulation early during development might produce subtle shifts in the function of selected central monoaminergic systems.

Effect of intra-accumbens dopamine receptor agents on reactivity to spatial and non-spatial changes in mice.

RATIONALE: Some evidence suggests an involvement of nucleus accumbens in spatial learning. However, it is controversial whether the mesoaccumbens dopaminergic pathways play a specific role in the acquisition of spatial information. OBJECTIVE: The goal of these experiments was to investigate the effect of dopaminergic manipulations in the nucleus accumbens on a non-associative task designed to estimate the ability to encode/transmit spatial and non-spatial information. METHODS: The effects of focal administrations of the D1 and D2 dopamine receptor antagonists, SCH 23390 (6.25, 12.5, 50 ng/side) and sulpiride (12.5, 50, 100 ng/side), respectively, and dopamine (DA; 1.25 and 2.5 microg/side) into the nucleus accumbens were studied on reactivity to spatial and non-spatial changes in an open field with objects. RESULTS: Both SCH 23390 and sulpiride impaired reactivity to spatial change. However, several differences were found in the effects induced by the two DA antagonists. SCH 23390 did not affect locomotor activity and only slightly impaired exploration of the novel object. On the contrary, the D2 antagonist, induced a general, dose-dependent, impairment on all variables measured. Local administration of DA increased locomotor activity, but did not affect reactivity to spatial and non-spatial changes. CONCLUSIONS: These results demonstrate a facilitatory role of mesoaccumbens dopamine in the acquisition of spatial information. Moreover, they suggest that nucleus accumbens D1 DA receptors, play a more selective role in the modulation of spatial learning than accumbens D2 DA receptors.

Role of dopaminergic system in reactivity to spatial and non-spatial changes in mice.

RATIONALE: While experimental evidence shows that dopamine (DA) systems have an important role in locomotor function and in motivation, their role in the reactivity to spatial and non-spatial novelty is less well established. OBJECTIVE: In this study, we investigated the effects of dopaminergic pharmacological manipulation on the capability of CD1 mice to encode spatial and non-spatial information in an open field with objects. METHODS: The effects of systemic administration of: (1) selective D1 and D2 antagonists (SCH23390, 0.015 mg/kg or 0.020 mg/kg; sulpiride, 10 mg/kg or 20 mg/kg); (2) direct and indirect DA agonists (apomorphine, 1 mg/kg or 2 mg/kg; amphetamine, 1 mg/kg or 2 mg/kg) were studied. RESULTS: On the one hand, systemic administration of either D1 or D2 antagonists induced a selective impairment in the detection of spatial change but did not affect reaction to non-spatial novelty. On the other hand, amphetamine induced a selective decrease in exploratory activity in the first three sessions. This decrease did not affect the ability of mice to react to spatial change, but a dose-dependent decrease was observed in reactivity to non-spatial novelty. Such an effect does not seem to be due to amphetamine-induced hyperactivity or to non-DA mechanisms, since apomorphine induced a similar neophobic profile, without affecting locomotion. CONCLUSIONS: Taken together, these results demonstrate that manipulations of DA transmission affect reactivity to spatial and non-spatial novelty. In particular, we suggest that these two behavioral responses are modulated in opposite ways by the DA system.

Social withdrawal, neophobia, and stereotyped behavior in developing rats exposed to neonatal asphyxia.

Perinatal asphyxia is a concern for public health and may promote subtle neuropsychiatric disorders. Anoxic insults to neonatal rats cause long-lasting neurobehavioral deficits. In the present study, we focussed on changes in emotional behaviors as a consequence of neonatal asphyxia in Wistar rats. Newborn pups (24 h after birth) underwent a single 30-min exposure to a 100% N2 atmosphere (or air). The offspring was tested for a) locomotor and exploratory activity with or without a d-amphetamine challenge (0, 1, or 2 mg/kg) on postnatal day (pnd) 15; b) social interactions and novelty seeking during adolescence; c) levels of the brain-derived neurotrophic factor (BDNF). In the open-field test (pnd 15), N2-exposed pups injected with the high (2 mg/kg) amphetamine dose exhibited reduced levels of locomotor hyperactivity, and a more marked involvement in stereotyped behaviors. Individual differences emerged in the locomotor response to the novelty-seeking test: two subgroups of rats (separated on the basis of the median value) showed either arousal/attraction or avoidance/inhibition in response to free-choice novelty. The N2-exposed group showed a more marked novelty-induced avoidance and inhibition. Time devoted to allogrooming and play-soliciting behaviors was reduced, whereas object exploration was increased. Levels of BDNF were reduced in the striatum of N2-exposed rats, suggesting poorer synaptic performance of dopamine pathways. In conclusion, these findings suggest an increased risk of developing social withdrawal, neophobia and behavioral stereotypies (common symptoms found in schizophrenia and autism) as a consequence of neonatal asphyxia in preterm humans.

