Central and Peripheral Inflammation: A Common Factor Causing Addictive and Neurological Disorders and Aging-Related Pathologies.

Many diseases and degenerative processes affecting the nervous system and peripheral organs trigger the activation of inflammatory cascades. Inflammation can be triggered by different environmental conditions or risk factors, including drug and food addiction, stress, and aging, among others. Several pieces of evidence show that the modern lifestyle and, more recently, the confinement associated with the COVID-19 pandemic have contributed to increasing the incidence of addictive and neuropsychiatric disorders, plus cardiometabolic diseases. Here, we gather evidence on how some of these risk factors are implicated in activating central and peripheral inflammation contributing to some neuropathologies and behaviors associated with poor health. We discuss the current understanding of the cellular and molecular mechanisms involved in the generation of inflammation and how these processes occur in different cells and tissues to promote ill health and diseases. Concomitantly, we discuss how some pathology-associated and addictive behaviors contribute to worsening these inflammation mechanisms, leading to a vicious cycle that promotes disease progression. Finally, we list some drugs targeting inflammation-related pathways that may have beneficial effects on the pathological processes associated with addictive, mental, and cardiometabolic illnesses.

Chronic Exposure to High Fat Diet Affects the Synaptic Transmission That Regulates the Dopamine Release in the Nucleus Accumbens of Adolescent Male Rats.

Obesity is a pandemic caused by many factors, including a chronic excess in hypercaloric and high-palatable food intake. In addition, the global prevalence of obesity has increased in all age categories, such as children, adolescents, and adults. However, at the neurobiological level, how neural circuits regulate the hedonic consumption of food intake and how the reward circuit is modified under hypercaloric diet consumption are still being unraveled. We aimed to determine the molecular and functional changes of dopaminergic and glutamatergic modulation of nucleus accumbens (NAcc) in male rats exposed to chronic consumption of a high-fat diet (HFD). Male Sprague-Dawley rats were fed a chow diet or HFD from postnatal day (PND) 21 to 62, increasing obesity markers. In addition, in HFD rats, the frequency but not amplitude of the spontaneous excitatory postsynaptic current is increased in NAcc medium spiny neurons (MSNs). Moreover, only MSNs expressing dopamine (DA) receptor type 2 (D2) increase the amplitude and glutamate release in response to amphetamine, downregulating the indirect pathway. Furthermore, NAcc gene expression of inflammasome components is increased by chronic exposure to HFD. At the neurochemical level, DOPAC content and tonic dopamine (DA) release are reduced in NAcc, while phasic DA release is increased in HFD-fed rats. In conclusion, our model of childhood and adolescent obesity functionally affects the NAcc, a brain nucleus involved in the hedonic control of feeding, which might trigger addictive-like behaviors for obesogenic foods and, through positive feedback, maintain the obese phenotype.

Obesogenic Diet-Induced Neuroinflammation: A Pathological Link between Hedonic and Homeostatic Control of Food Intake.

Obesity-induced neuroinflammation is a chronic aseptic central nervous system inflammation that presents systemic characteristics associated with increased pro-inflammatory cytokines such as interleukin 1 beta (IL-1ß) and interleukin 18 (IL-18) and the presence of microglia and reactive astrogliosis as well as the activation of the NLRP3 inflammasome. The obesity pandemic is associated with lifestyle changes, including an excessive intake of obesogenic foods and decreased physical activity. Brain areas such as the lateral hypothalamus (LH), lateral septum (LS), ventral tegmental area (VTA), and nucleus accumbens (NAcc) have been implicated in the homeostatic and hedonic control of feeding in experimental models of diet-induced obesity. In this context, a chronic lipid intake triggers neuroinflammation in several brain regions such as the hypothalamus, hippocampus, and amygdala. This review aims to present the background defining the significant impact of neuroinflammation and how this, when induced by an obesogenic diet, can affect feeding control, triggering metabolic and neurological alterations.

Corticotropin-releasing factor system in the lateral septum: Implications in the pathophysiology of obesity.

Obesity is a pandemic associated with lifestyles changes. These include excess intake of obesogenic foods and decreased physical activity. Brain areas, like the lateral hypothalamus (LH), ventral tegmental area (VTA), and nucleus accumbens (NAcc) have been linked in both homeostatic and hedonic control of feeding in experimental models of diet-induced obesity. Interestingly, these control systems are regulated by the lateral septum (LS), a relay of γ-aminobutyric (GABA) acid neurons (GABAergic neurons) that inhibit the LH and GABAergic interneurons of the VTA. Furthermore, the LS has a diverse receptor population for neurotransmitters and neuropeptides such as dopamine, glutamate, GABA and corticotropin-releasing factor (CRF), among others. Particularly, CRF a key player in the stress response, has been related to the development of overweight and obesity. Moreover, evidence shows that LS neurons neurophysiologically regulate reward and stress, although there is little evidence of LS taking part in homeostatic and hedonic feeding. In this review, we discuss the evidence that supports the role of LS and CRF on feeding, and how alterations in this system contribute to weight gain obesity.

