Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

Voluntary binge-patterned alcohol drinking and sex-specific influences on monoamine-related neurochemical signatures in the mouse gut and brain.

BACKGROUND: Altered monoamine (i.e., serotonin, dopamine, and norepinephrine) activity following episodes of alcohol abuse plays key roles not only in the motivation to ingest ethanol, but also physiological dysfunction related to its misuse. Although monoamine activity is essential for physiological processes that require coordinated communication across the gut-brain axis (GBA), relatively little is known about how alcohol misuse may affect monoamine levels across the GBA. Therefore, we evaluated monoamine activity across the mouse gut and brain following episodes of binge-patterned ethanol drinking. METHODS: Monoamine and select metabolite neurochemical concentrations were analyzed by ultra-high-performance liquid chromatography in gut and brain regions of female and male C57BL/6J mice following "Drinking in the Dark" (DID), a binge-patterned ethanol ingestion paradigm. RESULTS: First, we found that alcohol access had an overall small effect on gut monoamine-related neurochemical concentrations, primarily influencing dopamine activity. Second, neurochemical patterns between the small intestine and the striatum were correlated, adding to recent evidence of modulatory activity between these areas. Third, although alcohol access robustly influenced activity in brain areas in the mesolimbic dopamine system, binge exposure also influenced monoaminergic activity in the hypothalamic region. Finally, sex differences were observed in the concentrations of neurochemicals within the gut, which was particularly pronounced in the small intestine. CONCLUSION: Together, these data provide insights into the influence of alcohol abuse and biological sex on monoamine-related neurochemical changes across the GBA, which could have important implications for GBA function and dysfunction.

Offensive Behavior, Striatal Glutamate Metabolites, and Limbic-Hypothalamic-Pituitary-Adrenal Responses to Stress in Chronic Anxiety.

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.

Natural products present neurotrophic properties in neurons of the limbic system in aging rodents.

Aging is a complex process that can lead to neurodegeneration and, consequently, several pathologies, including dementia. Physiological aging leads to changes in several body organs, including those of the central nervous system (CNS). Morphological changes in the CNS and particularly the brain result in motor and cognitive deficits affecting learning and memory and the circadian cycle. Characterizing neural modifications is critical to designing new therapies to target aging and associated pathologies. In this review, we compared aging to the changes occurring within the brain and particularly the limbic system. Then, we focused on key natural compounds, apamin, cerebrolysin, Curcuma longa, resveratrol, and N-PEP-12, which have shown neurotrophic effects particularly in the limbic system. Finally, we drew our conclusions delineating future perspectives for the development of novel natural therapeutics to ameliorate aging-related processes.

Conditional inactivation of Npy1r gene in mice induces sex-related differences of metabolic and behavioral functions.

Sex hormone-driven differences in gene expression have been identified in experimental animals, highlighting brain neuronal populations implicated in dimorphism of metabolic and behavioral functions. Neuropeptide Y-Y1 receptor (NPY-Y1R) system is sexually dimorphic and sensitive to gonadal steroids. In the present study we compared the phenotype of male and female conditional knockout mice (Npy1rrfb mice), carrying the inactivation of Npy1r gene in excitatory neurons of the brain limbic system. Compared to their male control (Npy1r2lox) littermates, male Npy1rrfb mice exhibited hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis that is associated with anxiety and executive dysfunction, reduced body weight growth, after-fasting refeeding, white adipose tissue (WAT) mass and plasma leptin levels. Conversely, female Npy1rrfb mice displayed an anxious-like behavior but no differences in HPA axis activity, executive function and body weight, compared to control females. Moreover, conditional inactivation of Npy1r gene induced an increase of subcutaneous and gonadal WAT weight and plasma leptin levels and a compensatory decrease of Agouti-related protein immunoreactivity in the hypothalamic arcuate (ARC) nucleus in females, compared to their respective control littermates. Interestingly, Npy1r mRNA expression was reduced in the ARC and in the paraventricular hypothalamic nuclei of female, but not male mice. These results demonstrated that female mice are resilient to hormonal and metabolic effects of limbic Npy1r gene inactivation, suggesting the existence of an estrogen-dependent relay necessary to ensure the maintenance of the homeostasis, that can be mediated by hypothalamic Y1R.

