Chronic pain manifests in multiple disorders and is highly debilitating. While its pathophysiology is not fully understood, the involvement of the mesocorticolimbic monoaminergic systems have been shown to play a critical role in chronic pain emergence and/or maintenance. In this study, we analyzed the levels of monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in mesocorticolimbic areas - medial prefrontal cortex, orbitofrontal cortex, striatum, nucleus accumbens and amygdala - 1 month after a neuropathic lesion, Spared Nerve Injury (SNI). In SNI animals, were observed a marginal decrease of DA and 5-HT in the striatum and a rightward shift in the levels of NA in the nucleus accumbens. While mesocorticolimbic monoamines might be relevant for chronic pain pathophysiology its content appears to be relatively unaffected in our experimental conditions.

Trans-crocin 4 (TC4) is an important carotenoid constituent of saffron showing potential activity against Alzheimer's Disease (AD) due to its antioxidant and antiamyloidogenic properties. Metabolomics is an emerging scientific field that enhances biomarker discovery and reveals underlying biochemical mechanisms aiming towards the early subclinical diagnosis of diseases. To date, there are no reports on the changes induced to mice plasma metabolome after TC4 administration. We report a novel untargeted UHPLC-ESI HRMS metabolomics strategy to determine the alteration of the metabolic fingerprint following i.p. administration of TC4 in male and female mice. Blood samples from fiftysix mice treated with TC4 as well as from control animals were analyzed with UHPLC-ESI HRMS. Statistical evaluation of the results was achieved by multivariate analysis (MVA), i.e., principal component analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA) in order to discover the variables that contributed to the discrimination between treated and untreated groups which were identified by online database searching (e.g., Metlin, HMDB, KEGG) aided by chemometric processing, e.g., covariance searching etc. Due to the high variability imposed by various factors, e.g., sex of the animals participating in the study, administration dose and time-points of sacrifice, multilevel sparse PLS-DA analysis, e.g., splitting variation to each individual component, has been employed as a more efficient approach for such designs. This methodology allowed the identification of the time sequence of metabolome changes due to the administration of TC4, whereas a sex-related effect on the metabolome is indicated, denoting that the administration in both sexes is indispensable in order to acquire safe conclusions as reliable metabolome pictures. The results demonstrated a number of annotated metabolites playing a potential role in neuroprotection while they are closely related to AD. Moreover, five additional annotated metabolites were involved in the steroid biosynthesis pathway while two of them may be considered as putative neuroprotective agents.

RATIONALE: Νeurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3β,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects. OBJECTIVES: This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27. METHODS: Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and "depressive-like" behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis. RESULTS: Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected. CONCLUSIONS: BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.

The aim of this study was to determine the cognitive and behavioral effects of extra virgin olive oil total phenolic content (TPC) and Sideritis (SID) extracts in female mice, and identify the associated neurochemical changes in the hippocampus and the prefrontal cortex. All animals received intraperitoneal low or high doses of TPC, SID or vehicle treatment for 7 days and were subjected to the Open Field (OF), Novel Object Recognition (NOR) and Tail Suspension Test (TST). The prefrontal cortex and hippocampus were dissected for analysis of neurotransmitters and aminoacids with high performance liquid chromatography with electrochemical detection (HPLC-ED). Both TPC doses enhanced vertical activity and center entries in the OF, which could indicate an anxiolytic-like effect. In addition, TPC enhanced non-spatial working memory and, in high doses, exerted antidepressant effects. On the other hand, high SID doses remarkably decreased the animals' overall activity. Locomotor and exploratory activities were closely associated with cortical increases in serotonin turnover induced by both treatments. Cognitive performance was linked to glutamate level changes. Furthermore, TPC reduced cortical taurine levels, while SID reduced cortical aspartate levels. TPC seems to have promising cognitive, anxiolytic and antidepressant effects, whereas SID has sedative effects in high doses. Both extracts act in the brain, but their specific actions and properties merit further exploration.

Prevalence and symptoms of most psychiatric and neurological disorders differ in men and women and there is substantial evidence that their neurobiological basis and treatment also differ by sex. This special issue sought to bring together a series of empirical papers and targeted reviews to highlight the diverse impact of sex in neuroscience and neuropsychopharmacology. This special issue emphasizes the diverse impact of sex in neuroscience and neuropsychopharmacology, including 9 review papers and 17 research articles highlighting investigation in different species (zebrafish, mice, rats, and humans). Each contribution covers scientific topics that overlap with genetics, endocrinology, cognition, behavioral neuroscience, neurology, and pharmacology. Investigating the extent to which sex differences can impact the brain and behavior is key to moving forward in neuroscience research.

One of the most frequently prescribed selective serotonin reuptake inhibitor medications (SSRIs) for peripartum mood and anxiety disorders is sertraline (Zoloft®). Sertraline can help alleviate mood and anxiety symptoms in many women but it is not known how sertraline, or SSRIs in general, affect the neurobiology of the brain particularly when pregnant. The aim of this study was to investigate how sertraline affects plasticity in the hippocampus, a brain area integral in depression and SSRI efficacy (particularly in males), during late pregnancy and whether these effects differ from the effects of sertraline in non-pregnant females. To do this pregnant and age-matched non-pregnant female Sprague-Dawley rats were used. For the last half of pregnancy (10 days), and at matched points in non-pregnant females, rats were given sertraline (2.5 mg/kg/day or 10 mg/kg/day) or vehicle (0 mg/kg/day). Brains were used to investigate effects on the serotonergic system in the hippocampus and prefrontal cortex and measures of neuroplasticity in the hippocampus. Results show that pregnant females have significantly higher serum levels of sertraline compared to non-pregnant females but that rates of serotonin turnover in the hippocampus and PFC are similar between pregnant and non-pregnant females. Sertraline increased synaptophysin density in the dentate gyrus and CA3 and was associated with a decrease in cell proliferation in the dentate gyrus of non-pregnant, but not pregnant, females. During late pregnancy the hippocampus showed significant reductions in neurogenesis and increases in synaptophysin density. This research highlights the need to consider the unique effect of reproductive state on the neuropharmacology of SSRIs.

Cannabinoid administration during adolescence affects various physiological processes, such as motor and affective response, cognitive-related functions and modulates neurotransmitter activity. Literature remains scant concerning the parallel examination of the effects of adolescent escalating low-dose Δ(9) -tetrahydrocannabinol (Δ(9) -THC) on the behavioral and plasticity profile of adult rats in both sexes. Herein, we investigated the long-term behavioral, neurochemical and neurobiological effects of adolescent escalating low Δ(9) -THC doses in adult male and female rats. In adult males, adolescent low-dose Δ(9) -THC exposure led to increased spontaneous locomotor activity, impaired behavioral motor habituation and defective short-term spatial memory, paralleled with decreased BDNF protein levels in the prefrontal cortex. In this brain area, serotonergic activity was increased, as depicted by the increased serotonin turnover rate, while the opposite effect was observed in the hippocampus, a region where SERT levels were enhanced by Δ(9) -THC, compared with vehicle. In adult females, adolescent Δ(9) -THC treatment led to decreased spontaneous vertical activity and impaired short-term spatial memory, accompanied by increased BDNF protein levels in the prefrontal cortex. Present findings emphasize the key role of adolescent escalating low Δ(9) -THC exposure in the long-term regulation of motor response, spatial-related cognitive functions and neuroplasticity indices in adulthood. In this framework, these changes could, at a translational level, contribute to clinical issues suggesting the development of psychopathology in a sex-differentiated manner following Δ(9) -THC exposure during adolescence.