Biomedical subjects

Giovanni Laviola

Publications and source records attributed to Giovanni Laviola.

At least 37 records · Page 2Linked to original sources

PubMed2004

D-amphetamine-related reinforcing effects are reduced in mice exposed prenatally to estrogenic endocrine disruptors.

Estrogenic endocrine disruptors are hormonally active compounds that can bind to estradiol receptors. Central dopamine pathways have been reported to be affected by early developmental exposure to estrogenic endocrine disruptors. In the present study, pregnant female CD-1 mice were allowed to drink spontaneously either oil or environmentally relevant low doses of two estrogenic compounds, methoxychlor (20 microg/kg) or bisphenol-A (10 microg/kg) during gestation days 11-18. Their adult offspring were assessed for conditioned place preference produced by D-amphetamine (0, 1 or 2 mg/kg). Interestingly, prenatal treatment effects were sex-dependent and no changes in conditioned place preference emerged for the male offspring. Conversely, a clear-cut profile of D-amphetamine-induced conditioned place preference was only shown by oil-exposed females, whereas exposure to bisphenol-A or methoxychlor resulted in little or no place conditioning. Locomotor effects of acute d-amphetamine were not affected by prenatal exposure to bisphenol-A or methoxychlor. As a whole, prenatal exposure to estrogenic endocrine disruptors affected some steps in the organization of the brain dopaminergic systems in the female offspring, thus leading to long-term alterations in neurobehavioral function. These data confirm that exposure to weak environmental estrogens in the period of brain sexual differentiation can influence adult behavior.

Animals↗

PubMed2004

Behavioural, neural and cardiovascular adaptations in mice lacking the NPY Y1 receptor.

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

Adaptation, Physiological↗

PubMed2004

Single episode of maternal deprivation and adult depressive profile in mice: interaction with cannabinoid exposure during adolescence.

Early life adverse experiences have been shown to increase the likelihood of developing later depressive symptoms. In this frame, human adolescents have been suggested to approach psychoactive drugs in order to self-medicate emerging depressive states. In keeping with these considerations, outbred CD-1 mice of both sexes, which underwent a single 24-h episode of maternal deprivation early in development, were administered the cannabinoid agonist WIN 55,212-2 (0, 0.5 or 2 mg/kg i.p.) during adolescence. Maternal deprivation reduced the expected interest in socio-sexual interaction with peers during adolescence. When mice were then tested at adulthood in the forced-swim paradigm in drug-free state, the latency to reach a passive floating posture was markedly reduced by early maternal deprivation. Low doses of cannabinoid (0.5 mg/kg) administered during adolescence were either able to reduce the time spent floating and to increase episodes of active struggling only in control non-deprived animals. As a whole, the emergence of depressive symptoms during both adolescence and adulthood seems to be eased as a consequence of a single/prolonged episode of early maternal deprivation early in infancy.

Adaptation, Psychological↗

PubMed2004

Acetyl-L-carnitine reduces impulsive behaviour in adolescent rats.

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.

Acetylcarnitine↗

PubMed2004

Prenatal stress affects 3,4-methylenedioxymethamphetamine pharmacokinetics and drug-induced motor alterations in adolescent female rats.

We examined the influence of prenatal stress on 3,4-methylenedioxymethamphetamine (MDMA, 5 mg/kg p.o.) pharmacokinetics in adolescent female SD rats (30 days). Our results indicate that the metabolic rate of MDMA was higher in the prenatal stress group than in the control group. Moreover, MDMA-induced motor alterations were increased in prenatally stressed rats. These findings provide evidence that (i) prenatal stress increases sensitivity to MDMA, (ii) these effects are already detectable at the adolescent stage and (iii) early differences in metabolism may play a role in the behavioural changes associated with this drug of abuse.

Animals↗

PubMed2004

Effects of chronic psychosocial stress on cardiac autonomic responsiveness and myocardial structure in mice.

