Background Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), ... more Background Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. Methods As socially stressful events pose particular challenges at developmental stages, this research applied the resident–intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. Results Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intr...
Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale, 2018
Manipulations of the serotonin transmission during early development induce long-lasting changes ... more Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats,...
Stress-related neuropeptides are involved in setting up alcohol addiction. Ethanol is able to acu... more Stress-related neuropeptides are involved in setting up alcohol addiction. Ethanol is able to acutely induce CRH and ACTH release, while cronically a dampered response of the hypothalamus -pituitary- adrenal (HPA) axis has been observed. Also neuropeptide Y (NPY) has been shown to modulate ethanol consumption, and its central expression seems inversely correlated to ethanol intake. Recent in vivo and in vitro evidence have highlighted the key role of acetaldehyde (ACD), ethanol first metabolite, as a mediator of the central effects of ethanol, even as modulator of the neuropeptidergic transmission in the rat brain. The aim of this study was to investigate NPY immunoreactivity following a 4-day binge ACD treatment in hippocampus and nucleus accumbens, two areas particulary involved in addictive-related learning and reward processes. Wistar rats have been intragastrically administered with ACD (450mg/kg) five times per day, for four days, and have been sacrificed at early (16h) and late (72h) withdrawal. Our results show: i) an increased NPY expression at 16h and 72h after the last administration in hippocampus (p< 0.001; p< 0.001) and nucleus accumbens (p< 0.05; p< 0.001) compared to controls. ii) an increase in the number of NPY-positive neurons in the hippocampus (p< 0.001) and nucleus accumbens (p< 0.001) in late withdrawal with respect to early withdrawal. These findings are consistent with the hypothesis that NPY levels increase in a time- and region-specific fashion to reset homeostasis in the brain during withdrawal; and that ACD is able to affect neuropeptidergic transmission as well as ethanol, playing thus a key role in the neuroadaptative changes that characterize ethanol addiction
Sudden sensorineural hearing loss is a common and alarming symptom of about 360 million people th... more Sudden sensorineural hearing loss is a common and alarming symptom of about 360 million people that suffer from hearing impairment worldwide. The sudden sensorineural hearing loss usually arises unilaterally and it is habitually described as greater than 30dB hearing reduction, attributable to lesions of the cochlea, cranial nerve VIII, brainstem and temporal lobe. There are many factor that promote the onset of this lesions such us infections, circulatory diseases, inner ear neoplasia and neurological disorders. This pathology is characterized by primary symptoms such as the impairment of the comprehension of spoken language and the struggling to listen to music. Subsequently, secondary symptoms arise as well as anxiety, inadequate coping with illness and psychosomatic disturbances that have a negative impact on patients with a significant reduction in the quality of life. Treatment of the sudden sensorineural hearing loss remains one of the most problematic issues for contemporary otorhinolaryngology, because of the wide array of the presumed mechanisms that underpin this disorder. Although the pharmacological treatment remain even now empirical and the management is not standardized in term of medical treatment, duration and route of administration, different agents are used. In the past, pharmacological approaches have included antiviral agents, vitamin, herbal preparations, carbogen inhalations or magnesium, administered on either an inpatient or outpatient procedures. Nowadays, the corticosteroids therapy remains the mainstay strategy, but considering the multifaceted aspects of this disorder, diuretics, anticoagulants, vasodilatators and fibrinolityc agents have also been tried. In this chapter, we will focus mainly on the principal pharmacological approaches of the sudden sensorineural hearing loss that will be described and examined in terms of mechanism of action and effectiveness
Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is beli... more Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Ba...