Electro-acupuncture alleviates adolescent cocaine exposure-enhanced anxiety-like behaviors in adult mice by attenuating the activities of PV interneurons in PrL.

We recently found that adolescent cocaine exposure (ACE) resulted in an enhancement of the γ-aminobutyric acid (GABA) neurotransmitter system in the prelimbic cortex (PrL) of adult mice. Here, we aim to further investigate the role of GABAergic transmission, especially parvalbumin (PV) interneurons within PrL in the development of ACE-induced anxiety-like behavior, and to assess whether and how electro-acupuncture (EA) therapeutically manage the ACE-induced abnormal behaviors in adulthood. ACE mice exhibited the enhanced anxiety-like behaviors in their adulthood, accompanied by increased GABAergic transmission and PV interneurons in PrL. Chemogenetic blocking PV interneurons in PrL alleviated ACE-enhanced anxiety-like behaviors in mice. Importantly, 37-day EA treatments (mixture of 2 Hz/100 Hz, 1 mA, 30 minutes once a day) at the acupoints of Yintang (GV29) and Baihui (GV20) also alleviated ACE-induced anxiety-like behaviors, and rescued ACE-impaired GABAergic neurotransmitter system and PV interneurons in PrL. In parallel, EA treatments further suppressed the activities of pyramidal neurons in PrL, suggesting that EA treatments seem to perform it beneficial effects on the ACE-induced abnormal emotional behaviors by "calming down" the whole PrL. Collectively, these findings revealed that hyper-function of GABAergic transmission, especially mediating by PV interneurons in PrL may be key etiology underlying ACE-induced anxiety-like behaviors. At least by normalizing the function of GABAergic and PV interneurons, EA may represent a promising therapeutic strategy for managing adolescent substance use-related emotional disorders.

Limbic response to stress linking life trauma and hypothalamus-pituitary-adrenal axis function.

Trauma alters neuroendocrine responses to stress and increases vulnerability to stress-related disorders. Yet, relationships among trauma, stress-induced neural changes and hypothalamic-pituitary-adrenal (HPA) axis activity have not been determined. The present study used functional magnetic resonance imaging to investigate the impact of life trauma on basal cortisol levels and neural responses to acute stress in 73 healthy individuals during brief stress and neutral-relaxing imagery using a well-established, individualized imagery method. We hypothesized that trauma experience would have a negative impact on brain function, resulting in altered basal cortisol levels via dysregulated neural control over the HPA axis system. Results showed that higher life trauma exposure was significantly associated with lower basal cortisol levels. Neuroimaging results indicated that both higher life trauma and low morning cortisol levels were associated with increased response to acute stress in limbic-medial temporal lobe (MTL) regions including the amygdala and hippocampus. A mediation analysis showed that increased limbic-MTL response to stress mediated the relationship between life trauma and low cortisol levels. Findings revealed a significant impact of lifetime trauma on neural responses to acute stress and HPA axis activity. Life trauma may sensitize limbic-MTL regions and its related peripheral systems, which could compromise stress regulation and HPA axis function, and increase risk for negative stress-related health outcomes.

Central Modulation of Energy Homeostasis and Cognitive Performance After Bariatric Surgery.

In moderately or morbidly obese patients, bariatric surgery has been proven to be an effective therapeutic approach to control body weight and comorbidities. Surgery-mediated modulation of brain function via modified postoperative secretion of gut peptides and vagal nerve stimulation was identified as an underlying mechanism in weight loss and improvement of weight-related diseases. Increased basal and postprandial plasma levels of gastrointestinal hormones like glucagon-like peptide 1 and peptide YY that act on specific areas of the hypothalamus to reduce food intake, either directly or mediated by the vagus nerve, are observed after surgery while suppression of meal-induced ghrelin release is increased. Hormones released from the adipose tissue like leptin and adiponectin are also affected and leptin plasma levels are reduced in treated patients. Besides homeostatic control of body weight, surgery also changes hedonistic behavior in regard to food intake and cognitive performance involving the limbic system and prefrontal areas.

