Lack of interactions between prenatal immune activation and Δ9-tetrahydrocannabinol exposure during adolescence in behaviours relevant to symptom dimensions of schizophrenia in rats.

The causality in the association between cannabis use and the risk of developing schizophrenia has been the subject of intense debate in the last few years. The development of animal models recapitulating several aspects of the disease is crucial for shedding light on this issue. Given that maternal infections are a known risk for schizophrenia, here, we used the maternal immune activation (MIA) model combined with THC exposure during adolescence to examine several behaviours in rats (working memory in the Y maze, sociability in the three-chamber test, sucrose preference as a measure, prepulse inhibition and formation of incidental associations) that are similar to the different symptom clusters of the disease. To this end, we administered LPS to pregnant dams and when the offspring reached adolescence, we exposed them to a mild dose of THC to examine their behaviour in adulthood. We also studied several parameters in the dams, including locomotor activity in the open field, elevated plus maze performance and their response to LPS, that could predict symptom severity of the offspring, but found no evidence of any predictive value of these variables. In the adult offspring, MIA was associated with impaired working memory and sensorimotor gating, but surprisingly, it increased sociability, social novelty and sucrose preference. THC, on its own, impaired sociability and social memory, but there were no interactions between MIA and THC exposure. These results suggest that, in this model, THC during adolescence does not trigger or aggravate symptoms related to schizophrenia in rats.

The long-term effects of adolescent Δ9-tetrahydrocannabinol on brain structure and function assessed through neuroimaging techniques in male and female rats.

Several studies performed on human subjects have examined the effects of adolescent cannabis consumption on brain structure or function using brain imaging techniques. However, the evidence from these studies is usually heterogenous and affected by several confounding variables. Animal models of adolescent cannabinoid exposure may help to overcome these difficulties. In this exploratory study, we aim to increase our understanding of the protracted effects of adolescent Δ9-tetrahydrocannabinol (THC) in rats of both sexes using magnetic resonance (MR) to obtain volumetric data, assess grey and white matter microstructure with diffusion tensor imaging (DTI) and measure brain metabolites with 1H-MR spectroscopy (MRS); in addition, we studied brain function using positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose as the tracer. THC-exposed rats exhibited volumetric and microstructural alterations in the striatum, globus pallidus, lateral ventricles, thalamus, and septal nuclei in a sex-specific manner. THC administration also reduced fractional anisotropy in several white matter tracts, prominently in rostral sections, while in vivo MRS identified lower levels of cortical choline compounds. THC-treated males had increased metabolism in the cerebellum and olfactory bulb and decreased metabolism in the cingulate cortex. By contrast, THC-treated females showed hypermetabolism in a cluster of voxels comprising the entorhinal piriform cortices and in the cingulate cortex. These results indicate that mild THC exposure during adolescence leaves a lingering mark on brain structure and function in a sex-dependant manner. Some of the changes found here resemble those observed in human studies and highlight the importance of studying sex-specific effects in cannabinoid research.

Increase in educational inequalities in alcohol-related mortality in Spain during a period of economic growth.

BACKGROUND AND AIMS: Alcohol-related mortality risk is almost always greater in lower than higher socio-economic positions (SEPs). There is little information on the evolution of this SEP gradient and its relationship with the economic cycle. Some results suggest that during economic expansions, there is a hypersensitivity of low-SEP people to harmful drinking. The main objective of this study was to measure the evolution of educational inequality in alcohol-related and non-alcohol related mortality by sex and age group in Spain during 2012-19. DESIGN, SETTING AND MEASUREMENTS: This is a repeated cross-sectional study. This study includes all residents in Spain aged 25 years and over from 2012 to 2019. (1) We calculated age-standardized mortality rates (ASMRs) from strongly/moderately alcohol-related causes (directly alcohol-attributable, unspecified liver cirrhosis, liver and upper aerodigestive tract cancers and moderately alcohol-related), weakly alcohol-related causes and other causes by educational level. (2) We used age-adjusted relative index of inequality (RII) and slope index of inequality (SII) to measure relative and absolute educational inequality in mortality, respectively. (3) Age-adjusted annual percentage change (APC) was also used to measure linear trends in mortality by educational level. RII, SII and APC were obtained from negative binomial regression. FINDINGS: Between 2012-15 and 2016-19, economic growth accelerated, the RII in mortality from strongly/moderately alcohol-related causes increased from 2.0 to 2.2 among men and from 1.1 to 1.3 among women, and the SII in deaths/100 000 person-years from 181.4 to 190.9 among men and from 18.9 to 46.5 among women. It also increased relative and absolute inequality in mortality from weakly alcohol-related and other causes of death in both men and women. These increases in inequality were due primarily to a flattening or even reversal of the downward mortality trend among low- and medium-educated people. CONCLUSIONS: During the economic expansion of 2012-19 in Spain, changes in mortality risk from strongly/moderately alcohol-related causes were especially unfavourable among low- and medium-educated people.