Early-Life Exposure to Non-Absorbable Broad-Spectrum Antibiotics Affects the Dopamine Mesocorticolimbic Pathway of Adult Rats in a Sex-Dependent Manner.

Gut microbiota with a stable, rich, and diverse composition is associated with adequate postnatal brain development. Colonization of the infant's gut begins at birth when parturition exposes the newborn to a set of maternal bacteria, increasing richness and diversity until one to two first years of age when a microbiota composition is stable until old age. Conversely, alterations in gut microbiota by diet, stress, infection, and antibiotic exposure have been associated with several pathologies, including metabolic and neuropsychiatric diseases such as obesity, anxiety, depression, and drug addiction, among others. However, the consequences of early-life exposure to antibiotics (ELEA) on the dopamine (DA) mesocorticolimbic circuit are poorly studied. In this context, we administered oral non-absorbable broad-spectrum antibiotics to pregnant Sprague-Dawley dams during the perinatal period (from embryonic day 18 until postnatal day 7) and investigated their adult offspring (postnatal day 60) to assess methylphenidate-induced conditioned place preference (CPP) and locomotor activity, DA release, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) content in ventral tegmental area (VTA), and expression of key proteins within the mesocorticolimbic system. Our results show that ELEA affect the rats conduct by increasing drug-seeking behavior and locomotor activity induced by methylphenidate of males and females, respectively, while reducing dopamine striatal release and VTA content of DOPAC in females. In addition, antibiotics increased protein levels of DA type 1 receptor in prefrontal cortex and VTA of female rats, and tyrosine hydroxylase in VTA of adult male and female rats. Altogether, these results suggest that ELEA alters the development of the microbiota-gut-brain axis affecting the reward system and the response to abuse drugs in adulthood.

Effects of Early Life Exposure to Sex Hormones on Neurochemical and Behavioral Responses to Psychostimulants in Adulthood: Implications in Drug Addiction.

Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.

Estrogen, Cognitive Performance, and Functional Imaging Studies: What Are We Missing About Neuroprotection?

Menopause transition can be interpreted as a vulnerable state characterized by estrogen deficiency with detrimental systemic effects as the low-grade chronic inflammation that appears with aging and partly explains age-related disorders as cancer, diabetes mellitus and increased risk of cognitive impairment. Over the course of a lifetime, estrogen produces several beneficial effects in healthy neurological tissues as well as cardioprotective effects, and anti-inflammatory effects. However, clinical evidence on the efficacy of hormone treatment in menopausal women has failed to confirm the benefit reported in observational studies. Unambiguously, enhanced verbal memory is the most robust finding from longitudinal and cross-sectional studies, what merits consideration for future studies aiming to determine estrogen neuroprotective efficacy. Estrogen related brain activity and functional connectivity remain, however, unexplored. In this context, the resting state paradigm may provide valuable information about reproductive aging and hormonal treatment effects, and their relationship with brain imaging of functional connectivity may be key to understand and anticipate estrogen cognitive protective effects. To go in-depth into the molecular and cellular mechanisms underlying rapid-to-long lasting protective effects of estrogen, we will provide a comprehensive review of cognitive tasks used in animal studies to evaluate the effect of hormone treatment on cognitive performance and discuss about the tasks best suited to the demonstration of clinically significant differences in cognitive performance to be applied in human studies. Eventually, we will focus on studies evaluating the DMN activity and responsiveness to pharmacological stimulation in humans.

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice.