Decreased food anticipatory activity of obese mice relates to hypothalamic c-Fos expression.

During daily Food Restriction (FR), obese Neotomodon alstoni mice present decreased Food Anticipatory Activity (FAA) compared to lean mice. Here, we investigated whether FOS expression in hypothalamic nuclei involved in food synchronization and anticipation parallels decreased FAA during daily FR of obese N. alstoni. Locomotor activity of lean and obese mice in ad libitum feeding conditions was monitored for at least two weeks. Then, a gradual restriction of food access was followed to establish a 5h period of daily food access. FR was maintained during at least two weeks before sacrifice of mice at the starting point of the feeding period. Obese mice subjected to FR displayed an overall reduction of FOS-positive (FOS+) hypothalamic neurons, while lean mice in a similar protocol exhibited an increase in FOS+ neurons within the arcuate and dorsomedial hypothalamic nuclei. These results are consistent with decreased FAA displayed by obese mice in comparison to lean mice. Furthermore, limbic system areas of lean mice, such as the cingulate cortex and the hippocampus, showed an increase in FOS during FR, while no responses were observed in obese mice. The daily food intake of obese mice was severely reduced during FR, compared to the ad libitum condition, whereas food intake in lean mice was not affected by FR. Current data suggests that decreased hypothalamic and limbic neuronal activation may contribute to the reduction of FAA in obese N. alstoni mice.

Blockade of TrkB receptors in the nucleus accumbens prior to heterotypic stress alters corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway.

Inhibition of stress-induced elevations in brain-derived neurotrophic factor (BDNF) or its primary receptor tyrosine-related kinase B (TrkB) within the reward pathway may modulate vulnerability to anxiety and mood disorders. The current study examined the role of BDNF/TrkB signaling on biochemistry and behavior under basal conditions and following exposure to a 10-day heterotypic stress paradigm in male rats. Effects of intra-accumbal administration of TrkB antagonist ANA-12 (0.25µg/0.5µl/min) on anxiety, and expression of Trk-B, corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway were determined. Notably, ANA-12 attenuated anxiety-like behavior in stress rats while increasing anxiety in the non-stress group in the elevated plus maze (EPM). At the neurochemical level, ANA-12 blocked the increased vGluT2 and CRH expressions in the hypothalamic PVN and basolateral amygdala in stress rats, while it enhanced vGluT2 and CRH expressions in non-stress rats. ANA-12 also showed state-dependent effects at the NAc core, attenuating TrkB-ir in non-stress rats while reversing reduced expression in stressed rats. At the cingulate cortex, ANA-12 normalized stress-induced increase in TrkB expression. Notably, ANA-12 showed region-specific effects on GR-ir at the NAc core and shell, with increased GR-ir in non-stress rats, although the drug attenuated stress-induced GR-ir expression only in the core portion of the NAc, while having no impact at the cingulate cortex. Elevated blood CORT levels post-stress was not influenced by ANA-12 treatment. Together, these findings suggest that BDNF-mediated TrkB activation exerts differential impact in regulating emotional response under basal and stress conditions.

Proteomic analyses of limbic regions in neonatal male, female and androgen receptor knockout mice.

BACKGROUND: It is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (ARNesDel) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics. RESULTS: Our proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between ARNesDel and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes <1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes. CONCLUSIONS: Overall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.

Cortico-subthalamic inputs from the motor, limbic, and associative areas in normal and dopamine-depleted rats are not fully segregated.

