A gut (microbiome) feeling about addiction: Interactions with stress and social systems.

In recent years, an increasing attention has given to the intricate and diverse connection of microorganisms residing in our gut and their impact on brain health and central nervous system disease. There has been a shift in mindset to understand that drug addiction is not merely a condition that affects the brain, it is now being recognized as a disorder that also involves external factors such as the intestinal microbiota, which could influence vulnerability and the development of addictive behaviors. Furthermore, stress and social interactions, which are closely linked to the intestinal microbiota, are powerful modulators of addiction. This review delves into the mechanisms through which the microbiota-stress-immune axis may shape drug addiction and social behaviors. This work integrates preclinical and clinical evidence that demonstrate the bidirectional communication between stress, social behaviors, substance use disorders and the gut microbiota, suggesting that gut microbes might modulate social stress having a significance in drug addiction.

Evaluating the daily modulation of FADD and related molecular markers in different brain regions in male rats.

Fas-Associated protein with Death Domain (FADD), a key molecule controlling cell fate by balancing apoptotic versus non-apoptotic functions, is dysregulated in post-mortem brains of subjects with psychopathologies, in animal models capturing certain aspects of these disorders, and by several pharmacological agents. Since persistent disruptions in normal functioning of daily rhythms are linked with these conditions, oscillations over time of key biomarkers, such as FADD, could play a crucial role in balancing the clinical outcome. Therefore, we characterized the 24-h regulation of FADD (and linked molecular partners: p-ERK/t-ERK ratio, Cdk-5, p35/p25, cell proliferation) in key brain regions for FADD regulation (prefrontal cortex, striatum, hippocampus). Samples were collected during Zeitgeber time (ZT) 2, ZT5, ZT8, ZT11, ZT14, ZT17, ZT20, and ZT23 (ZT0, lights-on or inactive period; ZT12, lights-off or active period). FADD showed similar daily fluctuations in all regions analyzed, with higher values during lights off, and opposite to p-ERK/t-ERK ratios regulation. Both Cdk-5 and p35 remained stable and did not change across ZT. However, p25 increased during lights off, but exclusively in striatum. Finally, no 24-h modulation was observed for hippocampal cell proliferation, although higher values were present during lights off. These results demonstrated a clear daily modulation of FADD in several key brain regions, with a more prominent regulation during the active time of rats, and suggested a key role for FADD, and molecular partners, in the normal physiological functioning of the brain's daily rhythmicity, which if disrupted might participate in the development of certain pathologies.

The Microbiome-Gut-Brain axis regulates social cognition & craving in young binge drinkers.

BACKGROUND: Binge drinking is the consumption of an excessive amount of alcohol in a short period of time. This pattern of consumption is highly prevalent during the crucial developmental period of adolescence. Recently, the severity of alcohol use disorders (AUDs) has been linked with microbiome alterations suggesting a role for the gut microbiome in its development. Furthermore, a strong link has emerged too between microbiome composition and socio-emotional functioning across different disorders including AUD. The aim of this study was to investigate the potential link (and its predictive value) between alcohol-related altered microbial profile, social cognition, impulsivity and craving. METHODS: Young people (N = 71) aged 18-25 reported their alcohol use and underwent a neuropsychological evaluation. Craving was measured at baseline and three months later. Diet was controlled for. Blood, saliva and hair samples were taken for inflammatory, kynurenine and cortisol analysis. Stool samples were provided for shotgun metagenomic sequencing and short-chain fatty acids (SCFAs) were measured. FINDINGS: Binge drinking was associated with distinct microbiome alterations and emotional recognition difficulties. Associations were found for several microbiome species with emotional processing and impulsivity. Craving showed a strong link with alterations in microbiome composition and neuroactive potential over time. INTERPRETATION: In conclusion, this research demonstrates alterations in the gut microbiome of young binge drinkers (BDs) and identifies early biomarkers of craving. Associations between emotional processing and microbiome composition further support the growing literature on the gut microbiome as a regulator of social cognition. These findings are of relevance for new gut-derived interventions directed at improving early alcohol-related alterations during the vulnerability period of adolescence. FUNDING: C.C. and R.G-C. received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 754535. APC Microbiome Ireland is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan [grant no. SFI/12/RC/2273_P2]. J.F.C has research support from Cremo, Pharmavite, DuPont and Nutricia. He has spoken at meetings sponsored by food and pharmaceutical companies. G.C. has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite, Fonterra, Nestle and Reckitt; and is a paid consultant for Yakult, Zentiva and Heel pharmaceuticals. All the authors declare no competing interests.