Repeated single exposures to social stressors induce robust shifts of cardiac sympathovagal balance toward sympathetic dominance both during and after each agonistic interaction. However, little evidence is available regarding possible persistent pathophysiological changes due to chronic social challenge. In this study, male CD-1 mice (n = 14) were implanted with a radiotelemetry system for electrocardiographic recordings. We assessed the effects of chronic psychosocial stress (15-day sensory contact with a dominant animal and daily 5-min defeat episodes) on 1) sympathovagal responsiveness to each defeat episode, as measured via time-domain indexes of heart rate variability (R-R interval, standard deviation of R-R interval, and root mean square of successive R-R interval differences), 2) circadian rhythmicity of heart rate across the chronic challenge (night phase, day phase, and rhythm amplitude values), and 3) amount of myocardial structural damage (volume fraction, density, and extension of fibrosis). This study indicated that there was habituation of acute cardiac autonomic responsiveness, i.e., the shift of sympathovagal balance toward sympathetic dominance was significantly reduced across repeated defeat episodes. Moreover, animals exhibited significant changes in heart rate rhythmicity, i.e., increments in day and night values and reductions in the rhythm amplitude, but these were limited to the first 5 days of chronic psychosocial stress. The volume fraction of fibrosis was sixfold larger than in control animals, because of the appearance of many microscopic scarrings. In summary, although mice appeared to adapt to chronic psychosocial stress in terms of acute cardiovascular responsiveness and heart rate rhythmicity, structural alterations occurred at the myocardial level.

Adaptation, Physiological↗

PubMed2004

Behavioral and neurochemical vulnerability during adolescence in mice: studies with nicotine.

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.

Aging↗

PubMed2004

Beneficial effects of enriched environment on adolescent rats from stressed pregnancies.

The capacity of an early environmental intervention to normalize the behavioural and immunological dysfunctions produced by a stressed pregnancy was investigated. Pregnant Sprague-Dawley rats underwent three 45-min sessions per day of prenatal restraint stress (PS) on gestation days 11-21, and their offspring were assigned to either an enriched-environment or standard living cages throughout adolescence [postnatal days (pnd) 22-43]. Juvenile rats from stressed pregnancies had a prominent depression of affiliative/playful behaviour and of basal circulating CD4 T lymphocytes, CD8 T lymphocytes and T4/T8 ratio. They also showed increased emotionality and spleen and brain frontal cortex levels of pro-inflammatory interleoukin-1beta (IL-1beta) cytokine. A more marked response to cyclophosphamide (CPA: two 2 mg/kg IP injections) induced immunosuppression was also found in prenatal stressed rats. Enriched housing increased the amount of time adolescent PS rats spent in positive species-typical behaviours (i.e. play behaviour), reduced emotionality and reverted most of immunological alterations. In addition to its effects in PS rats, enriched housing increased anti-inflammatory IL-2 and reduced pro-inflammatory IL-1beta production by activated splenocytes, also producing a marked alleviation of CPA-induced immune depression. In the brain, enriched housing increased IL-1beta values in hypothalamus, while slightly normalizing these values in the frontal cortex from PS rats. This is a first indication that an environmental intervention, such as enriched housing, during adolescence can beneficially affect basal immune parameters and rats response to both early stress and drug-induced immunosuppression.

Age Factors↗

PubMed2004

Health-promoting factors and animal welfare.

The notion of "health" as the absence of disease has been replaced by a more holistic view based on the concept of "total wellbeing" and its interrelated physiological, psychological, and social components. This approach has radically changed biomedical research, both in terms of experimental methodology and in addressing ethical issues such as animal welfare. The present work focuses on the entire range of factors that can affect the wellbeing of experimental animals, including the physical, social, and psychological conditions of the housing environment, and the animal's behavioural and biological reaction to this environment.

Animal Welfare↗

PubMed2003

Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats.

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.

Animals↗

PubMed2003

The spontaneously hypertensive-rat as an animal model of ADHD: evidence for impulsive and non-impulsive subpopulations.

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.

Animals↗

PubMed2003

Chronic psychosocial stress persistently alters autonomic function and physical activity in mice.

We investigated heart rate (HR), temperature (T), and physical activity (Act) (by means of radiotelemetry) in male mice subjected to chronic psychosocial stress. Resident/intruder dyads lived in sensory contact for 15 days with the possibility to physically interact daily during the light phase for a maximum of 15 min. Intruders becoming dominants (InD) or subordinates (InS) were investigated here. The aims were to investigate; if a daily aggressive interaction would result in adaptation of autonomic responses; the effects of the social stress on daily rhythmicity and the way these effects change over time; whether acute and long-term autonomic changes do correlate; to compare dominants and subordinates. InD and InS showed a strong autonomic activation during the interactions, with moderate (InS) or no (InD) habituation over time. On the long term, InD showed tachycardia and marked hyperthermia but normal physical activity, while InS showed tachycardia, slight hyperthermia, and depressed physical activity. No correlation emerged between the acute and the long-term autonomic responses. These results highlight the existence of a sustained autonomic activation under chronic stress, which was also affected by mice social status.

