Postnatal hypofunction of N-methyl-D-aspartate receptors alters perforant path synaptic plasticity and filtering and impairs dentate gyrus-mediated spatial discrimination.

BACKGROUND AND PURPOSE: Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition. EXPERIMENTAL APPROACH: We identified a series of synaptic alterations of the lateral and medial perforant paths in animals postnatally treated with the NMDA antagonist MK-801. This dysregulation suggests decreased cognitive performance, for which the dentate gyrus is critical. KEY RESULTS: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in slices from MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of long-term potentiation (LTP) and CB1 receptor-mediated long-term depression (LTD). Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol (2-AG), an endogenous ligand of the CB1 receptor, we restored the LTD in animals treated with MK-801. Additionally, we showed for the first time, that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDA receptors. CONCLUSION AND IMPLICATIONS: Dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus has been demonstrated, which may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.

Stress hyper-reactivity increases vulnerability to developing binge-type eating and associated anxiety-like behavior; comparison between Wistar-Kyoto and Sprague-Dawley rats.

Introduction: Binge eating disorder (BED) is a widespread eating disorder that primarily affects women worldwide, and it is characterized by the presence of binge eating episodes and the absence of any compensatory behavior to prevent weight gain. BED presents elevated comorbidity with other psychiatric disorders, such as anxiety, and it has been suggested that stress sensibility could be a vulnerability factor for the development of BED and the associated anxiety comorbidity. In this study, we aim to investigate whether the Wistar-Kyoto rat strain (WKY), which has a stress hyper-reactive phenotype, could develop both binge-type eating and anxiety-like behaviors simultaneously. We also aim to compare its vulnerability to developing both behaviors with the Sprague Dawley rat strain (SD), a rat strain commonly used in binge-eating models. Methods: WKY and SD rats were subjected to the model of intermittent access to palatable food (sucrose solution 30% or shortening) without calorie restriction or stress exposure. We evaluated and compared the development of binge-type eating behavior, anxiety-like behavior, and serum corticosterone variation as an index of the stress response in both rat strains. Results: WKY rats presented a higher percentage of binge-type eaters and required less time to develop binge-type eating behavior than SD rats. The WKY eating pattern emulated a binge-eating episode regardless of the palatable food. Although the development of sucrose binge-type eating was similar between strains, WKY developed more easily the shortening binge-type eating than SD and was more susceptible to developing anxiety-like behavior. Additionally, sucrose binge eating seems to differentially affect both strains' hypothalamic-pituitary-adrenal (HPA) axis response to stress since it facilitated its response in SD and blunted it in WKY. Discussion: Our results show that high-stress sensitive phenotype is a common vulnerability factor for the development of binge-type eating and anxiety-like behavior. Regardless of the macronutrient composition of the palatable food, WKY is susceptible to developing a binge-type eating behavior and is more susceptible than SD to developing anxiety-like behavior simultaneously. In conclusion, results showed that a hyper-reactive stress phenotype predisposes the development of binge-type eating behavior and anxiety-like behavior in the absence of calorie restriction and stress exposure.

Chronic Variable Stress and Cafeteria Diet Combination Exacerbate Microglia and c-fos Activation but Not Experimental Anxiety or Depression in a Menopause Model.

The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-ß, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos-positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.

NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long-term potentiation of CA3 pyramidal cells.

Experimental manipulations that interfere with the functional expression of N-methyl-D-aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK-801 during early postnatal development alters glutamate release and impairs the induction of NMDAR-dependent long-term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated short- and long-term potentiation, are compromised in response to neonatal treatment with MK-801. Consistent with this tenet, short- and long-term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole-cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre- and postsynaptic modifications at the MF-CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired-pulse ratio, and reduced AMPAR-mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK-801-treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR-independent forms of synaptic plasticity of the hippocampus.

Anxiety-like Behavior and GABAAR/BDZ Binding Site Response to Progesterone Withdrawal in a Stress-Vulnerable Strain, the Wistar Kyoto Rats.