The gut microbiota alone and in combination with a social stimulus regulates cocaine reward in the mouse.

The gut microbiota is a key factor in the maintenance of physiological homeostasis and immunity. Correlational studies have demonstrated that alterations in microbiota composition have been associated with addiction. Moreover, animal studies have confirmed a link between reward and social processes, which may be shaped by the gut microbiota thus influencing neurodevelopment and the programming of social behaviors across diverse animal species. However, whether there is an interaction between the microbiota and social reward processes in the context of drug reward remains unclear. To this end, we explored the influence of gut microbiota in regulating behaviourally conditioned responses to different rewards (cocaine and social interactions). Depletion of the intestinal microbiota resulted in differential reward responses to both drug and social stimuli with an attenuation of the former and enhancement of the latter independent of concomitant immune changes. Moreover, the combination of depleting the gut microbiota in the presence of a positive social stimulus attenuates cocaine reward. Together these data suggest that the two-pronged approach of targeting the microbiota and enhancing social behaviour could constitute a valuable component in reducing harm in drug use by altering the salient effects of cocaine.

Microbiota and body weight control: Weight watchers within?

BACKGROUND: Despite several decades of research, managing body weight remains an unsolved clinical problem. Health problems associated with dysregulated body weight, such as obesity and cachexia, exhibit several gut microbiota alterations. There is an increased interest in utilising the gut microbiota for body weight control, as it responds to intervention and plays an important role in energy extraction from food, as well as biotransformation of nutrients. SCOPE OF THE REVIEW: This review provides an overview of the role of the gut microbiota in the physiological and metabolic alterations observed in two body weight dysregulation-related disorders, namely obesity and cachexia. Second, we assess the available evidence for different strategies, including caloric restriction, intermittent fasting, ketogenic diet, bariatric surgery, probiotics, prebiotics, synbiotics, high-fibre diet, and fermented foods - effects on body weight and gut microbiota composition. This approach was used to give insights into the possible link between body weight control and gut microbiota configuration. MAJOR CONCLUSIONS: Despite extensive associations between body weight and gut microbiota composition, limited success could be achieved in the translation of microbiota-related interventions for body weight control in humans. Manipulation of the gut microbiota alone is insufficient to alter body weight and future research is needed with a combination of strategies to enhance the effects of lifestyle interventions.

Associations between Mental Health, Alcohol Consumption and Drinking Motives during COVID-19 Second Lockdown in Ireland.

AIMS: The novel coronavirus pandemic (COVID-19) has impacted the lives of people worldwide since March 2020. Social restrictions aimed at flattening the curve may be associated with an increase in mental health problems and have raised concerns regarding their effect on alcohol consumption. The objective of this study was to characterize changes in alcohol use during lockdown in Ireland and associations with drinking motives and psychopathological symptoms. METHODS: We collected data from 713 adults (aged 18-60) during the second lockdown period (October/December 2020). By means of an online survey, participants self-reported their alcohol use before COVID and during lockdown. Motives to drink and psychopathological symptoms were also recorded. RESULTS: Our findings showed that 66% decreased their alcohol consumption, while 15% increased their alcohol consumption. An older age and coping motives were the strongest predictors of increased alcohol use during lockdown. Depression and hostility were the specific psychopathological dimensions associated with drinking to cope. CONCLUSIONS: Older adults who drink to cope-mainly with depression symptomatology-are an important at-risk population, in line with predictions from alcohol self-medication frameworks. Future research is needed to incorporate strategies into the public mental health ecosystem.

Electroconvulsive seizures protect against methamphetamine-induced inhibition of neurogenesis in the rat hippocampus.