The excitatory amino acid transporter EAAT3 plays an important role in the neuronal uptake of glutamate regulating the activation of glutamate receptors. Polymorphisms in the gene-encoding EAAT3 have been associated with obsessive-compulsive disorder (OCD), although the mechanisms underlying this relationship are still unknown. We recently reported that mice with increased EAAT3 expression in forebrain neurons (EAAT3 g lo /CMKII) display behavioral and synaptic features relevant to OCD, including increased grooming, higher anxiety-like behavior and altered cortico-striatal synaptic function. The dopamine neurotransmitter system is implicated in ritualistic behaviors. Indeed, dopaminergic neurons express EAAT3, and mice lacking EAAT3 exhibit decreased dopamine release and decreased expression of the dopamine D1 receptor. Moreover, EAAT3 plays a role on the effect of the psychostimulant amphetamine. As such, we sought to determine if the OCD-like behavior in EAAT3 g lo /CMKII mice is accompanied by altered nigro-striatal dopaminergic transmission. The aim of this study was to analyze dopamine transmission both in basal conditions and after an acute challenge of amphetamine, using behavioral, neurochemical, molecular, and cellular approaches. We found that in basal conditions, EAAT3 g lo /CMKII mice performed more grooming events and that they remained in phase 1 of the grooming chain syntax compared with control littermates. Administration of amphetamine increased the number of grooming events in control mice, while EAAT3 g lo /CMKII mice remain unaffected. Interestingly, the grooming syntax of amphetamine-control mice resembled that of EAAT3 g lo /CMKII mice in basal conditions. Using in vivo microdialysis, we found decreased basal dopamine levels in EAAT3 g lo /CMKII compared with control mice. Unexpectedly, we found that after acute amphetamine, EAAT3 g lo /CMKII mice had a higher release of dopamine compared with that of control mice, suggesting that EAAT3 overexpression leads to increased dopamine releasability. To determine postsynaptic effect of EAAT3 overexpression over dopamine transmission, we performed Western blot analysis of dopaminergic proteins and found that EAAT3 g lo /CMKII mice have higher expression of D2 receptors, suggesting a higher inhibition of the indirect striatal pathway. Together, the data indicate that EAAT3 overexpression impacts on dopamine transmission, making dopamine neurons more sensitive to the effect of amphetamine and leading to a disbalance between the direct and indirect striatal pathways that favors the performance of repetitive behaviors.

Neonatal programming with sex hormones: Effect on expression of dopamine D1 receptor and neurotransmitters release in nucleus accumbens in adult male and female rats.

Steroid sex hormones produce physiological effects in reproductive and non-reproductive tissues, such as the brain. In the brain, sex hormones receptors are expressed in cortical, limbic and midbrain areas modulating memory, arousal, fear and motivation between other behaviors. One neurotransmitters system regulated by sex hormones is dopamine (DA), where during adulthood, sex hormones promote neurophysiological and behavioral effects on DA systems such as tuberoinfundibular (prolactin secretion), nigrostriatal (motor circuit regulation) and mesocorticolimbic (driving of motivated behavior). However, the long-term effects induced by neonatal exposure to sex hormones on DA release induced by D1 receptor activation and its expression in nucleus accumbens (NAcc) have not been fully studied. To answer this question, neurochemical, cellular and molecular techniques were used. The data show sex differences in NAcc DA extracellular levels induced by D1 receptor activation and protein content of this receptor in male and female control rats. In addition, neonatal programming with a single dose of TP increases the NAcc protein content of D1 receptors of adult male and female rats. Our results show new evidence related with sex differences that could explain the dependence to drug of abuse in males and females, which may be associated with increased reinforcing effects of drugs of abuse.

Do your gut microbes affect your brain dopamine?

Increasing evidence shows changes in gut microbiota composition in association with psychiatric disorders, including anxiety and depression. Moreover, it has been reported that perturbations in gut microbe diversity and richness influence serotonergic, GABAergic, noradrenergic, and dopaminergic neurotransmission. Among these, dopamine is regarded as a main regulator of cognitive functions such as decision making, attention, memory, motivation, and reward. In this work, we will highlight findings that link alterations in intestinal microbiota and dopaminergic neurotransmission, with a particular emphasis on the mesocorticolimbic circuit, which is involved in reward to natural reinforcers, as well as abuse substances. For this, we reviewed evidence from studies carried out on germ-free animals, or in rodents subjected to intestinal dysbiosis using antibiotics, and also through the use of probiotics. All this evidence strongly supports that the microbiota-gut-brain axis is key to the physiopathology of several neuropsychiatric disorders involving those where dopaminergic neurotransmission is compromised. In addition, the gut microbiota appears as a key player when it comes to proposing novel strategies to the treatment of these psychiatric conditions.

Programming of Dopaminergic Neurons by Early Exposure to Sex Hormones: Effects on Morphine-Induced Accumbens Dopamine Release, Reward, and Locomotor Behavior in Male and Female Rats.

Neonatal programming with sex hormones produces long-term functional changes in various tissues, including the brain. Previously, we demonstrated a higher content of dopamine and an increase in potassium-induced dopamine release in the nucleus accumbens of adult rats exposed to estradiol valerate. On the other hand, sex hormones also affect the opioid system increasing the expression of the µ opioid receptor and ß-endorphins. Here, we investigated if neonatal programming with sex hormones alters the response to morphine during adulthood in rats and predispose them to neurochemical, rewarding and behavioral activating effects. We examined the effects of neonatal exposure to a single dose of estradiol valerate or testosterone propionate on morphine-induced (5 mg/kg, i.v.) dopamine release in the nucleus accumbens and morphine-induced (3 mg/kg, s.c.) locomotor activity and conditioned place preference when these rats were adults. Our results showed a significant increase in morphine-induced dopamine release in the nucleus accumbens of rats that were exposed neonatally to estradiol compared with control rats. This effect was correlated with higher place preference and locomotor activity induced by morphine in adult rats neonatally exposed to estradiol valerate. However, the effect of morphine on dopamine release and behaviors was similar in rats treated with testosterone compared to control rats. Additionally, the expression of mu (µ) opioid receptor, dopamine receptor type 1 (D1) and dopamine receptor type 2 (D2) in the nucleus accumbens of adult rats was not different after treatment with sex hormones. Taken together, our results demonstrated an enhancement of pharmacological effects produced by morphine in rats neonatally programmed with estradiol valerate, suggesting that early exposure to sex hormones could represent a vulnerability factor in the development of addiction to opioid drugs such as morphine and heroin in adulthood.