Stress susceptibility could play a role in developing premenstrual anxiety due to abnormalities in the hypothalamus-pituitary-adrenal (HPA) axis and impairments in the GABAA receptors' benzodiazepine (BDZ) site. Hence, we studied the stress-vulnerable Wistar Kyoto rat strain (WKY) to evaluate progesterone withdrawal (PW) effects on anxiety, HPA axis response, and to explore indicators of GABAA functionality in the BDZ site. For five days, ovariectomized WKY rats were administered 2.0 mg/kg of progesterone. Twenty-four hours after the last administration, rats were tested in the anxiety-like burying behavior test (BBT) or elevated plus maze test (EPM), and corticosterone was determined. [3H]Flunitrazepam binding autoradiography served as the BDZ binding site index of the GABAA receptor in amygdala nuclei and hippocampus's dentate gyrus (DG). Finally, different doses of diazepam in PW-WKY rats were tested in the BBT. PW induced anxiety-like behaviors in both BBT and EPM compared with No-PW rats. PW increased corticosterone, but was blunted when combined with PW and BBT. PW increased [3H]Flunitrazepam binding in the DG and central amygdala compared with No-PW rats. Diazepam at a low dose induced an anxiogenic-like response in PW rats, suggesting a paradoxical response to benzodiazepines. Overall, PW induced anxiety-like behavior, a blunted HPA axis response, and higher GABAAR/BZD binding site sensitivity in a stress-vulnerable rat strain. These findings demonstrate the role of stress-susceptibility in GABAAR functionality in a preclinical approximation of PMDD.

Can animal models resemble a premenstrual dysphoric condition?

Around 80% of women worldwide suffer mild Premenstrual Disorders (PMD) during their reproductive life. Up to a quarter are affected by moderate to severe symptoms, and between 3% and 8% experience a severe form. It is classified as premenstrual syndrome (PMS) with predominantly physical symptoms and premenstrual dysphoric disorder (PMDD) with psychiatric symptoms. The present review analyzes the factors associated with PMD and the Hypothalamus-Pituitary-Ovarian or Hypothalamus-Pituitary-adrenal axis and discusses the main animal models used to study PMDD. Evidence shows that the ovarian hormones participate in PMDD symptoms, and several points of regulation of their synthesis, metabolism, and target sites could be altered. PMDD is complex and implies several factors that require consideration when this condition is modeled in animals. Of particular interest are those points related to areas that may represent opportunities to develop new approximations to understand the mechanisms involved in PMDD and possible treatments.

Activation of D1/D5 receptors ameliorates decreased intrinsic excitability of hippocampal neurons induced by neonatal blockade of N-methyl-d-aspartate receptors.

BACKGROUND AND PURPOSE: Dysregulation of dopaminergic transmission combined with transient hypofunction of N-methyl-d-aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia. EXPERIMENTAL APPROACH: Therefore, we aimed to identify electrophysiologic alterations in animals neonatally treated with the NMDA receptor antagonist, MK-801, or with saline solution. KEY RESULTS: Patch-clamp whole-cell recordings from MK-801-treated animals revealed altered passive and active electrophysiologic properties compared with CA1 pyramidal cells from saline-treated animals, including up-regulation of the K+ inward-rectifier conductance and fast-inactivating and slow/non-inactivating K+ currents. Up-regulation of these membrane ionic currents reduced the overall excitability and altered the firing properties of CA1 pyramidal cells. We also explored the capability of cells treated with MK-801 to express intrinsic excitability potentiation, a non-synaptic form of hippocampal plasticity associated with cognition and memory formation. CA1 pyramidal cells from animals treated with MK-801 were unable to convey intrinsic excitability potentiation and had blunted synaptic potentiation. Furthermore, MK-801-treated animals also exhibited reduced cognitive performance in the Barnes maze task. Notably, activation of D1/D5 receptors with SKF-38,393 partially restored electrophysiologic alterations caused by neonatal treatment with MK-801. CONCLUSION AND IMPLICATIONS: Our results offer a molecular and mechanistic explanation based on dysregulation of glutamatergic transmission, in addition to dopaminergic transmission, that may contribute to the understanding of the cognitive deterioration associated with schizophrenia.