Adaptation, Physiological↗

PubMed2003

Intrauterine position has long-term influence on brain mu-opioid receptor density and behaviour in mice.

In multiparous rodents, a naturally occurring variation in degree of exposure to sex steroids during the prenatal phase of sexual differentiation derives from the in-utero proximity to opposite sex foetuses. So far, the studies on intrauterine position (IUP) phenomenon have mostly focused on traits relating to reproduction and behaviour, while its influence on neurochemical substrates and pharmacological response has been largely unexplored. We investigated possible variations in the function and the profile of expression of the mu-opioid receptor system in three groups of adult mice from known IUP: 2M mice (located between two males), 0M (between two females), and 1M (between a male and a female). Autoradiographic study revealed in female mice that proximity to at least a male in utero (1M and 2M position) resulted associated at adulthood with an increased density of midbrain mu-opioid receptors. Behavioural observations were conducted following injection with the specific mu-opioid agonist Fentanyl (at 0, 0.01 or 0.05 mg/kg IP). A drug-conditioned place preference test confirmed that 1M and 2M subjects were also more sensitive to the rewarding effects of the drug, since mice spent significantly more time in the drug-paired compartment than 0M subjects. In a hot-plate test, 2M subjects showed levels of drug-induced analgesia that were much higher than other IUP groups. No reliable differences were observed between the IUP groups for locomotor activity upon drug treatment. Overall, these data indicate for the first time that the organisation of the mu-opioid receptor system in the brain, as well as a differential vulnerability to abuse of opiate drugs can be modulated by epigenetic variables such as the prenatal in utero contiguity to male foetuses.

Analysis of Variance↗

PubMed2003

Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice.

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.

Adolescent↗

PubMed2003

Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats.

Prenatal stress (PS) can produce profound and long-lasting perturbations of individual adaptive capacities, which in turn can result in an increased proneness to behavioural disorders. Indeed, in PS rats there is evidence of impaired social play behaviour, disturbances in a variety of circadian rhythms, enhanced anxiety and increased hypothalamic-pituitary-adrenal (HPA) axis reactivity. This study was designed to experimentally investigate the degree of reversibility of PS-induced disturbances of social play and HPA reactivity by assessing the effect of the enrichment of the physical environment on PS rats during periadolescence. PS subjects showed a reduced expression of social play behaviour and a prolonged corticosterone secretion in response to restraint stress, but both these effects were markedly reversed following environmental enrichment. Interestingly, the enrichment procedure increased social behaviour but had no effect on corticosterone secretion in nonstressed animals, indicating a differential impact of the postnatal environment as a function of prenatal background. As a whole, results clearly indicate that rats prenatally exposed to stress can benefit during periadolescence from the modulatory effects of an enriched environment. Moreover, they confirm that PS may well represent a suitable animal model for the design and testing of new therapeutic strategies for behavioural disorders produced by early insults.

Adolescent↗

PubMed2003

Altered profiles of spontaneous novelty seeking, impulsive behavior, and response to D-amphetamine in rats perinatally exposed to bisphenol A.

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.

Administration, Oral↗

PubMed2002

Restricted daily access to water and voluntary nicotine oral consumption in mice: methodological issues and individual differences.

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.

Animals↗

PubMed2002

Acute and carryover effects in mice of MDMA ("ecstasy") administration during periadolescence.

In spite of the increasing evidence concerning its neurotoxicity, young human individuals are often involved in the recreational use of amphetamine-type stimulants such as 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). A study aimed to investigate short- and long-term consequences of a repeated and intermittent MDMA administration (0, 5 or 10 mg/kg i.p., 3 days treatment history) was conducted in mice. Mice were injected at different phases in development, namely at early (28 days old), middle (38 days old) or late (52 days old) adolescence. When assessed for nociceptive response, a dose-dependent analgesia was found in middle and late adolescent mice. Carryover consequences of previous MDMA treatment were then investigated at adulthood (80 days old). In a social interaction test, levels of environment exploration and social behaviour resulted markedly increased in drug-free state as a function of drug exposure during development, whereas others behaviours were reduced. MDMA challenge (5-mg/kg dose) produced the expected hyperactivity, as well as a marked increment of hypothalamic serotonin (5-hydroxyhyptamine, 5-HT) levels. Mice treated chronically with MDMA during middle and late adolescence were associated with important reductions of the indoleamine. As a whole, these results indicate a differential long-term vulnerability to behavioural and neurotoxicant effects of MDMA as a function of the developmental stage of exposure.

Aging↗