The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the "hyperdirect" pathway. The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented. Using extracellular electrophysiological approaches, we investigated to what degree the motor and non-motor regions in the STN are segregated in control and dopamine (DA) depleted rats. We performed electrical stimulation of different cortical areas and recorded STN neuronal responses. We showed that motor and non-motor cortico-subthalamic pathways are not fully segregated, but partially integrated in the rat. This integration was mostly present through the indirect pathway. The spatial distribution and response latencies were the same in sham and 6-hydroxydopamine lesioned animals. The inhibitory phase was, however, less apparent in the lesioned animals. In conclusion, this study provides the first evidence that motor and non-motor cortico-subthalamic pathways in the rat are not fully segregated, but partially integrated. This integration was mostly present through the indirect pathway. We also show that the inhibitory phase induced by GABAergic inputs from the external segment of the globus pallidus is reduced in the DA-depleted animals.

Variations in myo-inositol in fronto-limbic regions and clinical response to electroconvulsive therapy in major depression.

Though electroconvulsive therapy (ECT) is an established treatment for severe depression, the neurobiological factors accounting for the clinical effects of ECT are largely unknown. Myo-inositol, a neurometabolite linked with glial activity, is reported as reduced in fronto-limbic regions in patients with depression. Whether changes in myo-inositol relate to the antidepressant effects of ECT is unknown. Using magnetic resonance spectroscopy ((1)H-MRS), we measured dorsomedial anterior cingulate cortex (dmACC) and left and right hippocampal myo-inositol in 50 ECT patients (mean age: 43.78, 14 SD) and 33 controls (mean age: 39.33, 12 SD) to determine cross sectional effects of diagnosis and longitudinal effects of ECT. Patients were scanned prior to treatment, after the second ECT and at completion of the ECT index series. Controls were scanned twice at intervals corresponding to patients' baseline and end of treatment scans. Myo-inositol increased over the course of ECT in the dmACC (p = 0.042). A significant hemisphere by clinical response effect was observed for the hippocampus (p = 0.003) where decreased myo-inositol related to symptom improvement in the left hippocampus. Cross-sectional differences between patients and controls at baseline were not detected. Changes in myo-inositol observed in the dmACC in association with ECT and in the hippocampus in association with ECT-related clinical response suggest the mechanisms of ECT could include gliogenesis or a reversal of gliosis that differentially affect dorsal and ventral limbic regions. Change in dmACC myo-inositol diverged from control values with ECT suggesting compensation, while hippocampal change suggested normalization.

Coping with the Forced Swim Stressor: Towards Understanding an Adaptive Mechanism.

In the forced swim test (FST) rodents progressively show increased episodes of immobility if immersed in a beaker with water from where escape is not possible. In this test, a compound qualifies as a potential antidepressant if it prevents or delays the transition to this passive (energy conserving) behavioural style. In the past decade however the switch from active to passive "coping" was used increasingly to describe the phenotype of an animal that has been exposed to a stressful history and/or genetic modification. A PubMed analysis revealed that in a rapidly increasing number of papers (currently more than 2,000) stress-related immobility in the FST is labeled as a depression-like phenotype. In this contribution we will examine the different phases of information processing during coping with the forced swim stressor. For this purpose we focus on the action of corticosterone that is mediated by the closely related mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the limbic brain. The evidence available suggests a model in which we propose that the limbic MR-mediated response selection operates in complementary fashion with dopaminergic accumbens/prefrontal executive functions to regulate the transition between active and passive coping styles. Upon rescue from the beaker the preferred, mostly passive, coping style is stored in the memory via a GR-dependent action in the hippocampal dentate gyrus. It is concluded that the rodent's behavioural response to a forced swim stressor does not reflect depression. Rather the forced swim experience provides a unique paradigm to investigate the mechanistic underpinning of stress coping and adaptation.

Expression of c-Fos in rat auditory and limbic systems following 22-kHz calls.