Chronic Social Defeat During Adolescence Induces Short- and Long-Term Behavioral and Neuroendocrine Effects in Male Swiss-Webster Mice.

Chronic stress exposure during adolescence is a significant risk factor for the development of depression. Chronic social defeat (CSD) in rodents is an animal model of depression with excellent ethological, predictive, discriminative, and face validity. Because the CSD model has not been thoroughly examined as a model of stress-induced depression within the adolescence stage, the present study analyzed the short- and long-term behavioral and neuroendocrine effects of CSD during early adolescence. Therefore, adolescent male Swiss-Webster (SW) mice were exposed to the CSD model from postnatal day (PND) 28 to PND37. Twenty-four hours (mid-adolescence) or 4 weeks (early adulthood) later, mice were tested in two models of depression; the social interaction test (SIT) and forced swimming test (FST); cognitive deficits were evaluated in the Barnes maze (BM). Finally, corticosterone and testosterone content was measured before, during, and after CSD exposure, and serotonin transporter (SERT) autoradiography was studied after CSD in adolescent and adult mice. CSD during early adolescence induced enduring depression-like behaviors as inferred from increased social avoidance and immobility behavior in the SIT and FST, respectively, which correlated in an age-dependent manner with SERT binding in the hippocampus; CSD during early adolescence also induced long-lasting learning and memory impairments in the Barnes maze (BM). Finally, CSD during early adolescence increased serum corticosterone levels in mid-adolescence and early adulthood and delayed the expected increase in serum testosterone levels observed at this age. In conclusion: (1) CSD during early adolescence induced long-lasting depression-like behaviors, (2) sensitivity of SERT density during normal brain development was revealed, (3) CSD during early adolescence induced enduring cognitive deficits, and (4) results highlight the vulnerability of the adolescent brain to social stressors on the adrenal and gonadal axes, which emphasizes the importance of an adequate interaction between both axes during adolescence for normal development of brain and behavior.

Estrogen receptors-ß and serotonin mediate the antidepressant-like effect of an aqueous extract of pomegranate in ovariectomized rats.

Pomegranate (Punica granatum) fruit is of particular interest because of its high nutritional value and therapeutic actions. Recently, we showed that an aqueous extract of pomegranate (AE-PG) given by oral route induced antidepressant-like actions mediated by estrogen receptors (ERs) suggesting its potential to function as an alternative to estrogen therapy replacement in menopause-related depression treatment. Orally administered AE-PG allows the biotransformation of ellagitannins into active estrogenic compounds through the intestinal microbiota. However, it is necessary to know if compounds that do not need to be biotransformed by the intestinal microbiota are involved in the antidepressant-like effects. Therefore, the first aim of this study was to determine if AE-PG produces an antidepressant-like effect when administered intraperitoneally. Also, to determine the participation of specific ER-subtypes (α or ß) and to analyze the role of the serotonergic system. Young female Wistar rats were ovariectomized as a surgical model of menopause. The intraperitoneal administration of AE-PG (1 mg/kg; i. p.) was evaluated in the forced swimming test and open field tests. Also, the ERα antagonist (TPBM; 50 µg/rat; s. c.) or the ERß antagonist (PHTPP; 25 µg/rat; s. c.) were administered with AE-PG to analyze the participation of the specific ERs. Finally, the effect of the serotonin neurotoxin 5,7-DHT (200 µg/rat; i. c.v.) on the antidepressant-like effect of the AE-PG was studied in independent experimental groups. RESULTS: showed that AE-PG administered by intraperitoneal route induced antidepressant-like effects. This result suggests that gut microbiota biotransformation is not necessary to exert its actions. The mechanism of action involves the activation of the ERß and the serotonergic system. Altogether, this information contributes to the elucidation of the antidepressant action of the pomegranate fruit, which could be further considered as an alternative treatment for depression during menopause.