Untargeted metabolomic study by liquid chromatography-mass spectrometry in brain tissues on the effects of combined cocaine and ethanol self-administration in male and female young rats.

The combined use of ethanol and cocaine is frequent among drug-abuse users and leads to further exacerbation of health consequences compared to individual consumption and this is of special concern during the transition to adulthood. Despite its high prevalence, the effect of combined consumption of cocaine and ethanol has been scarcely studied. In this work, we report the first untargeted metabolomic study in brain tissues to contribute to the advancement in the knowledge of the possible neurobiological effects of this polysubstance dependence. Liquid Chromatography coupled to high resolution Mass Spectrometry was employed to analyze three different brain tissues samples, prefrontal cortex, striatum and hippocampus, from male and female young rats exposed intravenously to a self-administration of these drugs. After optimizing the best sample treatment and selecting the chromatographic and detection conditions to find the maximum number of significant features (possible biomarker metabolites), the high resolution of the Orbitrap analyzer used in this work has made it possible to find up to 761 significant features with assigned molecular formula, of which up to 190 were tentatively identified and 44 unequivocally confirmed. The results demonstrated that the altered metabolic pathways are involved in multiple functions: receptor systems, such as the Glutamine-Glutamic acid-GABA axis or the catecholamine pathway, purinergic and pyrimidine pathways, fatty acids or oxidative stress, among others.

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome.

Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

Saturated and unsaturated triglyceride-enriched diets modify amino acid content in the mice hippocampus.

Elevated intake of fat modulates l-glutamate (l-Glu) turnover within the hippocampus (HIP). Our aim has been to investigate the effect of saturated vs unsaturated fat on the content of l-Glu and other amino acids involved in synaptic transmission within the HIP. The study was carried out in male mice fed (2 h or 8 weeks) with standard chow or with diets enriched either with saturated (SOLF) or unsaturated triglycerides (UOLF). An in vitro assay was performed in HIP slices incubated with palmitic (PA), oleic (OA), or lauric acid (LA). Amino acids were quantified by capillary electrophoresis. While both diets increased the amount of l-Glu and l-aspartate and decreased l-glutamine levels, only UOLF affected d-serine and taurine levels. γ-Aminobutyric acid was specifically decreased by SOLF. In vitro assays revealed that PA and OA modified l-Glu, glycine, l-serine and d-serine concentration. Our results suggest that fatty acids contained in SOLF and UOLF have an impact on HIP amino acid turnover that may account, at least partially, for the functional changes evoked by these diets.

Pharmacological characterization of novel synthetic opioids: Isotonitazene, metonitazene, and piperidylthiambutene as potent µ-opioid receptor agonists.

Recent trends of opioid abuse and related fatalities have highlighted the critical role of Novel Synthetic Opioids (NSOs). We studied the µ-opioid-like properties of isotonitazene (ITZ), metonitazene (MTZ), and piperidylthiambutene (PTB) using different approaches. In vitro studies showed that ITZ and MTZ displayed a higher potency in both rat membrane homogenates (EC50:0.99 and 19.1 nM, respectively) and CHO-MOR (EC50:0.71 and 10.0 nM, respectively) than [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), with no difference in maximal efficacy (Emax) between DAMGO and NSOs. ITZ also has higher affinity (Ki:0.06 and 0.05 nM) at the MOR than DAMGO in both systems, whilst MTZ has higher affinity in CHO-MOR (Ki=0.23 nM) and similar affinity in rat cerebral cortex (Ki = 0.22 nM). PTB showed lower affinity and potency than DAMGO. In vivo, ITZ displayed higher analgesic potency than fentanyl and morphine (ED50:0.00156, 0.00578, 2.35 mg/kg iv, respectively); ITZ (0.01 mg/kg iv) and MTZ (0.03 mg/kg iv) reduced behavioral activity and increased dialysate dopamine (DA) in the NAc shell (max. about 200% and 170% over basal value, respectively. Notably, ITZ elicited an increase in DA comparable to that of higher dose of morphine (1 mg/kg iv), but higher than the same dose of fentanyl (0.01 mg/kg iv). In silico, induced fit docking (IFD) and metadynamic simulations (MTD) showed that binding modes and structural changes at the receptor, ligand stability, and the overall energy score of NSOs were consistent with the results of the biological assays.