Following methamphetamine consumption and during abstinence many behavioral consequences emerge (i.e., cognitive deficits, ongoing episodes of psychosis, depression, severe cravings, brain neurotoxicity), which are likely linked to propensity to relapse. In this line of thought, we recently showed that binge methamphetamine administration enhanced negative affect and voluntary drug consumption in rats, while it induced persistent neurotoxic effects (i.e., impaired hippocampal neurogenesis), effects that emerged long after drug removal. To date, no pharmacological strategies have been proven to be effective for the treatment of methamphetamine toxicity. A few studies have evaluated the impact of combining methamphetamine pretreatment with electroconvulsive seizures (ECS) post-treatment, an alternative non-pharmacological option used in psychiatry for resistant depression that offers a safe and really potent therapeutic response. Against this background, the present study aimed at testing whether repeated ECS treatment could ameliorate some of the long-term neurotoxicity effects induced by adolescent methamphetamine exposure in rats and emerging after drug removal. At the behavioral level, the main results showed that methamphetamine administration did not alter negative affect immediate during adolescence or later on in adulthood. Interestingly, repeated ECS improved the negative impact of methamphetamine administration on reducing hippocampal neurogenesis, demonstrating that ECS can attenuate certain degree of methamphetamine-induced neurotoxicity in rats, and suggesting ECS as a good therapeutical candidate that deserves further studies.

Dose-dependent opposite effects of nortriptyline on affective-like behavior in adolescent rats: Comparison with adult rats.

Antidepressant drugs elicit different behavioral and neurochemical responses with age. In fact, the use of antidepressants during adolescence is associated with an increased risk of suicidal thinking, being the best pharmacological treatment during this critical period a matter of constant debate in terms of its risk-benefit outcome. In this regard, the present study compared the effects of nortriptyline (3-10 mg/kg, 7 days) on regulating different aspects of affective-like behavior by screening adolescent and adult Sprague-Dawley rats through several consecutive tests (forced-swim, open field, sucrose preference). Brains were later collected to evaluate hippocampal neurogenesis and mBDNF protein content as potential molecular correlates of the observed behavioral responses. The main results in adolescent rats showed that nortriptyline induced dose-dependent opposite effects: while 3 mg/kg decreased immobility and increased mBDNF (indicative of an antidepressant-like response), 10 mg/kg decreased exploratory time in the open field and mBDNF (suggestive of an anxiogenic-like response). These effects were not associated with changes in neurogenesis regulation. In adult rats, nortriptyline failed to modulate affective-like behavior or the neuroplasticity markers evaluated at the doses tested. In conclusion, clear behavioral and neurochemical differences were observed between adolescent and adult rats in response to nortriptyline treatment. Interestingly, while nortriptyline displayed an antidepressant-like potential at the lowest dose examined in adolescence, a higher dose shifted these results towards a negative outcome, thus reinforcing the need to extreme caution when considering this treatment for our younger population.

Antidepressant-like effects of cannabidiol in a rat model of early-life stress with or without adolescent cocaine exposure.

BACKGROUND: Further studies are needed to better understand the effects of potential novel antidepressants, such as cannabidiol, for the treatment of psychiatric disorders during adolescence. In this context, we evaluated in a rodent model of early-life stress (a single 24-h episode of maternal deprivation, PND 9), the antidepressant-like effects of adolescent cannabidiol alone and/or in combination with adolescent cocaine exposure (given the described beneficial effects of cannabidiol on reducing cocaine effects). METHODS: Maternally deprived Sprague-Dawley male rats were treated in adolescence with cannabidiol (with or without concomitant cocaine) and exposed to a battery of behavioral tests (forced-swim, novelty-suppressed feeding, open field, sucrose preference) across time. Putative enduring molecular correlates (CB receptors, BDNF) were evaluated in the hippocampus by western blot. RESULTS: Cannabidiol exerted antidepressant- and anxiolytic-like effects in rats exposed to early-life stress. Cocaine did not alter affective-like behavior during adolescence in rats exposed to early-life stress; however, a depressive- and anxiogenic-like phenotype emerged during adulthood, and cannabidiol exerted some behavioral improvements, along with the growing literature supporting its beneficial role for reducing cocaine intake and/or reinstatement in rodents. Finally, cannabidiol did not modulate hippocampal CB receptors or BDNF proteins, and although the data raised interesting questions about the possible role of CB1 receptors on modulating the long-term effects of cocaine, future research is needed to expand these findings. CONCLUSION: Cannabidiol showed a promising therapeutic response in terms of ameliorating affect in a rat model of early-life stress during adolescence and up to adulthood.