Anxiolytic- and anxiogenic-like effects of Montanoa tomentosa (Asteraceae): Dependence on the endocrine condition.

ETHNOPHARMACOLOGICAL RELEVANCE: Montanoa tomentosa Cerv. (MT) is a native plant from Mexico used in traditional medicine as a remedy for reproductive impairments and relaxing effects. In previous studies, it has been shown that the endocrine state could modify the antianxiety-like actions of anxiolytic compounds. Although women are the primary user of MT, no studies have evaluated the potential impact of the endocrine milieu on its anti-anxiety actions. AIMS OF THE STUDY: Ascertain the antianxiety effects of M. tomentosa in rats with different hormonal conditions, and to analyze the participation of the GABAA receptor in ovariectomized rats treated with MT. MATERIALS AND METHODS: The animal model of anxiety used was the elevated plus-maze (EPM). Rats' endocrine conditions were: a) Low hormone levels (rats in diestrus I and II phases); b) High hormone levels (proestrus/estrus phases); c) No hormones (ovariectomized rats); and d) Rats under progesterone withdrawal (PW). To evaluate the participation of the GABAA receptor in the anxiolytic-like action of MT the antagonist picrotoxin was used. RESULTS: Results showed that MT induced dose-dependent anxiolytic-like actions in rats with low hormone level conditions. Also, MT reduced anxiety-like behavior in female rats under PW, in contrast to diazepam which was ineffective. MT's anxiolytic-like effect was blocked by picrotoxin, suggesting the participation of the GABAA receptor complex. However, increased anxiety-like behavior was observed in rats with a high hormone level condition and low doses of MT. CONCLUSIONS: Beneficial anxiolytic-like actions of MT are observed under low hormone conditions, particularly in the PW challenge (a condition that can be related to a premenstrual period). Furthermore, the participation of the GABAA receptor is evidenced. However, hormonal variations could induce the opposite effects, hence women should be cautious.

Structure-activity study of acute neurobehavioral effects of cyclohexane, benzene, m-xylene, and toluene in rats.

Toluene is a widely misused solvent that causes a variety of behavioral effects in both humans and animals. Preclinical and clinical research has provided evidence that toluene inhalation produces psychoactive effects similar to those caused by other Central Nervous System depressant drugs, but little is known about the consequences of inhaling solvents other than toluene that are also present in commercial products. As part of this research project, we studied the effects of hydrocarbon solvents chemically related to toluene on anxiety-like behavior, passive-avoidance learning, nociception, motor coordination and social interaction. We tested independent groups of adolescent male Wistar rats in the burying behavior task, step through avoidance learning task, hot plate test, shock threshold test, social interaction or rotarod tests after a 30 min exposure to either cyclohexane, benzene, toluene or m-xylene (2000 to 8000 ppm). Control animals breathed only air. Benzene, toluene and m-xylene produced anxiolytic-like actions, impaired learning, caused antinociception and decreased social interaction in a concentration-dependent manner. Locomotor coordination was impaired only with 8000 ppm m-xylene and 8000 ppm toluene. Cyclohexane had no effect on any of the behavioral tasks. Our data suggest that the aromatic ring is critical for solvents to produce a wide variety of behavioral effects.

The Systemic Administration of the Histamine H1 Receptor Antagonist/Inverse Agonist Chlorpheniramine to Pregnant Rats Impairs the Development of Nigro-Striatal Dopaminergic Neurons.

