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.

Paradoxical effects of D-amphetamine in infant and adolescent mice: role of gender and environmental risk factors.

The psychostimulant D-amphetamine (AMPH) increases generalised activity in adult subjects, while exerting a paradoxical "calming effect" in children with Attention-deficit Hyperactivity Disorder (AD/HD). A number of animal models have been developed to characterise the neurobiological basis of this AMPH action. In this line, the present review summarises recent work on the effects of AMPH on behavioural and physiological parameters in developing mice with a special emphasis on the role of gender and environmental risk factors. Behavioural and neuroendocrine responses to AMPH administration (0, 1, or 3 mg/kg, IP) and their relation to changes in the environment, represented by social stimuli, were studied in infant CD-1 mouse pups of both sexes at three different developmental ages (3, 8, or 18 postnatal (pnd) days). Mouse pups were assessed either in baseline condition or following 24 h maternal deprivation. AMPH exerted a paradoxical effect on CORT secretion only in maternally deprived subjects while affecting behaviour mainly in deprived female subjects, which showed a generalised shift to the left in the dose-response curve to this drug. Unwanted perseverative motor effects and possible dependence states represent side effects of AMPH administration. Further knowledge on these aspects comes from another set of studies where a shortened conditioned place preference (CPP) paradigm was employed to assess the reinforcing properties of AMPH (0, 1, 3.3, or 10 mg/kg) in developing mice on 14-17, 21-24, and 28-31 pnd. Data indicate that AMPH-CPP develops early, mice being able, already at two weeks of age, to acquire a place preference that relies on adult-like sensory, motor, and associative capacities. AMPH-CPP appears earlier in females, compared to males. A detailed analysis of acute D-amphetamine effects evidenced that the drug produces a dose-dependent increase in locomotor activity and in several responses (including stereotypes). These effects appear much larger at both post weaning stages than in preweanlings and are significantly more pronounced in females than in males. Overall these data suggest that AMPH action is dependent on the baseline level of activity and indicate a strong role of gender in the effects of this drug measured early on during development, with females showing greater sensitivity to this drug. A better understanding of AMPH action during the early ontogenetic phases, particularly its interaction with environmental factors, might extend our knowledge on the neurobiological basis of AD/HD, possibly improving the clinical efficacy of psychostimulant drugs.

Interacting effects of oxazepam in late pregnancy and fostering procedure on mouse maternal behavior.

The present study was designed to assess the proactive effects of late pregnancy benzodiazepine (BDZ) treatment on maternal behavior in the postpartum period, using cross-fostering procedures to control for the role of changes produced prenatally in the offspring. Outbred CD-1 mouse dams were treated with either oxazepam (OX, 15 mg/kg PO twice/day on pregnancy days 12-16) or vehicle (VEH). After parturition, entire litters were exchanged either within treatments (in-fostered groups, IF) or between treatments (cross-fostered groups, CF), while additional litters were left undisturbed (un-fostered groups, UF). The behavior of lactating dams was observed in their home cages at 4, 8, and 12 days postpartum. Maternal responses, particularly nursing, were reduced in the OX-UF and OX-CF conditions and either normal or enhanced in the OX-IF condition. Correspondingly, locomotor/exploratory activity was markedly enhanced in the former conditions and close to the control level in the latter condition. In sum, the fostering variable appeared to determine whether pups raised by dams treated previously with BDZ receive either insufficient or exaggerated maternal care. This points to the need for a better understanding of mother/pup interactions in studies aimed at characterizing drug and toxicant effects on offspring development.

The developmental psychobiology of behavioural plasticity in mice: the role of social experiences in the family unit.

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.

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.

Prenatal cocaine potentiates the effects of morphine in adult mice.

Prenatal cocaine exposure has been reported to result in abnormal neurobehavioral development, both in animals and humans. In this study, outbred CD-1 mice were exposed in utero to cocaine hydrochloride administered daily as i.p. injections to dams from day 10 of gestation to day 16, at the dose 0, 5 or 50 mg/kg. Cocaine did not alter duration of pregnancy while it decreased the difference in maternal body weight from days 10 to 16 in the dams receiving the higher dose of cocaine. The body weight of the offspring from birth to 15 days of age and the physical maturation were not affected by prenatal cocaine exposure. The development of the response to strong tactile stimulation was either slightly delayed in the 5 mg/kg group or markedly accelerated in the 50 mg/kg group. At adulthood, animals were assessed for behavioral responses to a novel environment, for response to painful stimulation (hot-plate test set at 55 +/- 1 degree C), and for the effects of a single morphine injection (30 mg/kg, i.p.). Data showed that in the absence of prenatal cocaine exposure effects, morphine increased the time spent in inactivity, while it decreased rearing, grooming and bar-holding behaviors. In the case of sniffing, morphine increased this behavior, except in the 5 mg/kg cocaine group. Moreover, morphine administration induced the expected increase of locomotion, irrespective of prenatal condition. With respect to pain reactivity, prenatal cocaine exposure resulted in an increase of licking latency in the 5 mg/kg group.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats.