Alcohol consumption during perinatal periods is common, despite the warning of adverse effects on... more Alcohol consumption during perinatal periods is common, despite the warning of adverse effects on the foetal development. In female rats, the intermittent pattern of alcohol consumption is responsible for higher drinking levels and more profound disruption of maternal care than traditional continuous free-access paradigm, which can have persistent effects on the offspring. The environmental enrichment, a powerful form of experience-dependent plasticity that allows high cognitive, motor and sensory stimulations, is helpful for recovering from different neurological pathologies. Thus, this study aimed at exploring the effects of environmental enrichment on alcohol vulnerability and affective behaviour in the offspring that was perinatally exposed to continuous or intermittent alcohol. Dams were given two-bottle choice to water and 20% alcohol with either continuous- or intermittent access (CA vs IA), along a 12-week period. They were alcohol-deprived during breeding and resumed alcohol self-administration from late gestation and throughout lactation. Alcohol-exposed offspring, reared in either standard- or enriched- conditions, were assessed for alcohol drinking behaviour in a free-choice paradigm and were also tested for the deprivation effect. Moreover, they were tested for behavioural reactivity in the open field; anxiety-like behaviour in the elevated plus maze and depressive-like behaviour in the forced swim test during the drinking paradigm. Our results show that perinatal CA to alcohol did not increase alcohol-drinking behaviour with respect to controls. On the other hand, rats perinatally exposed to IA displayed a high vulnerability to alcohol, in terms of drinking behaviour and deprivation effect. The environmental enrichment was able to exert a protective role on alcohol vulnerability in perinatally IA exposed rats and controls, especially during relapse. Moreover, it was able to induce an increase in behavioural reactivity in the open field and a decrease in anxiety-like behaviour in the elevated plus maze, in both perinatally CA and IA exposed groups. In conclusion, the pattern of alcohol consumption during pregnancy and lactation can influence long-term alcohol vulnerability in the offspring. Rearing conditions that promote high cognitive, motor and sensory stimulations improve resilience to alcohol abuse and affective tone, although they cannot be sufficient to full recovery from detrimental effects of perinatal alcohol exposure
Under current diagnostics depression and stress related mood disorders have a higher occurrence i... more Under current diagnostics depression and stress related mood disorders have a higher occurrence in women than men. Little is known of the biological mechanisms contributing to these sex differences and how they may impact potential new therapeutics. Here we examine how DNA methylation contributes to sex specific stress vulnerability in adult animals. Mice of both sexes were exposed to variable stress and given a behavioral test battery to examine stress sensitivity. Female mice expressed depressionassociated behavior across all tests stress exposure whereas males were behaviorally resilient. Markers of pre and post-synaptic plasticity and spine morphology were examined using a combination of immunohistochemistry and cell filling. Females demonstrated circuit specific pre-synaptic alterations that may contribute to stress susceptibility in the absence of post-synaptic alterations in spine density or phenotype. Viral over-expression in combination with transgenic knockout strategies was used to manipulate DNA methyltransferase (DNMT) 3a levels in NAc and examine behavior. Transcriptional profiles were measured following DNMT3a knockout. Increasing the expression of DNMT3a site specifically in NAc shifted both males and females to a stress susceptible state following exposure to a sub-threshold variable stress. Excising DNMT3a site specifically from NAc in adulthood made female mice behaviorally resilient to variable stress. Removal of DNMT3a shifted the female transcriptome to a more male like state. Together, these studies examine an epigenetic mechanism that regulates transcriptional sex differences in reward circuitry mediating behavioral susceptibility and resilience to variable stres
Pathological gambling (PG) is a disorder recently conceptualized as a behavioural addiction, beca... more Pathological gambling (PG) is a disorder recently conceptualized as a behavioural addiction, because of its neurobiological, neurophysiological and psychological features (American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th ed., 2013; Potenza et al., 2012). PG represents both a social and a sanitary cost, in terms of pharmacological and psychological therapies. The aim of this study was to examine the correlation between personality disorders, clinical syndromes and alexithymia levels in a group of pathological gamblers. Furthermore this study aimed at highlighting a relationship between PG and alexithymia, over and above the relationship between personality disorders, clinical syndromes and PG. Sixty treatmentseeking pathological gamblers and 60 healthy controls were included in the study. Psychological assessment included the South Oaks Gambling Screen (SOGS), the Millon Clinical Multiaxial Inventory (MCMI-III) and the Toronto Alexithymia Sc...