The dopaminergic and histaminergic systems are the first to appear during the development of the nervous system. Through the activation of H1 receptors (H1Rs), histamine increases neurogenesis of the cortical deep layers, while reducing the dopaminergic phenotype (cells immunoreactive to tyrosine hydroxylase, TH+) in embryo ventral mesencephalon. Although the function of histamine in neuronal differentiation has been studied, the role of H1Rs in neurogenesis has not been addressed. For this purpose, the H1R antagonist/inverse agonist chlorpheniramine was systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats (gestational days 12-14, E12-14), and control and experimental embryos (E14 and E16) and pups (21-day-old) were evaluated for changes in nigro-striatal development. Western blot and immunohistochemistry determinations showed a significant increase in the dopaminergic markers' TH and PITX3 in embryos from chlorpheniramine-treated rats at E16. Unexpectedly, 21-day-old pups from the chlorpheniramine-treated group, showed a significant reduction in TH immunoreactivity in the substantia nigra pars compacta and dorsal striatum. Furthermore, striatal dopamine content, evoked [3H]-dopamine release and methamphetamine-stimulated motor activity were significantly lower compared to the control group. These results indicate that H1R blockade at E14-E16 favors the differentiation of dopaminergic neurons, but hampers their migration, leading to a decrease in dopaminergic innervation of the striatum in post-natal life.

Progressive Alterations in Synaptic Transmission and Plasticity of Area CA1 Precede the Cognitive Impairment Associated with Neonatal Administration of MK-801.

Transient hypofunction of NMDA receptors during brain maturation has been linked to cellular and behavioral alterations that mirror symptoms of schizophrenia. In line with this notion, neonatal administration of the non-competitive NMDA receptor antagonist, MK-801, mimics the negative and cognitive symptoms of schizophrenia. By combining behavioral evaluations with extracellular recordings in acute hippocampal slices, we uncovered a progressive alteration of synaptic transmission of animals neonatally treated with MK-801. During the periadolescent stage (up to postnatal day 30), before any behavioral alterations were observed, the synaptic transmission of hippocampal area CA1 exhibited progressive signs of alteration, such as the reduction in synaptic strength and impairment of short- and long-term forms of synaptic plasticity. As expected, behavioral impairments were consistently observed during the young adult stage (postnatal day 90), a period in which a steady deterioration of long-term depression and long-term potentiation was observed. Taken together, these results suggest that synaptic dysregulation precedes behavioral deterioration in a model that mimics the negative and cognitive symptoms of schizophrenia.

Aqueous Extract of Pomegranate Alone or in Combination with Citalopram Produces Antidepressant-Like Effects in an Animal Model of Menopause: Participation of Estrogen Receptors.

It has been reported that the aqueous extract of pomegranate (AE-PG) has polyphenols with estrogenic-like activities. The present work determines if AE-PG alone or in combination with the selective serotonin reuptake inhibitor, citalopram, has antidepressant-like effects. It was also analyzed the participation of estrogen receptors (ER). AE-PG (0.1, 1.0, 10, or 100 mg/kg) was evaluated in ovariectomized female Wistar rats subjected to the forced swimming test. The effects induced by AE-PG were compared with those of citalopram (2.5, 5.0, 10, and 20.0 mg/kg) and 17ß-estradiol (E2; 2.5 5.0, and 10 µg/rat). Likewise, the combination of suboptimal doses of AE-PG (0.1 mg/kg) plus citalopram (2.5 mg/kg) was evaluated. To determine if ER participates in the antidepressant-like action of pomegranate, the estrogen antagonist tamoxifen (15 mg/kg) was administered with AE-PG (1 mg/kg). AE-PG produced antidepressant-like actions with a similar behavioral profile induced by citalopram and E2. Suboptimal doses of citalopram plus AE-PG produced antidepressant-like effects. Tamoxifen was able to block AE-PG's antidepressant-like actions. These results confirm the participation of ER in AE-PG's antidepressant-like effects. Furthermore, the additive effects observed with the combined treatment of AE-PG plus citalopram could be advantageous in the treatment of depressive disorders, such as menopause.

Maternal separation induces long-term effects on monoamines and brain-derived neurotrophic factor levels on the frontal cortex, amygdala, and hippocampus: differential effects after a stress challenge.