Plasma Amino Acid Concentrations in Patients with Alcohol and/or Cocaine Use Disorders and Their Association with Psychiatric Comorbidity and Sex.

(1) Background: Co-occurrence of mental and substance use disorders (SUD) is prevalent, but complicates their clinical courses, and specific biomarkers are required. Amino acids are altered in primary mental disorders; however, little is known about SUD and psychiatric comorbidity. Because most psychiatric disorders and biomarkers show sex differences, we investigated amino acids in men and women with alcohol and/or cocaine use disorders (AUD and/or CUD) and psychiatric comorbidity. (2) Methods: A cross-sectional study was conducted in 295 participants, who were divided into four groups (AUD, n = 60; CUD, n = 41; AUD + CUD, n = 64; and control, n = 130). Participants were clinically assessed, and plasma amino acid concentrations were analyzed in relation to sex, diagnosis of SUD and psychiatric comorbidity (3) Results: In the total sample, there were sex differences, and women showed lower Iso, Leu, Gln and Glu than men. While patients with CUD and AUD + CUD had higher Glu, Gly, Orn and Ser than controls, patients with AUD showed no differences. In SUD, patients with psychiatric comorbidity had lower Orn and higher Ala than non-comorbid patients in the AUD group. (4) Conclusions: There was a dysregulation of plasma amino acids in abstinent patients with SUD. However, our results suggest the importance of considering the clinical characteristics and sex in the validity of amino acids as potential biomarkers for SUD.

Effects of heroin self-administration and forced withdrawal on the expression of genes related to the mTOR network in the basolateral complex of the amygdala of male Lewis rats.

RATIONALE: The development of substance use disorders involves long-lasting adaptations in specific brain areas that result in an elevated risk of relapse. Some of these adaptations are regulated by the mTOR network, a signalling system that integrates extracellular and intracellular stimuli and modulates several processes related to plasticity. While the role of the mTOR network in cocaine- and alcohol-related disorders is well established, little is known about its participation in opiate use disorders. OBJECTIVES: To use a heroin self-administration and a withdrawal protocol that induce incubation of heroin-seeking in male rats and study the associated effects on the expression of several genes related to the mTOR system and, in the specific case of Rictor, its respective translated protein and phosphorylation. RESULTS: We found that heroin self-administration elicited an increase in the expression of the genes Igf1r, Igf2r, Akt2 and Gsk3a in the basolateral complex of the amygdala, which was not as evident at 30 days of withdrawal. We also found an increase in the expression of Rictor (a protein of the mTOR complex 2) after heroin self-administration compared to the saline group, which was occluded at the 30-day withdrawal period. The activation levels of Rictor, measured by the phosphorylation rate, were also reduced after heroin self-administration, an effect that seemed more apparent in the protracted withdrawal group. CONCLUSIONS: These results suggest that heroin self-administration under extended access conditions modifies the expression profile of activators and components of the mTOR complexes and show a putative irresponsive mTOR complex 2 after withdrawal from heroin use.

Neuroimaging reveals distinct brain glucose metabolism patterns associated with morphine consumption in Lewis and Fischer 344 rat strains.

Vulnerability to addiction may be given by the individual's risk of developing an addiction during their lifetime. A challenge in the neurobiology of drug addiction is understanding why some people become addicted to drugs. Here, we used positron emission tomography (PET) and statistical parametric mapping (SPM) to evaluate changes in brain glucose metabolism in response to chronic morphine self-administration (MSA) in two rat strains with different vulnerability to drug abuse, Lewis (LEW) and Fischer 344 (F344). Four groups of animals were trained to self-administer morphine or saline for 15 days. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG)-PET studies were performed on the last day of MSA (acquisition phase) and after 15 days of withdrawal. PET data were analyzed using SPM12. LEW-animals self-administered more morphine injections per session than F344-animals. We found significant brain metabolic differences between LEW and F344 strains in the cortex, hypothalamus, brainstem, and cerebellum. In addition, the different brain metabolic patterns observed after the MSA study between these rat strains indicate differences in the efficiency of neural substrates to translate the drug effects, which could explain the differences in predisposition to morphine abuse between one individual and another. These findings have important implications for the use of these rat strains in translational morphine and opiate research.