Prenatal metformin treatment improves ovarian function in offspring of obese rats.

Maternal obesity causes a wide range of impairment in offspring, such as metabolic and reproductive dysfunctions. We previously demonstrated that female offspring of obese rats have increased serum estradiol levels during early postnatal life, probably because of decreased hepatic cytochrome P450 3A2 levels, which could lead to early onset of puberty and polycystic ovary condition in adulthood. Using metformin during pregnancy and nursing to improve the metabolic status of obese mothers could prevent the sequence of events that lead to an increase in postnatal serum estradiol levels in female offspring and, hence, reproductive dysfunction. We found that metformin prevented an increase in serum estradiol levels at postnatal day 14 in female offspring of obese mothers, which was associated with a restoration of hepatic cytochrome P450 3A2 levels to control values. Treatment using metformin could not prevent advanced puberty, but we observed that the number of antral follicles, follicular cysts and multi-oocyte follicles returned to control values in the female offspring of obese mothers treated with metformin. We also observed an increase in the levels of norepinephrine and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol in the ovaries, indicating increased sympathetic activity in female offspring induced by an obesogenic uterine environment. We found that this effect was prevented by metformin administration. From the results of this study, we concluded that metformin administration to obese mothers during pregnancy and nursing partially prevents ovarian dysfunction in female offspring during adulthood.

Neonatal programming with testosterone propionate reduces dopamine transporter expression in nucleus accumbens and methylphenidate-induced locomotor activity in adult female rats.

Research in programming is focused on the study of stimuli that alters sensitive periods in development, such as prenatal and neonatal stages, that can produce long-term deleterious effects. These effects can occur in various organs or tissues such as the brain, affecting brain circuits and related behaviors. Our laboratory has demonstrated that neonatal programming with sex hormones affects the mesocorticolimbic circuitry, increasing the synthesis and release of dopamine (DA) in striatum and nucleus accumbens (NAcc). However, the behavioral response to psychostimulant drugs such as methylphenidate and the possible mechanism(s) involved have not been studied in adult rats exposed to sex hormones during the first hours of life. Thus, the aim of this study was to examine the locomotor activity induced by methylphenidate (5mg/kg i.p.) and the expression of the DA transporter (DAT) in NAcc of adult rats exposed to a single dose of testosterone propionate (TP: 1mg/50µLs.c.) or estradiol valerate (EV: 0.1mg/50µLs.c.) at postnatal day 1. Our results demonstrated that adult female rats treated with TP have a lower methylphenidate-induced locomotor activity compared to control and EV-treated adult female rats. This reduction in locomotor activity is related with a lower NAcc DAT expression. However, neither methylphenidate-induced locomotor activity nor NAcc DAT expression was affected in EV or TP-treated adult male rats. Our results suggest that early exposure to sex hormones affects long-term dopaminergic brain areas involved in the response to psychostimulants, which could be a vulnerability factor to favor the escalating doses of drugs of abuse.

Cytoplasmic and nuclear STAT3 in GH-stimulated fibroblasts of children with idiopathic short stature.

BACKGROUND: STAT5, which plays an important role in GH signal transduction, has been studied extensively in children with growth retardation, but there is scarce information regarding STAT3. AIM: We determined total and phosphorylated STAT3 after GH stimulation in fibroblasts from children with idiopathic short stature (ISS) and control children with normal stature. SUBJECTS AND METHODS: We studied 15 prepubertal children (age 7.6 ± 0.4 years) with short stature (height -2.8 ± 0.2 SDS), decreased growth velocity (10 ng/ml to the clonidine stimulation test and decreased serum IGF-I concentrations (<-1 SDS), and 19 control children with normal stature (age 6.7 ± 0.3 years). We determined the levels of total and phosphorylated STAT3 in the cytoplasmic and nuclear fractions of fibroblast cultures obtained from a skin biopsy, stimulated with GH (200 ng/ml) for 15-60 min. RESULTS: We observed a reduction in nuclear pSTAT3 levels and a lower nuclear/cytoplasmic STAT3 phosphorylated ratio in 3 patients from the study group compared to the control children. CONCLUSION: These results suggest that some children with ISS may exhibit a reduction in the nuclear content of their phosphorylated STAT3.