The maternal separation (MS) paradigm is a well-known animal model that resembles the stress of early adverse life experiences and produces structural and functional abnormalities when animals are adults. The present study analyzed the effect of MS, in adult mice, on brain-derived neurotrophic factor (BDNF), serotonin (5-HT), and dopamine (DA) levels, and the turnover rate in the hippocampus, frontal cortex, and amygdala, and brain regions that are associated with emotion. Also, the effects of MS in depression-like responses in adult mice were studied. The results showed that MS from postnatal day 8-21 induces depression-like behaviors. In MS mice, the three brain areas showed differential responses in 5-HT, DA, and BDNF concentrations both in basal levels and when animals were challenged with an acute stressor in adulthood. Specifically, under basal conditions, MS increased monoamine and BDNF levels in the hippocampus and amygdala, but decreased these levels in the frontal cortex. In MS, but not in control mice, the amygdala responded to the stress challenge, whereas the frontal cortex showed no response. Finally, the hippocampus showed increased 5-HT and DA activity, but not increased BDNF after the stress challenge in MS mice. The present results support the theory of the hypofunctionality of the frontal cortex and hyperactivity of mesolimbic areas in depression-like conditions.

Wistar-Kyoto Female Rats Are More Susceptible to Develop Sugar Binging: A Comparison with Wistar Rats.

The hedonic component of the feeding behavior involves the mesolimbic reward system and resembles addictions. Nowadays, the excessive consumption of sucrose is considered addictive. The Wistar-Kyoto (WKY) rat strain is prone to develop anxiety and addiction-like behavior; nevertheless, a lack of information regarding their vulnerability to develop sugar binging-like behavior (SBLB) and how it affects the reward system persist. Therefore, the first aim of the present study was to compare the different predisposition of two rat strains, Wistar (W) and WKY to develop the SBLB in female and male rats. Also, we studied if the SBLB-inducing protocol produces changes in anxiety-like behavior using the plus-maze test (PMT) and, analyzed serotonin (5-HT) and noradrenaline (NA) concentrations in brain areas related to anxiety and ingestive behavior (brain stem, hypothalamus, nucleus accumbens, and amygdala). Finally, we evaluated whether fluoxetine, a drug that has been effective in reducing the binge-eating frequency, body weight, and severity of binge eating disorder, could also block this behavior. Briefly, WKY and W female rats were exposed to 30% sucrose solution (2 h, 3 days/week for 4 weeks), and fed up ad libitum. PMT was performed between the last two test periods. Immediately after the last test where sucrose access was available, rats were decapitated and brain areas extracted for high-performance liquid chromatography analysis. The results showed that both W and WKY female and male rats developed the SBLB. WKY rats consumed more calories and ingested a bigger amount of sucrose solution than their W counterpart. This behavior was reversed by using fluoxetine, rats exposed to the SBLB-inducing protocol presented a rebound effect during the washout period. On female rats, the SBLB-inducing protocol induced changes in NA concentrations on WKY, but not on W rats. No changes were found in 5-HT levels. Finally, animals that developed SBLB showed increased anxiety-like behavior in the PMT. In conclusion, WKY female rats can be considered as a more susceptible rat strain to develop SBLB.

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

ETHNOPHARMACOLOGICAL RELEVANCE: Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. AIM OF THE STUDY: To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. METHODS: We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. RESULTS: The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. CONCLUSIONS: There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding of the mechanism of action is inconclusive. The need for systematic studies in preclinical and clinical research is evident, and efforts should be done to fulfill these research. Finally, it is important also to study possible drug-herbal interactions to establish specific recommendations for people that use these plants as anxiolytic or antidepressant treatments either alone or in combination with another type of medicine.

Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems.

RATIONALE: Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-D-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized. OBJECTIVES: This study aims (a) to study toluene's effects on the 5-HT2A-mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene's and ketamine's effects by selective drugs. METHODS: Independent groups of rats inhaled toluene (500-12,000 ppm) for 30 min during which the occurrence of serotonergic signs was analyzed. Brains were obtained after exposure to determine DA and 5-HT levels by HPLC. RESULTS: Toluene concentration-dependently induced HTR. Other serotonin syndrome signs were evident at high concentrations. Toluene (4000 and 8000 ppm), and ketamine (3 and 10 mg/kg), significantly increased 5-HT levels in the frontal cortex (FC) striatum, hippocampus, and brain stem, as well as DA levels in the striatum and FC. Pretreatment with ketanserin (5HT2A/2C receptor antagonist), M100907 (selective 5-HT2A receptor antagonist), D-serine (co-agonist of the NMDA receptor glycine site), and haloperidol (D2 receptor antagonist) significantly decreased toluene's and ketamine's actions. The 5HT1A receptor antagonist WAY100635 had no effect. CONCLUSION: Toluene stimulates 5HT2A and 5HT2C receptors, and increases 5-HT and DA levels. These actions are similar to those produced by ketamine and involve activation of a complex neurotransmitter network that includes NMDA receptor antagonism.