In the present study, adult Long-Evans rats were exposed either to natural conspecific aversive 22-kHz vocalizations or to artificial call-like stimuli with comparable frequency-temporal features, followed by c-Fos immunohistochemistry. The natural 22-kHz vocalizations was either played from a recording or produced by a foot-shocked animal located nearby (live vocalizations). In comparison with controls (non-exposed animals), c-Fos immunoreactivity was significantly increased in the inferior colliculus (IC), auditory cortex (AC), periaqueductal grey (PAG), basolateral amygdala (BA), and hippocampus (Hip) of rats exposed to either live or recorded 22-kHz natural vocalizations. Exposure to live natural vocalizations of the foot-shocked animal resulted in a similar pattern of c-Fos activity, as did exposure to the playback of the natural vocalizations. In contrast to this, foot-shocked rats (emitting the 22-kHz vocalizations) had the c-Fos positivity increased markedly in the PAG and only slightly in the AC. The expression of c-Fos also increased in the IC, AC, and in the PAG in animals exposed to the artificial call-like stimuli, when compared to controls; however, the increase was much less pronounced. In this case, c-Fos expression was not increased in the hippocampus or basolateral amygdala. Interestingly, almost no c-Fos expression was found in the medial nucleus of the geniculate body in any of the experimental groups. These findings suggest that differences exist between the processing of important natural conspecific vocalizations and artificial call-like stimuli with similar frequency-temporal features, and moreover they suggest the specific role of individual brain structures in the processing of such calls.

Development and Structural Variety of the Chondroitin Sulfate Proteoglycans-Contained Extracellular Matrix in the Mouse Brain.

Chondroitin sulfate proteoglycans (CSPGs) are major components of the extracellular matrix (ECM) in the brain. In adult mammals, CSPGs form the specialized ECM structure perineuronal nets (PNNs) that surround somata and dendrites of certain types of neurons. PNNs restrict synaptic plasticity and regulate the closure of critical periods. Although previous studies have examined the starting period of PNN formation, focusing on primary sensory cortices, there are no systematic studies at the whole brain level. Here, we examined the starting period of PNN formation in male mice ranging in age from postnatal day 3 to week 11, mainly focusing on several cortical areas, limbic structures, hypothalamus, and brain stem, using lectin histochemistry with Wisteria floribunda agglutinin (WFA). Results showed that early PNN formation was observed in several reticular formations of the brain stem related to the cranial nerves and primary somatosensory cortices. In the limbic system, PNN formation in the hippocampus started earlier than that of the amygdala. Furthermore, in the medial amygdaloid nucleus and some hypothalamic regions, WFA labeling did not show typical PNN-like forms. The present study suggests spatiotemporal differences at the beginning of PNN formation and a structural variety of CSPG-contained ECM in the brain.

The importance of the context in the hippocampus and brain related areas throughout the performance of a fear conditioning task.

The importance context has been broadly studied in the management of phobias and in the drug addiction literature. The way in which changes to a context influence behavior after the simple acquisition of a passive avoidance task remains unclear. The hippocampus has long been implicated in the contextual and spatial processing required for contextual fear, but its role in encoding the aversive component of a contextual fear memory is still inconclusive. Our work tries to elucidate whether a change in context, represented as differences in the load of the stimuli, is critical for learning about the context-shock association and whether this manipulation of the context could be linked to any change in metabolic brain activity requirements. For this purpose, we used an avoidance conditioning task. Animals were divided into three different experimental conditions. In one group, acquisition was performed in an enriched stimuli environment and retention was performed in a typically lit chamber (the PA-ACQ-CONTX group). In another group, acquisition was performed in the typically lit chamber and retention was undertaken in the highly enriched chamber (the PA-RET-CONTX group). Finally, for the control group, PA-CN-CONTX, acquisition, and retention were performed in the enriched stimuli environment. Our results showed that the PA-ACQ-CONTX group had longer escape latencies and poorer retention than the PA-RET-CONTX and PA-CN-CONTX groups after 24 h of acquisition under contextual changes. To study metabolic brain activity, histochemical labelling of cytochrome c-oxidase (CO) was performed. CO results suggested a neural circuit including the hippocampus, amygdala, thalamus, parahippocampal cortices, and mammillary nuclei that is involved in the learning and memory processes that enable context-dependent behavior. These results highlight how dysfunction in this network may be involved in the contextualization of fear associations that underlie several forms of psychopathology, including post-traumatic stress disorder, schizophrenia, and substance abuse disorders.

Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies.