Acetaldehyde contributes to alcohol’s neuroactive effects through its own motivational properties... more Acetaldehyde contributes to alcohol’s neuroactive effects through its own motivational properties. This chapter gathers current evidence on acetaldehyde psychoactive action, focusing on behavioral investigations able to unveil acetaldehyde rewarding effects and their pharmacological modulation in vivo. Acetaldehyde induces conditioned place preference for paired environment and cues and is dose-dependently self-administered in a two-bottle choice drinking paradigm. Acetaldehyde’s motivational properties are further highlighted by operant paradigms tailored to model several addiction-like behaviors, such as induction and maintenance of operant responding, drug-seeking in extinction, relapse following deprivation, and resistance to punishment. Acetaldehyde-related behaviors are sensitive to pharmacological manipulations of dopamine and endocannabinoid signaling, two systems that functionally interplay in controlling motivation. This evidence holds promising potential for the developme...
Acetaldehyde (ACD), ethanol first metabolite, is rewarding in rodents and humans; it induces \u20... more Acetaldehyde (ACD), ethanol first metabolite, is rewarding in rodents and humans; it induces \u201cplace preference\u201d, is self-administer directly in the VTA, orally in an operant/conflict paradigm and increases DA neurons\u2019 firing. This research aims at investigating DA2-receptor role in the reinstatement of acetaldehyde operant-drinking behaviour, following induction, maintenance and abstinence in the rat. Male Wistar rats are trained to orally self-administer ACD solution (3.2% v/v) or water, in an operant chamber under a FR1. Afterwards animals undergo cyclic periods of deprivation and relapse to ACD. The effect ofD2-receptor activation by quinpirole (0.03mg/kg,i.p.) on operant ACD self-administration is tested during relapse sessions. Rats show a peak-and-drop drinking pattern that reaches regular and higher values in the last training days. Quinpirole administration produces lever press reduction in ACD group when compared to basal intake(p<0.001) and to vehicle (p<0.05;p<0.001), while when treatment is suspended, rats reinstate lever presses for ACD. ACD incentive properties involve dopamine neurotransmission: D2-receptor activation is able to reduce reinstatement of operant drinking behaviour for ACD, following periods of abstinence, probably acting at a pre-synaptic level, thus reducing DA release in mesolimbic areas. These findings further support ACD pivotal role in ethanol central effects
Social interaction is essential for life but is impaired in many psychiatric disorders. We presen... more Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous “maternal” heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; “mixed” heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed...
Binge alcohol consumption among adolescents affects the developing neural networks underpinning r... more Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposure. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively in...
Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptom... more Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptoms can be investigated in knock out rats for the DA transporter (DAT‐KO). Recent studies evidenced the role of epigenetic DAT modulation in depressive‐like behavior. Accordingly, we used heterozygous (HET) rats born from both HET parents (termed MIX‐HET), compared to HET rats born from WT‐mother and KO‐father (MAT‐HET), implementing the role of maternal care on DAT modulation. We developed a “sudden fright” paradigm (based on dark‐light test) to study reaction to fearful inputs in the DAT‐KO, MAT‐HET, MIX‐HET, and WT groups. Rats could freely explore the whole 3‐chambers apparatus; then, they were gently confined in one room where they experienced the fright; finally, they could freely move again. As expected, after the fearful stimulus only MAT‐HET rats showed a different behavior consisting of avoidance towards the fear‐associated chamber, compared to WT rats. Furthermore, ex‐vivo immuno‐fluorescence reveals higher prefrontal DAT levels in MAT‐HET compared to MIX‐HET and WT rats. Immuno‐fluorescence shows also a different histone deacetylase (HDAC) enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT‐HET fore brain, the enhanced expression of DAT could well impair the corticostriatal‐thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT‐HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation. This could imply significant prefronto‐cortical influences onto the emotional processes: hence an excessively frightful response, even to mild stressful agents, may draw developmental trajectories toward anxious and depressed‐like behavior.