Microbiota-gut-brain axis as a regulator of reward processes.

Our gut harbours trillions of microorganisms essential for the maintenance of homeostasis and host physiology in health and disease. In the last decade, there has been a growing interest in understanding the bidirectional pathway of communication between our microbiota and the central nervous system. With regard to reward processes there is accumulating evidence from both animal and human studies that this axis may be a key factor in gating reward valence. Focusing on the mesocorticolimbic pathway, we will discuss how the intestinal microbiota is involved in regulating brain reward functions, both in natural (i.e. eating, social or sexual behaviours) and non-natural reinforcers (drug addiction behaviours including those relevant to alcohol, psychostimulants, opioids and cannabinoids). We will integrate preclinical and clinical evidence suggesting that the microbiota-gut-brain axis could be implicated in the development of disorders associated with alterations in the reward system and how it may be targeted as a promising therapeutic strategy. Cover Image for this issue: https://doi.org/10.1111/jnc.15065.

Increased negative affect when combining early-life maternal deprivation with adolescent, but not adult, cocaine exposure in male rats: regulation of hippocampal FADD.

RATIONALE: Besides early drug initiation during adolescence, another vulnerability factor associated with increased risk for substance abuse later in life is early-life stress. One way of assessing such combined risk is by evaluating the emergence of increased negative affect during withdrawal (i.e., linked to persistence in drug seeking). OBJECTIVES: To compare the impact of maternal deprivation with cocaine exposure at different ages on affective-like behavior and hippocampal neuroplasticity regulation. METHODS: Maternal deprivation was performed in whole-litters of Sprague-Dawley rats (24 h, PND 9-10). Cocaine (15 mg/kg, 7 days, i.p.) was administered in adolescence (PND 33-39) or adulthood (PND 64-70). Changes in affective-like behavior were assessed by diverse tests across time (forced-swim, open field, novelty-suppressed feeding, sucrose preference). Hippocampal multifunctional FADD protein (balance between cell death and plasticity) was evaluated by Western blot. RESULTS: Exposing rats to either maternal deprivation or adolescent cocaine did not modulate affective-like behavior immediately during adolescence, but increased negative affect in adulthood. Maternal deprivation combined with adolescent cocaine advanced the negative impact to adolescence. Adult cocaine exposure alone and/or in combination with maternal deprivation did not induce any behavioral changes at the time-points analyzed. FADD regulation might participate in the neural adaptations taking place in the hippocampus in relation to the observed behavioral changes. CONCLUSIONS: Adolescence is a more vulnerable period, as compared to adulthood, to the combined impact of cocaine and early maternal deprivation, thus suggesting that the accumulation of stress early in life can anticipate the negative behavioral outcome associated with drug consumption.

Sex differences in the antidepressant-like potential of repeated electroconvulsive seizures in adolescent and adult rats: Regulation of the early stages of hippocampal neurogenesis.

Age and sex are critical factors for the diagnosis and treatment of major depression, since there is a well-known age-by-sex difference in the prevalence of major depression (being females the most vulnerable ones) and in antidepressant efficacy (being adolescence a less responsive period than adulthood). Although the induction of electroconvulsive seizures (ECS) is a very old technique in humans, there is not much evidence reporting sex- and age-specific aspects of this treatment. The present study evaluated the antidepressant- and neurogenic-like potential of repeated ECS across time in adolescent and adult rats (naïve or in a model of early life stress capable of mimicking a pro-depressive phenotype), while including a sex perspective. The main results demonstrated age- and sex-specific differences in the antidepressant-like potential of repeated ECS, since it worked when administered during adolescence or adulthood in male rats (although with a shorter length in adolescence), while in females rendered deleterious during adolescence and ineffective in adulthood. Yet, repeated ECS increased cell proliferation and vastly boosted young neuronal survival in a time-dependent manner for both sexes and independently of age. Moreover, pharmacological inhibition of basal cell proliferation prevented the antidepressant-like effect induced by repeated ECS in male rats, but only partially blocked the very robust increase in the initial cell markers of hippocampal neurogenesis. Overall, the present results suggest that the induction of the early phases of neurogenesis by ECS, besides having a role in mediating its antidepressant-like effect, might participate in some other neuroplastic actions, opening the path for future studies.