The interactions of alcohol and cocaine regulate the expression of genes involved in the GABAergic, glutamatergic and endocannabinoid systems of male and female rats.

Although the pharmacological and behavioural interactions between cocaine and alcohol are well established, less is known about how polyconsumption of these drugs affects the neurotransmitter systems involved in their psychoactive effects and in particular, in the process of addiction. Here, rats of both sexes at two stages of development were studied under a chronic regime of intravenous cocaine and/or alcohol administration. Brain samples from the medial prefrontal cortex, nucleus accumbens, hippocampus and amygdala were extracted to analyse the mRNA expression of genes encoding subunits of the GABA, NMDA and AMPA receptors, as well as the expression of the CB1 receptor, and that of enzymes related to the biosynthesis and degradation of endocannabinoids. Moreover, two synaptic scaffold proteins related to GABA and NMDA receptors, gephyrin and PSD-95, were quantified in Western blots. Significant interactions between cocaine and alcohol were common, affecting the GABAergic and endocannabinoid systems in the medial prefrontal cortex and amygdala of young adults, whereas such interactions were evident in the glutamatergic and endocannabinoid systems in adults, as well as a more pronounced sex effect. Significant interactions between these drugs affecting the scaffold proteins were evident in the medial prefrontal cortex and nucleus accumbens of young adults, and in the nucleus accumbens and amygdala of adults, but not in the hippocampus. These results highlight the importance of considering the interactions between cocaine and alcohol on neurotransmitter systems in the context of polyconsumption, specifically when treating problems of abuse of these two substances.

Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of neurodevelopmental disorders: Prenatal immune activation and peripubertal stress.

Prenatal infections are environmental risk factors for neurodevelopmental disorders. In addition, traumatic experiences during adolescence in individuals exposed to infections during gestation could increase the risk of schizophrenia. It is of the most crucial importance to discover potential markers of the disease in its early stages or before its onset, so that therapeutic strategies may be implemented. In the present study, we combined a proposed two-hit model of schizophrenia-related symptoms with proton magnetic resonance spectroscopy (1H-MRS) to discover potential biomarkers. To this end, we i.p. injected 100 µg/kg/ml of lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to five episodes of stress or handling on alternate days during postnatal days (PND) 28-38. Once the animals reached adulthood (PND70), we evaluated prepulse inhibition (PPI). At PND90, we performed an ex vivo 1H-MRS study in the cortex and striatum. While we did not detect alterations in PPI at the age tested, we found neurochemical disturbances induced by LPS, stress or (more interestingly) their interaction. LPS decreased glucose levels in the cortex and striatum and altered glutamate, glutamine and N-acetylaspartate levels. Glutamate and glutamine levels in the left (but not right) striatum were differentially affected by prenatal LPS exposure in a manner that depended on stress experiences. These results suggest that alterations in the glutamate cycle in the striatum could be used as early markers of developmental disorders.

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner.

BACKGROUND: Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown. METHODS: We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior. RESULTS: THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females). CONCLUSIONS: Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.

Cocaine-induced Fos expression in the rat brain: Modulation by prior Δ9-tetrahydrocannabinol exposure during adolescence and sex-specific effects.