Background Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), ... more Background Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. Methods As socially stressful events pose particular challenges at developmental stages, this research applied the resident–intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. Results Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intr...
Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale, 2018
Manipulations of the serotonin transmission during early development induce long-lasting changes ... more Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats,...
Stress-related neuropeptides are involved in setting up alcohol addiction. Ethanol is able to acu... more Stress-related neuropeptides are involved in setting up alcohol addiction. Ethanol is able to acutely induce CRH and ACTH release, while cronically a dampered response of the hypothalamus -pituitary- adrenal (HPA) axis has been observed. Also neuropeptide Y (NPY) has been shown to modulate ethanol consumption, and its central expression seems inversely correlated to ethanol intake. Recent in vivo and in vitro evidence have highlighted the key role of acetaldehyde (ACD), ethanol first metabolite, as a mediator of the central effects of ethanol, even as modulator of the neuropeptidergic transmission in the rat brain. The aim of this study was to investigate NPY immunoreactivity following a 4-day binge ACD treatment in hippocampus and nucleus accumbens, two areas particulary involved in addictive-related learning and reward processes. Wistar rats have been intragastrically administered with ACD (450mg/kg) five times per day, for four days, and have been sacrificed at early (16h) and late (72h) withdrawal. Our results show: i) an increased NPY expression at 16h and 72h after the last administration in hippocampus (p< 0.001; p< 0.001) and nucleus accumbens (p< 0.05; p< 0.001) compared to controls. ii) an increase in the number of NPY-positive neurons in the hippocampus (p< 0.001) and nucleus accumbens (p< 0.001) in late withdrawal with respect to early withdrawal. These findings are consistent with the hypothesis that NPY levels increase in a time- and region-specific fashion to reset homeostasis in the brain during withdrawal; and that ACD is able to affect neuropeptidergic transmission as well as ethanol, playing thus a key role in the neuroadaptative changes that characterize ethanol addiction
Sudden sensorineural hearing loss is a common and alarming symptom of about 360 million people th... more Sudden sensorineural hearing loss is a common and alarming symptom of about 360 million people that suffer from hearing impairment worldwide. The sudden sensorineural hearing loss usually arises unilaterally and it is habitually described as greater than 30dB hearing reduction, attributable to lesions of the cochlea, cranial nerve VIII, brainstem and temporal lobe. There are many factor that promote the onset of this lesions such us infections, circulatory diseases, inner ear neoplasia and neurological disorders. This pathology is characterized by primary symptoms such as the impairment of the comprehension of spoken language and the struggling to listen to music. Subsequently, secondary symptoms arise as well as anxiety, inadequate coping with illness and psychosomatic disturbances that have a negative impact on patients with a significant reduction in the quality of life. Treatment of the sudden sensorineural hearing loss remains one of the most problematic issues for contemporary otorhinolaryngology, because of the wide array of the presumed mechanisms that underpin this disorder. Although the pharmacological treatment remain even now empirical and the management is not standardized in term of medical treatment, duration and route of administration, different agents are used. In the past, pharmacological approaches have included antiviral agents, vitamin, herbal preparations, carbogen inhalations or magnesium, administered on either an inpatient or outpatient procedures. Nowadays, the corticosteroids therapy remains the mainstay strategy, but considering the multifaceted aspects of this disorder, diuretics, anticoagulants, vasodilatators and fibrinolityc agents have also been tried. In this chapter, we will focus mainly on the principal pharmacological approaches of the sudden sensorineural hearing loss that will be described and examined in terms of mechanism of action and effectiveness
Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is beli... more Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Ba...