Decreased sensitivity in adolescent versus adult rats to the antidepressant-like effects of cannabidiol.

RATIONALE: Cannabidiol is a non-psychoactive phytocannabinoid with great therapeutic potential in diverse psychiatric disorders; however, its antidepressant potential has been mainly ascertained in adult rats. OBJECTIVES: To compare the antidepressant-like response induced by cannabidiol in adolescent and adult rats and the possible parallel modulation of hippocampal neurogenesis. METHODS: Male Sprague-Dawley rats were repeatedly treated with cannabidiol (3, 10, and 30 mg/kg) or vehicle (1 mL/kg) during adolescence (postnatal days, PND 27-33) or adulthood (PND 141-147) and exposed to 3 consecutive tests (forced swim, open field, two-bottle choice) that quantified behavioral despair, anxiety, and sucrose intake respectively. RESULTS: Cannabidiol induced differential effects depending on the age and dose administered, with a decreased sensitivity observed in adolescent rats: (1) cannabidiol (30 mg/kg) decreased body weight only in adult rats; (2) cannabidiol ameliorated behavioral despair in adolescent and adult rats, but with a different dose sensitivity (10 vs. 30 mg/kg), and with a different extent (2 vs. 21 days post-treatment); (3) cannabidiol did not modulate anxiety-like behavior at any dose tested in adolescent or adult rats; and (4) cannabidiol increased sucrose intake in adult rats. CONCLUSIONS: Our findings support the notion that cannabidiol exerts antidepressant- and anorexigenic-like effects in adult rats and demonstrate a decreased potential when administered in adolescent rats. Moreover, since cannabidiol did not modulate hippocampal neurogenesis (cell proliferation and early neuronal survival) in adolescent or adult rats, the results revealed potential antidepressant-like effects induced by cannabidiol without the need of regulating hippocampal neurogenesis.

Methamphetamine binge administration dose-dependently enhanced negative affect and voluntary drug consumption in rats following prolonged withdrawal: role of hippocampal FADD.

While prior studies have established various interacting mechanisms and neural consequences (i.e. monoaminergic nerve terminal damage) that might contribute to the adverse effects caused by methamphetamine administration, the precise mechanisms that mediate relapse during withdrawal remain unknown. This study evaluated the long-term consequences of binge methamphetamine administration (three pulses/day, every 3 hours, 4 days, i.p.; dose-response: 2.5, 5 and 7.5 mg/kg) in adult Sprague-Dawley rats at two behavioral levels following 25 days of withdrawal: (1) negative affect (behavioral despair-forced-swim test, and anhedonia-1% sucrose consumption, two-bottle choice test) and (2) voluntary methamphetamine consumption (20 mg/l, two-bottle choice test). Striatal and hippocampal brain samples were dissected to quantify monoamines content by high-performance liquid chromatography and to evaluate neurotoxicity (dopaminergic and serotonergic markers) and neuroplasticity markers [i.e. cell fate regulator (Fas-associated protein with death domain) FADD] by Western blot. The results showed that methamphetamine administration induced dose-dependent negative effects during prolonged withdrawal in adult rats. In particular, rats treated repeatedly with methamphetamine (7.5 mg/kg) showed (1) enhanced negative affect-increased anhedonia associated with behavioral despair, (2) increased voluntary methamphetamine consumption, (3) enhanced neurotoxicity-decreased dopamine and metabolites in striatum and decreased serotonin in hippocampus, (4) altered neuroplasticity markers-decreased FADD protein and increased p-FADD/FADD balance selectively in hippocampus and (5) higher consumption rates of methamphetamine that were associated with lower FADD content in hippocampus. These results confirm that methamphetamine withdrawal dose-dependently induced negative affect and decreased monoamines content, while also increased voluntary methamphetamine consumption and suggested a role for hippocampal FADD neuroplasticity in these drug-withdrawal adaptations.