It has been suggested that cannabis consumption during adolescence may be an initial step to cocaine use in adulthood. Indeed, previous preclinical data show that adolescent exposure to cannabinoids (both natural and synthetic) potentiates cocaine self-administration in rats. Here we aimed at gaining a deeper understanding of the cellular activation patterns induced by cocaine as revealed by Fos imaging and how these patterns may change due to adolescent exposure to THC. Male and female Wistar rats were administered every other day THC (3 mg/kg i.p.) or vehicle from postnatal day 28-44. At adulthood (PND90) they were given an injection of cocaine (20 mg/kg i.p.) or saline and sacrificed 90 min later. Cocaine-induced Fos activation was measured by immunohistochemistry as an index of cellular activation. We found that cocaine-induced activation in the motor cortex was stronger in THC-exposed rats. Moreover, there was significant sex-dependent interaction between cocaine and adolescent THC exposure in the dorsal hypothalamus, suggesting that cocaine induced a more robust cellular activation in THC-exposed females but not in THC-treated males. Other THC- and cocaine-induced effects were also evident. These results add to the previous literature suggesting that the behavioral, cellular, molecular, and brain-activating actions of cocaine are modulated by early experience with cannabinoids and provide additional knowledge that may explain the enhanced actions of cocaine in rats exposed to cannabinoids during their adolescence.

A "Drug-Dependent" Immune System Can Compromise Protection against Infection: The Relationships between Psychostimulants and HIV.

Psychostimulant use is a major comorbidity in people living with HIV, which was initially explained by them adopting risky behaviors that facilitate HIV transmission. However, the effects of drug use on the immune system might also influence this phenomenon. Psychostimulants act on peripheral immune cells even before they reach the central nervous system (CNS) and their effects on immunity are likely to influence HIV infection. Beyond their canonical activities, classic neurotransmitters and neuromodulators are expressed by peripheral immune cells (e.g., dopamine and enkephalins), which display immunomodulatory properties and could be influenced by psychostimulants. Immune receptors, like Toll-like receptors (TLRs) on microglia, are modulated by cocaine and amphetamine exposure. Since peripheral immunocytes also express TLRs, they may be similarly affected by psychostimulants. In this review, we will summarize how psychostimulants are currently thought to influence peripheral immunity, mainly focusing on catecholamines, enkephalins and TLR4, and shed light on how these drugs might affect HIV infection. We will try to shift from the classic CNS perspective and adopt a more holistic view, addressing the potential impact of psychostimulants on the peripheral immune system and how their systemic effects could influence HIV infection.

Transplantation with Lewis bone marrow induces the reinstatement of cocaine-seeking behavior in male F344 resistant rats.

One of the main challenges to understand drug addiction is defining the biological mechanisms that underlie individual differences in recidivism. Studies of these mechanisms have mainly focused on the brain, yet we demonstrate here a significant influence of the peripheral immune system on this phenomenon. Lewis (LEW) and Fischer 344 (F344) rats have different immunological profiles and they display a distinct vulnerability to the reinforcing effects of cocaine, with F344 more resistant to reinstate cocaine-seeking behavior. Bone marrow from male LEW and F344 rats was transferred to male F344 rats (F344/LEW-BM and F344/F344-BM, respectively), and these rats were trained to self-administer cocaine over 21 days. Following extinction, these animals received a sub-threshold primer dose of cocaine to evaluate reinstatement. F344/LEW-BM but not F344/F344-BM rats reinstated cocaine-seeking behavior, in conjunction with changes in their peripheral immune cell populations to a profile that corresponded to that of the LEW donors. After cocaine exposure, higher CD4+ T-cells and lower CD4+CD25+ T-cells levels were observed in F344/LEW-BM rats referred to control, and the splenic expression of Il-17a, Tgf-ß, Tlr-2, Tlr-4 and Il-1ß was altered in both groups. We propose that peripheral T-cells respond to cocaine, with CD4+ T-cells in particular undergoing Th17 polarization and generating long-term memory, these cells releasing mediators that trigger central mechanisms to induce reinstatement after a second encounter. This immune response may explain the high rates of recidivism observed despite long periods of detoxification, shedding light on the mechanisms underlying the vulnerability and resilience of specific individuals, and opening new perspectives for personalized medicine in the treatment of relapse.

Comparative analysis of the modulation of perineuronal nets in the prefrontal cortex of rats during protracted withdrawal from cocaine, heroin and sucrose self-administration.