Alcohol consumption during perinatal periods is common, despite the warning of adverse effects on... more Alcohol consumption during perinatal periods is common, despite the warning of adverse effects on the foetal development. In female rats, the intermittent pattern of alcohol consumption is responsible for higher drinking levels and more profound disruption of maternal care than traditional continuous free-access paradigm, which can have persistent effects on the offspring. The environmental enrichment, a powerful form of experience-dependent plasticity that allows high cognitive, motor and sensory stimulations, is helpful for recovering from different neurological pathologies. Thus, this study aimed at exploring the effects of environmental enrichment on alcohol vulnerability and affective behaviour in the offspring that was perinatally exposed to continuous or intermittent alcohol. Dams were given two-bottle choice to water and 20% alcohol with either continuous- or intermittent access (CA vs IA), along a 12-week period. They were alcohol-deprived during breeding and resumed alcohol self-administration from late gestation and throughout lactation. Alcohol-exposed offspring, reared in either standard- or enriched- conditions, were assessed for alcohol drinking behaviour in a free-choice paradigm and were also tested for the deprivation effect. Moreover, they were tested for behavioural reactivity in the open field; anxiety-like behaviour in the elevated plus maze and depressive-like behaviour in the forced swim test during the drinking paradigm. Our results show that perinatal CA to alcohol did not increase alcohol-drinking behaviour with respect to controls. On the other hand, rats perinatally exposed to IA displayed a high vulnerability to alcohol, in terms of drinking behaviour and deprivation effect. The environmental enrichment was able to exert a protective role on alcohol vulnerability in perinatally IA exposed rats and controls, especially during relapse. Moreover, it was able to induce an increase in behavioural reactivity in the open field and a decrease in anxiety-like behaviour in the elevated plus maze, in both perinatally CA and IA exposed groups. In conclusion, the pattern of alcohol consumption during pregnancy and lactation can influence long-term alcohol vulnerability in the offspring. Rearing conditions that promote high cognitive, motor and sensory stimulations improve resilience to alcohol abuse and affective tone, although they cannot be sufficient to full recovery from detrimental effects of perinatal alcohol exposure
Under current diagnostics depression and stress related mood disorders have a higher occurrence i... more Under current diagnostics depression and stress related mood disorders have a higher occurrence in women than men. Little is known of the biological mechanisms contributing to these sex differences and how they may impact potential new therapeutics. Here we examine how DNA methylation contributes to sex specific stress vulnerability in adult animals. Mice of both sexes were exposed to variable stress and given a behavioral test battery to examine stress sensitivity. Female mice expressed depressionassociated behavior across all tests stress exposure whereas males were behaviorally resilient. Markers of pre and post-synaptic plasticity and spine morphology were examined using a combination of immunohistochemistry and cell filling. Females demonstrated circuit specific pre-synaptic alterations that may contribute to stress susceptibility in the absence of post-synaptic alterations in spine density or phenotype. Viral over-expression in combination with transgenic knockout strategies was used to manipulate DNA methyltransferase (DNMT) 3a levels in NAc and examine behavior. Transcriptional profiles were measured following DNMT3a knockout. Increasing the expression of DNMT3a site specifically in NAc shifted both males and females to a stress susceptible state following exposure to a sub-threshold variable stress. Excising DNMT3a site specifically from NAc in adulthood made female mice behaviorally resilient to variable stress. Removal of DNMT3a shifted the female transcriptome to a more male like state. Together, these studies examine an epigenetic mechanism that regulates transcriptional sex differences in reward circuitry mediating behavioral susceptibility and resilience to variable stres
Pathological gambling (PG) is a disorder recently conceptualized as a behavioural addiction, beca... more Pathological gambling (PG) is a disorder recently conceptualized as a behavioural addiction, because of its neurobiological, neurophysiological and psychological features (American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th ed., 2013; Potenza et al., 2012). PG represents both a social and a sanitary cost, in terms of pharmacological and psychological therapies. The aim of this study was to examine the correlation between personality disorders, clinical syndromes and alexithymia levels in a group of pathological gamblers. Furthermore this study aimed at highlighting a relationship between PG and alexithymia, over and above the relationship between personality disorders, clinical syndromes and PG. Sixty treatmentseeking pathological gamblers and 60 healthy controls were included in the study. Psychological assessment included the South Oaks Gambling Screen (SOGS), the Millon Clinical Multiaxial Inventory (MCMI-III) and the Toronto Alexithymia Sc...