Adolescent cocaine exposure enhanced negative affect following drug re-exposure in adult rats: Attenuation of c-Fos activation.

BACKGROUND: The goal of the present study was to utilize the adolescent drug experience as an emerging vulnerability factor for developing psychiatric comorbidities in adulthood that could, in turn, help to elucidate and/or hypothesize possible mechanisms contributing to higher relapse rates. OUTCOMES: The current results showed that adolescent cocaine exposure (15 mg/kg, intraperitoneally, seven days) during early-mid adolescence (postnatal days 33-39) enhanced negative affect in adulthood, by increasing behavioral despair following drug re-exposure and by increasing anhedonia. Thus, these behavioral data provided a good model to further ascertain the long-term cellular and molecular adaptations that might take place in the brain in response to adolescent cocaine exposure as well as the impact of drug re-exposure in adulthood. In this regard, the results showed that adolescent cocaine exposure did not modulate cell proliferation (Ki-67+ cells) or c-Fos protein activation in the dentate gyrus region of the hippocampus, but attenuated c-Fos activation in the dorsal striatum. CONCLUSIONS: These results proved that a history of cocaine exposure during adolescence increased the vulnerability to induce negative affect (i.e. emergence of psychiatric comorbidity) in adulthood while it decreased neuronal activation in the dorsal striatum. Interestingly, these effects were only observed following cocaine re-exposure in adulthood, suggesting that avoiding drug contact in adulthood could prevent the long-term negative effects induced by adolescent cocaine.

Methamphetamine binge administration during late adolescence induced enduring hippocampal cell damage following prolonged withdrawal in rats.

A recent study from our laboratory demonstrated that binge methamphetamine induced hippocampal cell damage (i.e., impaired cell genesis) in rats when administered specifically during late adolescence (postnatal day, PND 54-57) and evaluated 24 h later (PND 58). The results also suggested a possible role for brain-derived neurotrophic factor (BDNF) regulating cell genesis and survival. This subsequent study evaluated whether these effects persisted in time as measured following prolonged withdrawal. Male Sprague-Dawley rats were treated (i.p.) with BrdU (2 × 50 mg/kg, 3 days, PND 48-50) followed by a binge paradigm (3 pulses/day, every 3 h, 4 days, PND 54-57) of methamphetamine (5 mg/kg, n = 14, M) or saline (0.9% NaCl, 1 ml/kg, n = 12, C). Following 34 days of forced withdrawal (PND 91), rats were killed 45 min after a challenge dose of saline (Sal: C-Sal, n = 6; M-Sal, n = 7) or methamphetamine (Meth: C-Meth, n = 6; M-Meth, n = 7). Neurogenesis markers (Ki-67: cell proliferation; NeuroD: early neuronal survival; BrdU: prolonged cell survival, 41-43 days old cells) were evaluated by immunohistochemistry while neuroplasticity markers (BDNF and Fos forms) were evaluated by Western blot. The main results showed that a history of methamphetamine administration (PND 54-57) induced enduring hippocampal cell damage (i.e., observed on PND 91) by decreasing cell survival (BrdU + cells) and mature-BDNF (m-BDNF) protein content, associated with neuronal survival, growth and differentiation. Interestingly, m-BDNF regulation paralleled hippocampal c-Fos protein content, indicating decreased neuronal activity, and thus reinforcing the persisting negative effects induced by methamphetamine in rat hippocampus following prolonged withdrawal.

Comparative effects of amphetamine-like psychostimulants on rat hippocampal cell genesis at different developmental ages.