GABAA/benzodiazepine receptor complex mediates the anxiolytic-like effect of Montanoa tomentosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Montanoa tomentosa also named Cihuapatli is a native plant of Mexico that has been used in traditional medicine for the last five centuries mainly as a remedy for reproductive impairments. However, there are reports indicating that this plant was also consumed by Mexican ancient people for its relaxing properties. In order to corroborate this information, the present study was conducted to evaluate the effect of Montanoa tomentosa lyophilisate (MT) on rat׳s anxiety-like behavior and to analyze its mechanism of action. MATERIALS AND METHODS: The anxiolytic-like action of MT (1.5, 3.0, 6.0 and 12.0 mg/kg) was investigated in male Wistar rats tested in three animal models of anxiety: the burying behavior, the elevated plus maze and the hole-board tests. As a positive control, the anti-anxiety effects of different doses of the selective GABAA receptor agonist muscimol were also analyzed. In order to evaluate the participation of the GABAA and oxytocin receptors in the anxiolytic-like actions of MT, the GABAA receptors blockers picrotoxin (0.25 and 0.50 mg/kg), bicuculline (2.0 mg/kg) and flumazenil (5.00 and 10.0 mg/kg), the neurosteroid inhibitor finasteride (50.0 and 100 mg/kg) and the oxytocin receptor antagonist atosiban (0.25 µg) were used. Finally, to evaluate general activity, and motor coordination, the open field and rota-rod tests were used. RESULTS: MT at 3.0 mg/kg showed anxiolytic-like effects in the three anxiety paradigms without affecting reactivity, general motor activity or motor coordination; however, at higher doses sedative effects were observed. Picrotoxin (0.25 and 0.50 mg/kg), flumazenil (10.0 mg/kg) and finasteride (100 mg/kg) antagonized the anxiolytic-like actions of MT in the burying behavior test. In the plus maze and hole-board tests bicuculline (2.0 mg/kg) blocked the effects of the plant as well. Atosiban (0.25 µg) did not antagonize the anxiolytic-like actions of MT. CONCLUSIONS: The results corroborate the anxiolytic-like actions of Montanoa tomentosa and suggest that this effect is mediated through GABAA receptors but not oxytocin receptors.

Exposure to toluene and stress during pregnancy impairs pups' growth and dams' lactation.

Inhalant misuse starts at an early age, and a large number of users are women in reproductive age. This study investigates whether exposure to toluene, a commonly misused solvent, alone or combined with restraint stress during pregnancy, produces adverse effects in pregnant mice and their offspring during lactation and adulthood. Pregnant animals were exposed to either 8000ppm toluene (30min/twice daily from gestational days 7-19), restraint stress (three times/day during the same gestation period) or both; control mice were only exposed to air. Our results show that toluene, stress and their combination reduced body weight gain in pregnant females without changing food consumption. In the offspring, all treatments resulted in low body weight at weaning, but with the toluene and stress combination this effect was seen from birth. Weight deficiency could not be attributed to poor maternal behavior during the first 3weeks of age, but to a reduction in pro-TRH mRNA expression in the hypothalamic paraventricular nucleus and serum prolactin levels in dams. After weaning, pups that were subjected to toluene and stress during gestation had lower body weight and ate less than control animals. In conclusion, the combined exposure to toluene and stress during pregnancy lead to more pronounced effects in dams and longer-lasting actions in pups than exposure to either toluene or stress.