Prenatal stress in the rat induces enhanced reactivity of the hypothalamus-pituitary-adrenal (HPA) axis, disturbances in a variety of circadian rhythms and increased anxiety-like behaviour. Such abnormalities parallel those found in human depressed patients. Prenatally stressed (PS) rats could represent, therefore, an interesting animal model for the evaluation of the efficacy of pharmacotherapeutic intervention in psychiatric disorders that has often been addressed using control animals. In the present study, PS and non-stressed rats were chronically treated with the tricyclic antidepressant imipramine (10 mg/kg i.p. for 21 days) and assessed in the forced swim test. Glucocorticoid receptor binding sites in the hippocampus were measured and 5-HT(1A) receptor mRNA levels in the frontal cortex were also assessed. PS rats were characterised by increased immobility in the forced swim test, reduced hippocampal corticosteroid receptor binding and increased levels of cortical 5-HT(1A) mRNA. All these parameters were significantly reversed by chronic imipramine treatment. Conversely, no significant effects were observed for non-stressed rats. All these effects are consistent with the expected pharmacotherapy of depression-like abnormalities in PS rats. These results further indicate that PS rats are a relevant animal model of depression.

Behavioral and hormonal effects of partner familiarity in periadolescent rat pairs upon novelty exposure.

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.

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.

d-amphetamine conditioned place preference in developing mice: relations with changes in activity and stereotypies.

Conditioned place preference (CPP) with both visual and tactile cues, hyperactivity, and stereotypies produced by d-amphetamine (1-10 mg/kg ip, single dose) were studied in CD-1 mice at 2, 3, and 4 weeks from birth. CPP was shown from the youngest age onward in female mice and from 3 weeks in male mice. Hyperactivity was much more pronounced in postweanlings (3 and 4 weeks) than in preweanlings. Stereotypies (at 3.3 and 10 mg/kg) occurred from the youngest age and tended to peak at 3 weeks. Stereotypies may indicate a sickness experience or "poor welfare" (G.J. Mason, 1991; A. Wall, R.E. Hinson, E. Schmidt, C. Johnston, & A. Streather, 1990) due to an aversive component of amphetamine's action. Therefore, the delayed development of fully fledged amphetamine CPP, relative to cocaine CPP (G. Laviola, G. Dell'Omo, E. Alleva, & G. Bignami, 1992), may be due to an age-dependent diminution of the positive hedonic value of the former drug by negative effects that are minimal or absent in the case of the latter drug.

Ontogeny of muscimol effects on locomotor activity, habituation, and pain reactivity in mice.

Three hundred and twenty mouse pups of both sexes of the CD-1 outbred strain received IP muscimol and were subsequently assessed for locomotor activity (single Varimex 30-min session) and for hot-plate responding. Muscimol doses were 0.05, 0.1, or 0.2 mg/kg at 8 and 14 days, and 0.1, 0.5, or 1.0 mg/kg at 21, 28, and 35 days. Activity data showed a shift from an immature pattern at 8 and 14 days to an adult-like pattern from day 21 onwards (high initial activity followed by a marked within-session decrement). Muscimol was ineffective on day 8, and depressed activity from day 14 onwards. At 28 days, however, the higher-dose male group showed a non-monotonic trend of activity; that is an initial depression followed by a marked rebound hyperactivity. With regard to hot-plate exposure, muscimol was ineffective at 8 days, while it produced maximal analgesic effects on day 14, followed by a progressive decrease in drug sensitivity. Around day 70, mice of the former 0.1 mg/kg and saline groups were re-tested for locomotor activity and pain reactivity without additional drug treatment. Activity was generally higher in males than in females, and two groups habituated significantly less than the others (females tested in the muscimol state at 8 days and males tested in the saline state at 35 days). Moreover, prior testing at the earliest ages and prior muscimol exposure had additive attenuating effects on pain reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)