BACKGROUND: Major depressive disorder (MDD) is a common mental illness with high lifetime prevalence close to 20%. Positron emission tomography (PET) studies have reported decreased prefrontal, insular and limbic cerebral glucose metabolism in depressed patients compared with healthy controls. However, the literature has not always been consistent. To evaluate current evidence from PET studies, we conducted a voxel-based meta-analysis of cerebral metabolism in MDD. METHOD: Data were collected from databases including PubMed and Web of Science, with the last report up to April 2013. Voxel-based meta-analyses were performed using the revised activation likelihood estimation (ALE) software. RESULTS: Ten whole-brain-based FDG-PET studies in MDD were included in the meta-analysis, comprising 188 MDD patients and 169 healthy controls. ALE analyses showed the brain metabolism in bilateral insula, left lentiform nucleus putamen and extra-nuclear, right caudate and cingulate gyrus were significantly decreased. However, the brain activity in right thalamus pulvinar and declive of posterior lobe, left culmen of vermis in anterior lobe were significantly increased in MDD patients. CONCLUSION: Our meta-analysis demonstrates the specific brain regions where possible dysfunctions are more consistently reported in MDD patients. Altered metabolism in insula, limbic system, basal ganglia, thalamus, and cerebellum and thus these regions are likely to play a key role in the pathophysiology of depression.

Cathinone, an active principle of Catha edulis, accelerates oxidative stress in the limbic area of swiss albino mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cathinone hydrochloride is an active principle of the khat plant (Catha edulis) that produces pleasurable and stimulating effects in khat chewers. To the best of our knowledge no data of cathinone on oxidative stress in limbic areas of mice is available. This is the first study of cathinone on oxidative stress in limbic areas of the brain in Swiss albino male mice. MATERIALS AND METHODS: The animals were divided into four groups. Group-I was the control group and received vehicle, while groups-II to IV received (-)-cathinone hydrochloride (0.125, 0.25 and 0.5 mg/kg body wt., i.p.) once daily for 15 days. RESULTS: The level of lipid peroxidation (LPO) was elevated dose-dependently and was significant (p<0.05, p<0.01) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. In contrast, the content of reduced glutathione (GSH) was decreased significantly (p<0.01, p<0.001) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. The activity of antioxidant enzymes (GPx, GR, GST, CAT, and SOD) was also decreased dose-dependently: the decreased activity of GPx, GR, catalase and SOD was significant with doses of 0.25 and 0.5 mg of cathinone as compared to control group, while the activity of GST was decreased dose-dependently and was significant with 0.5mg of cathinone as compared to control group. CONCLUSIONS: The results indicate that the cathinone generated oxidative stress hampered antioxidant enzymes, glutathione and lipid peroxidation.

Rewarding, reinforcing and incentive salient events involve orexigenic hypothalamic neuropeptides regulating mesolimbic dopaminergic neurotransmission.

The hypothalamus is an integrated energy sensing system interfacing with higher motivational structures of the mesocorticolimbic dopamine (DA) system. This interconnectivity is strictly regulated by a number of orexigenic hypothalamic neuropeptides, including especially ghrelin, orexins and neuropeptide Y (NPY), enabling the latter to modulate salient events of natural and chemical reinforcers. In this review we aim to analyse the current knowledge on these three orexigenic neuropeptide systems that are involved in the DAergic regulation of psychostimulant behaviours. We will first review the co-existing interactions between ghrelin, orexins and NPY in hypothalamic nuclei. We will next outline whether these neuropeptides can affect DAergic neurotransmission by either regulating the firing rate of DA neurons in the ventral tegmental area (VTA) or by presynaptically interacting on the DAergic nerve terminals. Finally, we will underscore the main studies that outlined the involvement of ghrelin, orexins and NPY with rewarding, reinforcing and incentive properties of natural reinforcers and drugs of abuse. The reciprocal hypothalamic interaction of ghrelin, orexins and NPY might represent a new central view on neuronal mechanisms regulating the behavioural phenomenology of addiction maintained by the DA system.