Evaluation of unconditioned novelty-seeking and d-amphetamine-conditioned motivation in mice.

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 strength 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 i.p. 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 reminiscent 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.

[Psychobiologic risk factors and vulnerability to psychostimulants in adolescents and animal models]. / Fattori psicobiologici di rischio e vulnerabilità agli psicostimolanti in soggetti adolescenti e modelli animali.

Adolescence is associated with an increased risk of developing drug abuse/dependence. During this ontogenetic phase, brain and hormonal systems are still undergoing crucial maturational rearrangements, which take place together with significant modifications in psychosocial development. However, the neurohormonal and behavioural facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants such as MDMA ("ecstasy") and amphetamine. Novelty-seeking, a temperamental/behavioural trait that is typical of this age period, might substantially contribute to psychobiological vulnerability to drugs. In animal models of periadolescence, the search for novel stimuli and sensations actually shares a common neurobiological substrate (the reward-related brain mesolimbic pathways) with psychostimulants. Periadolescent mice are characterized by an unbalanced and "extremes-oriented" behaviour and by elevated levels of novelty-seeking. A deeper understanding of psychostimulant effects during adolescence, and the interaction between genetic, neurobiologic, psychosocial, and environmental factors, will lead to earlier and more effective prevention strategies.

[Impact of socio-environmental factors on physiological processes of brain damage recovery: contribution of animal models]. / L'influenza dei fattori socio-ambientali sui processi fisiologici di recupero dal danno cerebrale: il contributo dei modelli animali.

This review presents the experimental approaches more widely used in animal models to investigate possible strategies aimed to stimulate plasticity in the nervous system and possibly to increase spontaneous recovery from functional/neurological diseases such as neonatal anoxia. Methods used in laboratory rodents are briefly described. Attention is focused on possible enrichments of the social and physical environment during the development.

MR imaging-detectable metabolic alterations in attention deficit/hyperactivity disorder: from preclinical to clinical studies.

MR spectroscopy represents one of the most suitable in vivo tool to assess neurochemical dysfunction in several brain disorders, including attention deficit/hyperactivity disorder. This is the most common neuropsychiatric disorder in childhood and adolescence, which persists into adulthood (in approximately 30%-50% of cases). In past years, many studies have applied different MR spectroscopy techniques to investigate the pathogenesis and effect of conventional treatments. In this article, we review the most recent clinical and preclinical MR spectroscopy results on subjects with attention deficit/hyperactivity disorder and animal models, from childhood to adulthood. We found that the most investigated brain regions were the (pre)frontal lobes and striatum, both involved in the frontostriatal circuits and networks that are known to be impaired in this pathology. Neurometabolite alterations were detected in several regions: the NAA, choline, and glutamatergic compounds. The creatine pool was also altered when an absolute quantitative protocol was adopted. In particular, glutamate was increased in children with attention deficit/hyperactivity disorder, and this can apparently be reversed by methylphenidate treatment. The main difficulties in reviewing MR spectroscopy studies were in the nonhomogeneity of the analyzed subjects, the variety of the investigated brain regions, and also the use of different MR spectroscopy techniques. As for possible improvements in future studies, we recommend the use of standardized protocols and the analysis of other brain regions of particular interest for attention deficit hyperactivity disorder, like the hippocampus, limbic structures, thalamus, and cerebellum.

Compromised decision-making and increased gambling proneness following dietary serotonin depletion in rats.

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.