Acetaldehyde contributes to alcohol’s neuroactive effects through its own motivational properties... more Acetaldehyde contributes to alcohol’s neuroactive effects through its own motivational properties. This chapter gathers current evidence on acetaldehyde psychoactive action, focusing on behavioral investigations able to unveil acetaldehyde rewarding effects and their pharmacological modulation in vivo. Acetaldehyde induces conditioned place preference for paired environment and cues and is dose-dependently self-administered in a two-bottle choice drinking paradigm. Acetaldehyde’s motivational properties are further highlighted by operant paradigms tailored to model several addiction-like behaviors, such as induction and maintenance of operant responding, drug-seeking in extinction, relapse following deprivation, and resistance to punishment. Acetaldehyde-related behaviors are sensitive to pharmacological manipulations of dopamine and endocannabinoid signaling, two systems that functionally interplay in controlling motivation. This evidence holds promising potential for the developme...
Acetaldehyde (ACD), ethanol first metabolite, is rewarding in rodents and humans; it induces \u20... more Acetaldehyde (ACD), ethanol first metabolite, is rewarding in rodents and humans; it induces \u201cplace preference\u201d, is self-administer directly in the VTA, orally in an operant/conflict paradigm and increases DA neurons\u2019 firing. This research aims at investigating DA2-receptor role in the reinstatement of acetaldehyde operant-drinking behaviour, following induction, maintenance and abstinence in the rat. Male Wistar rats are trained to orally self-administer ACD solution (3.2% v/v) or water, in an operant chamber under a FR1. Afterwards animals undergo cyclic periods of deprivation and relapse to ACD. The effect ofD2-receptor activation by quinpirole (0.03mg/kg,i.p.) on operant ACD self-administration is tested during relapse sessions. Rats show a peak-and-drop drinking pattern that reaches regular and higher values in the last training days. Quinpirole administration produces lever press reduction in ACD group when compared to basal intake(p<0.001) and to vehicle (p<0.05;p<0.001), while when treatment is suspended, rats reinstate lever presses for ACD. ACD incentive properties involve dopamine neurotransmission: D2-receptor activation is able to reduce reinstatement of operant drinking behaviour for ACD, following periods of abstinence, probably acting at a pre-synaptic level, thus reducing DA release in mesolimbic areas. These findings further support ACD pivotal role in ethanol central effects
Social interaction is essential for life but is impaired in many psychiatric disorders. We presen... more Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous “maternal” heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; “mixed” heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed...
Binge alcohol consumption among adolescents affects the developing neural networks underpinning r... more Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposure. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively in...
Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptom... more Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptoms can be investigated in knock out rats for the DA transporter (DAT‐KO). Recent studies evidenced the role of epigenetic DAT modulation in depressive‐like behavior. Accordingly, we used heterozygous (HET) rats born from both HET parents (termed MIX‐HET), compared to HET rats born from WT‐mother and KO‐father (MAT‐HET), implementing the role of maternal care on DAT modulation. We developed a “sudden fright” paradigm (based on dark‐light test) to study reaction to fearful inputs in the DAT‐KO, MAT‐HET, MIX‐HET, and WT groups. Rats could freely explore the whole 3‐chambers apparatus; then, they were gently confined in one room where they experienced the fright; finally, they could freely move again. As expected, after the fearful stimulus only MAT‐HET rats showed a different behavior consisting of avoidance towards the fear‐associated chamber, compared to WT rats. Furthermore, ex‐vivo immuno‐fluorescence reveals higher prefrontal DAT levels in MAT‐HET compared to MIX‐HET and WT rats. Immuno‐fluorescence shows also a different histone deacetylase (HDAC) enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT‐HET fore brain, the enhanced expression of DAT could well impair the corticostriatal‐thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT‐HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation. This could imply significant prefronto‐cortical influences onto the emotional processes: hence an excessively frightful response, even to mild stressful agents, may draw developmental trajectories toward anxious and depressed‐like behavior.
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