The aim of this study was to compare the effects of amphetamine-like psychostimulant drugs (i.e., MDMA, methamphetamine, D-amphetamine) on rat hippocampal cell genesis at different developmental ages (i.e., early adolescence vs. young adulthood) to determine if there were periods of vulnerability to drug-induced brain changes. Although adolescence is a period of great vulnerability to the neurochemical effects of specific drugs of abuse, several reports suggest that adult rats are more susceptible than adolescents to the negative effects of these drugs. The main results suggest that the effects of these amphetamine drugs on cell genesis depend on the rat's developmental age, with the young adult period being more sensitive than the early adolescent one. In particular, MDMA and methamphetamine, but not D-amphetamine impaired hippocampal cell genesis (i.e., cell proliferation and cell survival) in young adult rats. These effects were dependent on the accumulative dose administered, as they were only observed with the highest dose tested (12 pulses of 5mg/kg over 4days: 60mg/kg total). The present results extend previous reports on adolescent insensitivity (i.e., better adaptation) to amphetamine-drugs and suggest for young adult rats certain degree of hippocampal damage that may mediate some of the addiction-like behaviors that depend on this brain region. Moreover, the present results, in line with previous data, suggest a possible role for the neuroplasticity marker BDNF and serotonin in regulating cell survival, as mBDNF protein regulation paralleled hippocampal cell survival and 5-HT2C-receptor content in young adult rats treated with these psychostimulant drugs.

Opposite regulation of cannabinoid CB1 and CB2 receptors in the prefrontal cortex of rats treated with cocaine during adolescence.

The endocannabinoid system is implicated in the neurobiology of cocaine addiction, although it is not clear how cocaine regulates brain CB1 and CB2 receptors, especially during adolescence, a critical moment for shaping adult response to drug use. This study evaluated CB1 and CB2 protein levels in prefrontal cortex (PFC) and hippocampus (HC) by western blot analysis with specific and validated antibodies: (1) basally during adolescence (post-natal day PND 40, PND 47, PND 54), (2) by a sensitizing regimen of cocaine (15mg/kg, 7 days, i.p.) during different windows of adolescence vulnerability (PND 33-39, PND 40-46, PND 47-53), and (3) following repeated cocaine administration during adolescence (PND 33-39) in adulthood (PND 64). The results demonstrated a dynamic and opposite basal modulation of CB1 and CB2 receptors in PFC and HC during adolescence. CB1 receptor levels were increased while CB2 receptors were decreased as compared to adulthood with asymptotes values around mid adolescence (PND 47) both in PFC (CB1: +45±22, p<0.05; CB2: -24±6%, p<0.05) and HC (CB1: +53±23, p<0.05; CB2: -20±8%, p<0.05). Interestingly, cocaine only altered CB1 (+55±10%, p<0.05) and CB2 (-25±10%, p<0.05) receptors when administered during early adolescence and only in PFC. However, the changes observed in PFC by repeated cocaine administration in adolescence were transient and did not endure into adulthood. These results identified a period of vulnerability during adolescence at which cocaine dysregulated the content of CB receptors in PFC, suggesting an opposite role for these receptors in the effects mediated by cocaine.

Chronic MDMA induces neurochemical changes in the hippocampus of adolescent and young adult rats: Down-regulation of apoptotic markers.

While hippocampus is a brain region particularly susceptible to the effects of MDMA, the cellular and molecular changes induced by MDMA are still to be fully elucidated, being the dosage regimen, the species and the developmental stage under study great variables. This study compared the effects of one and four days of MDMA administration following a binge paradigm (3×5 mg/kg, i.p., every 2 h) on inducing hippocampal neurochemical changes in adolescent (PND 37) and young adult (PND 58) rats. The results showed that chronic MDMA caused hippocampal protein deficits in adolescent and young adult rats at different levels: (1) impaired serotonergic (5-HT2A and 5-HT2C post-synaptic receptors) and GABAergic (GAD2 enzyme) signaling, and (2) decreased structural cytoskeletal neurofilament proteins (NF-H, NF-M and NF-L). Interestingly, these effects were not accompanied by an increase in apoptotic markers. In fact, chronic MDMA inhibited proteins of the apoptotic pathway (i.e., pro-apoptotic FADD, Bax and cytochrome c) leading to an inhibition of cell death markers (i.e., p-JNK1/2, cleavage of PARP-1) and suggesting regulatory mechanisms in response to the neurochemical changes caused by the drug. The data, together with the observed lack of GFAP activation, support the view that chronic MDMA effects, regardless of the rat developmental age, extends beyond neurotransmitter systems to impair other hippocampal structural cell markers. Interestingly, inhibitory changes in proteins from the apoptotic pathway might be taking place to overcome the protein deficits caused by MDMA.