Relapse into drug use is a significant problem for people recovering from addiction. The ability that conditioned cues have to reinstate and reinvigorate drug-seeking is potentiated over time (incubation of seeking), posing an additional difficulty for maintaining abstinence. While the prefrontal cortex has been involved in the incubation phenomenon and the extracellular matrix, perineuronal nets (PNNs) in particular, may play a vital role in brain plasticity associated to drug relapse, there are no comparative analyses between different drug classes and natural reinforcers. Here, we compare the effects of early (1 day) and protracted (30 days) withdrawal from to cocaine, heroin and sucrose self-administration on the total density and density per intensity range of PNNs of different territories of the prefrontal cortex of male Lewis rats. Our results show that cocaine self-administration increases the density of PNNs in the dorsal prelimbic, infralimbic and ventral orbitofrontal cortices, while protracted withdrawal reversesthis effect in the dorsal prelimbic cortex. Also, heroin self-administration increases the density of PNNs in the infralimbic cortex and ventral orbitofrontal cortices, but this effect is lost after 30 days of withdrawal in the infralimbic cortex. Finally, the self-administration of sucrose-sweetened water or the protracted withdrawal from this powerful reinforcer does not affect any of the PNN parameters analysed. Our results show that two different drugs of abuse (but not a natural reward) with specific pharmacological and physiological actions, differentially modulate PNNs in specific areas of the rodent prefrontal cortex with potential implications for the incubation of seeking phenomenon.

The role of the mTOR pathway in models of drug-induced reward and the behavioural constituents of addiction.

BACKGROUND: Exposure to drugs of abuse induces neuroadaptations in critical nodes of the so-called reward systems that are thought to mediate the transition from controlled drug use to the compulsive drug-seeking that characterizes addictive disorders. These neural adaptations are likely to require protein synthesis, which is regulated, among others, by the mechanistic target of the rapamycin kinase (mTOR) signalling cascade. METHODS: We have performed a narrative review of the literature available in PubMed about the involvement of the mTOR pathway in drug-reward and addiction-related phenomena. AIMS: The aim of this study was to review the underlying architecture of this complex intracellular network and to discuss the alterations of its components that are evident after exposure to drugs of abuse. The aim was also to delineate the effects that manipulations of the mTOR network have on models of drug reward and on paradigms that recapitulate some of the psychological components of addiction. RESULTS: There is evidence for the involvement of the mTOR pathway in the acute and rewarding effects of drugs of abuse, especially psychostimulants. However, the data regarding opiates are scarce. There is a need to use sophisticated animal models of addiction to ascertain the real role of the mTOR pathway in this pathology and not just in drug-mediated reward. The involvement of this pathway in behavioural addictions and impulsivity should also be studied in detail in the future. CONCLUSIONS: Although there is a plethora of data about the modulation of mTOR by drugs of abuse, the involvement of this signalling pathway in addictive disorders requires further research.

Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement.

There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In the present work, we use a maternal immune activation model to test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Also, given that D3 and CB2 receptor expression in immune cells is altered in patients with schizophrenia, we examined the populations of immune cells expressing these receptors. Pregnant rats were daily injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline during pregnancy, and we tested prepulse inhibition -PPI- in the offspring. After this, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer D3R+ granulocytes in the LPS-offspring and an exciting trend for CB2R+ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that D3R+ granulocytes and possibly CB2R+ lymphocytes could be potential biomarkers of schizophrenia.

The effects of combined intravenous cocaine and ethanol self-administration on the behavioral and amino acid profile of young adult rats.

Under paradigms of combined intravenous cocaine and ethanol self-administration, the effects on behavior have been poorly explored. Numerous studies have found sex differences in amino acids profile and behavioral responses to each drug, yet few have focused on the interactions between cocaine and ethanol. The main objective of this work was to explore the acquisition and maintenance of intravenous self-administration behavior with a combination of cocaine and ethanol in male and female young adult rats. Likewise, the amino acids profile in blood plasma was quantified 48 hours after the last self-administration session. Male and female 52 days old Wistar rats were randomly assigned to one of 3 groups: i) saline control, ii) cocaine (1 mg/kg bodyweight/injection) and iii) cocaine and ethanol (1 mg + 133 mg/kg bodyweight/ injection). After 24 self-administration sessions carried out on a fixed-ratio-1 schedule, with a limit of 15 doses per session, 14 plasma amino acids were quantified by mean Capillary Electrophoresis technique. The curve of cocaine and ethanol combined self-administration was similar to that associated with cocaine administration alone, with females acquiring self-administration criterion before males. The self-administration of cocaine and ethanol altered the plasma concentration and relative ratios of the amino acid L-Tyrosine. In our intravenous self-administration model, females appeared more vulnerable to acquire abusive consumption of the cocaine and ethanol combination, which altered plasma L-Tyrosine levels.