Search

Transgenic mouse models of Alzheimer's disease (AD) have been recently advanced. Tg2576 mice have been shown to develop progressive beta-amyloid (Abeta) neuritic plaques and exhibit impairment of cognitive function. The aim of this study was a better characterization of different aspects of spatial memory performance of transgenic mice, observed at a time when levels of soluble Abeta are elevated and Abeta neuritc plaques start to appear. A general elevation of basal locomotory activity in the home cage was found in Tg2576 mice, which also exhibited an impairment of spontaneous alternation in the Y-maze test. Tg2576 mice were not flexible upon changes in the schedule and failed to codify spatially the testing environment. Consistently, a deficit of spatial memory was also observed when mice were assessed for levels of reactivity to spatial change in the modified open-field test with objects. Compared to controls, Tg2576 mice also exhibited an increased number of explorative approaches to the different objects, and failed to discriminate the displacement of the object. Consistently with the hypothesis of increased disinhibition, a differential behavioural response to the plus-maze paradigm was exhibited by Tg2576 mice. Results clearly indicate that Tg2576 mice are characterized by a number of specific behavioral cognitive alterations, compatible with Alzheimer's disease (AD), which make them a suitable animal model for testing of novel anti-AD drugs.

The attention deficit/hyperactivity disorder (ADHD) can affect human infants and adolescents. One important feature of this disorder is behavioural impulsivity. This study assessed the ability of chronic acetyl-L-carnitine (ALC, saline or 100 mg/kg SC, plus 50 mg/kg orally) to reduce impulsivity in a validated animal model for ADHD. Food-restricted rats were tested during adolescence (postnatal days, pnd, 30-45) in operant chambers with two nose-poking holes, one delivering one food pellet immediately, and the other five pellets after a delay. Delay length was increased over days (from 0 to 80 s). Individual differences in the preference-delay curve emerged, with the identification of two distinct subpopulations, i.e. one with a nearly horizontal curve and another with a very steep ("impulsive") slope. The impulsivity profile was slightly but consistently reduced by chronic ALC administration. Consistent results were also obtained with methylphenidate (MPH, saline or 3 mg/kg IP twice daily). Impulsive rats exhibited a lower metabolite/serotonin (5HIAA/5HT) ratio in the medial frontal cortex (MFC) and lower noradrenaline (NA) levels in the MFC and cingulate cortex (CC) when compared with the other subgroup. The ALC treatment increased NA levels in the CC and the 5HIAA/5HT ratio in both CC and MFC. Present data suggest that ALC, a drug devoid of psychostimulant properties, may have some beneficial effects in the treatment of ADHD children.

People are very likely to start psychoactive drug use during adolescence, an earlier onset being associated with a higher risk of developing addiction later in life. In experiment I, Pre- (postnatal day (pnd) 23-35), Mid- (pnd 36-48), or Post- (pnd 49-61) adolescent mice underwent a restricted-drinking period (2 h/day for 12 days), one bottle containing water and the other containing nicotine (10 mg/l) or water. After this period, Mid-adolescents showed prominent exploration and reduced anxiety in the plus-maze. This ontogenetic profile was dampened by nicotine consumption. After 2 months, these mice were tested in a novel environment (30 min/day for 3 days). Locomotor-habituation profiles were specifically disrupted by nicotine consumption during Mid-adolescence, suggesting this age as a critical period. In experiment II, Mid-adolescent (pnd 35-44) and adult (pnd > 70) mice were pretreated with nicotine (0, 0.03, 0.10, 0.30 mg/kg/day for 10 days). Acute nicotine administration had opposite effects on anxiety in adolescents and adults. At 2 months after pretreatment, we measured levels of AMPA GluR2/3 subunits, thought to be involved in the control of addictive behaviors. Nicotine exposure during Mid-adolescence dose-dependently downregulated these subunits in the striatum and hippocampus, but comparable exposure during adulthood had either opposite or no effects. NMDA NR2A/B subunits were affected by nicotine, but without age-related differences. The present data identified a nicotine-vulnerable age window, characterized by long-term disruption of locomotor habituation and downregulation of AMPA receptors. These findings support neurobiological vulnerability to drugs in adolescent humans.

Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric syndrome, affecting human infants and adolescents. Two main behavioural features are reported: (1). impaired attention and (2). an impulsive-hyperactive behavioural trait. The latter has been studied in a series of experiments, using the spontaneously hypertensive-rat (SHR) strain (which is regarded as a validated animal model for ADHD) in operant tasks. Food-restricted SHRs and their Wistar-Kyoto (WKY) controls were tested during adolescence (i.e. post-natal days 30-45), in operant chambers provided with two nose-poking holes. Nose-poking in one hole (H1) resulted in the immediate delivery of a small amount of food, whereas nose-poking in the other hole (H5) delivered a larger amount of food after a delay, which was increased progressively each day (0-100 s). As expected, all animals showed a shift in preference from the large (H5) to the immediate (H1) reinforcer as the delay length increased. Impulsivity can be measured by the steepness of this preference-delay curve. The two strains differed in home-cage circadian activity, SHRs being more active than WKYs at several time-points. During the test for impulsivity, inter-individual differences were completely absent in the WKY strain, whereas a huge inter-individual variability was evident for SHRs. On the basis of the median value of average hole-preference, we found an 'impulsive' SHR subgroup, with a very quick shift towards the H1 hole, and a flat-slope ('non-impulsive') SHR subgroup, with little or no shift. The impulsive subpopulation also presented reduced noradrenaline levels in both cingulated and medial-frontal cortex, as well as reduced serotonin turnover in the latter. Also, cannabinoid CB1 receptor density resulted significantly lower in the prefrontal cortex of impulsive SHRs, when compared to both the non-impulsive subgroup and control WKYs. Interestingly, acute administration of a cannabinoid agonist (WIN 55,212, 2 mg/kg s.c.) normalized the impulsive behavioural profile, without any effect on WKY rats. Thus, two distinct subpopulations, differing for impulsive behaviour and specific neurochemical parameters, were evidenced within adolescent SHRs. These results support the notion that a reduced cortical density of cannabinoid CB1 receptors is associated with enhanced impulsivity. This behavioural trait can be positively modulated by administration of a cannabinoid agonist. Present results confirm and extend previous literature, indicating that adolescent SHRs represent a suitable animal model for the preclinical investigation of the early-onset ADHD syndrome.

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.

Epidemiological research has emphasized that adolescence is associated with some temperamental and behavioral traits that are typical of this age and that might substantially contribute to both psychological and psychobiological vulnerability. The contribution of the important developmental rearrangements in neurobiological and neuroendocrinological processes has received surprisingly little investigation. The present review summarizes recent work in animal models, indicating that adolescent rodents exhibit marked peculiarities in their spontaneous behavioral repertoire. When compared to adults, adolescents show an unbalanced and 'extremes-oriented' behavior, consisting of an increased novelty seeking, together with decreased novelty-induced stress and anxiety, an increased risk-taking behavior in the plus-maze, as well as elevated levels of impulsivity and restlessness. Age-related discontinuities in the function of monoaminergic systems, which are a main target of abused drugs, can perhaps account for such a profile. In particular, a peculiar function within reward-related dopaminergic brain pathways actually seems to underlie the search for novel and rewarding sensations, as well as changes in the magnitude of psychostimulant effects. The role played by early epigenetic factors in the shaping of novelty-seeking behavior of adolescent and adult rodents are also reviewed. Two examples are considered, namely, subtle variations in the hormonal milieu as a function of intrauterine position and precocious or delayed maturation of nutritional independence as a function of changes in time of weaning. As for spontaneous drug consumption, a prominent vulnerability to the oral intake of nicotine during early adolescence is reported. In conclusion, adolescence in rodents may represent a suitable animal model with enough face- and construct-validity. Actually, this model is able to show behavioral features that resemble those found in human adolescents, including vulnerability to the consumption of psychoactive drugs.

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., (Copyright 2002 Elsevier Science B.V.)

Nicotine, the neuroactive compound responsible for tobacco addiction, is primarily believed to have beneficial effects on the adult brain. However, in heavy smokers, abstinence from nicotine is accompanied by cognitive impairments that suggest adverse effects of nicotine on brain plasticity. For this reason, we studied changes in plasticity-related processes in the dentate gyrus (DG) of the hippocampal formation of animals trained to self-administer nicotine. The DG was chosen because it undergoes profound plastic rearrangements, many of which have been related to memory and learning performances. In this region, we examined the expression of the polysialylated (PSA) forms of neural cell adhesion molecule (NCAM), PSA-NCAM, neurogenesis, and cell death by measuring the number of pyknotic cells. It was found that nicotine self-administration profoundly decreased, in a dose-dependent manner, the expression of PSA-NCAM in the DG; a significant effect was observed at all the doses tested (0.02, 0.04, and 0.08 mg/kg per infusion). Neurogenesis was also decreased in the DG, but a significant effect was observed only for the two highest doses of nicotine. Finally, the same doses that decreased neurogenesis also increased cell death. These results raise an important additional concern for the health consequences of nicotine abuse and open new insight on the possible neural mechanisms of tobacco addiction.

Human adolescence is mainly characterised by an elevated number of psychological, biological and behavioural changes. This rapid as well as challenging change in the "inner state" during adolescence in humans seems to share a number of similarities with the age-dependent alteration of the normal and "linear" development in other mammalian species. Hence, in order to further investigate the biological bases of these idiosyncratic age-related responses, it seems worth to develop and to study suitable animal models for this developmental phase. Aim of the present review is to show experimental results indicating an elevated similarity between humans and rodents (mice and rats) in a number of psychological (elevated levels of novelty seeking as well as of harmavoidance due to a reduced anxiety) behavioural (elevated exploration of novel as well as potentially dangerous environments and peculiar vulnerability to incentive properties of drugs of abuse) and neurobiological (developing state of the underlying cortical pathways implicated in the above mentioned responses) processes. These findings could prove really useful in view of a general deeper comprehension of this age period and helpful in developing earlier and more effective prevention strategies aimed at reducing the social impact of dangerous and reckless behaviours frequently shown by human adolescents (drug addiction, undesired pregnancy. AIDS and car accident).

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.

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.

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.

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.

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.

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.