2-Deoxy-D-glucose prevents and nicotinamide potentiates 3, 4-methylenedioxymethamphetamine-induced serotonin neurotoxicity

Neurotoxicity induced by different substituted amphetamines has been associated with the exhaustion of intracellular energy stores. Accordingly, we examined the influence of 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glucose uptake and metabolism, and nicotinamide, an agent that improves energy metabolism, on 3, 4-methylenedioxymethamphetamine (MDMA)-induced 5-hydroxytryptamine (5-HT; serotonin) deficits. Administration of MDMA (15 mg/kg i.p.) produced a significant hyperthermia, whereas 2-DG caused a profound hypothermia that lasted throughout the experiment. When MDMA was given to 2-DG-treated rats, an immediate but transient hyperthermia occurred and was followed by a return to hypothermia. 2-DG had no effect on 5-HT concentrations in the frontal cortex, hippocampus, and striatum but prevented the neurotoxicity induced by MDMA. When rats were injected with 2-DG/MDMA and were warmed to prevent hypothermia, the protection afforded by 2-DG was abolished. Nicotinamide had no effect on body temperature of the rats, and the hyperthermia induced by the nicotinamide/MDMA treatment was similar to that of the saline/MDMA-treated rats. However, the long-term 5-HT deficits induced by MDMA were potentiated by nicotinamide in all the brain regions examined. Finally, no change on ATP concentrations in the frontal cortex, hippocampus, and striatum was observed up to 3 h after a single dose of MDMA. These results suggest that an altered energy metabolism is not the main cause of the neurotoxic effects induced by MDMA.     

Effects of chronic maternal stress on hypothalamo-pituitary-adrenal (HPA) function and behavior: no reversal by environmental enrichment

Maternal stress during pregnancy is linked to increased risk for impaired behavioral and emotional development and affective disorders in children. In animal models, acute periods of prenatal or postnatal stress have profound effects on HPA function and behavior in adult offspring. However, few animal studies have determined the impact of chronic exposure to stress throughout the perinatal period. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on HPA function, locomotor behavior and prepulse inhibition in adult guinea pig offspring, as well as to determine whether environmental enrichment (EE) could reverse the effects of CMS. Guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). Following weaning, offspring were housed in either standard conditions or EE. In both adult male and female offspring, there was no effect of CMS on basal or activated HPA function. CMS significantly increased locomotor activity in an open-field in male offspring, though no effect was observed in females. In female offspring, CMS disrupted PPI; however there was no effect on male PPI. EE had a number of effects on HPA function and behavior but in most cases these were independent of the influence of CMS. EE significantly elevated basal cortisol levels in male offspring at pnd70, whereas in female offspring, EE interacted with CMS to elevate basal cortisol levels from pnd35 to pnd70. In female offspring, EE decreased locomotor activity. In males, EE enhanced PPI; however in female offspring EE disrupted PPI. In conclusion, while CMS had minimal effects on HPA function, there were significant long-term sex-specific effects on behavior. EE did not reverse the effects observed as a result of CMS, but rather modified HPA function and behavior independently of CMS. Further, there was significant interaction of CMS with EE that resulted in elevation of basal HPA function in female offspring. These data, combined with previous studies from our laboratory, suggest that acute phases of maternal stress in late pregnancy may have greater long-term effects on HPA function and related behaviors than prolonged chronic maternal stress.     

Effects of chronic maternal stress on hypothalamo–pituitary–adrenal (HPA) function and behavior: No reversal by environmental enrichment

Maternal stress during pregnancy is linked to increased risk for impaired behavioral and emotional development and affective disorders in children. In animal models, acute periods of prenatal or postnatal stress have profound effects on HPA function and behavior in adult offspring. However, few animal studies have determined the impact of chronic exposure to stress throughout the perinatal period. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on HPA function, locomotor behavior and prepulse inhibition in adult guinea pig offspring, as well as to determine whether environmental enrichment (EE) could reverse the effects of CMS. Guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). Following weaning, offspring were housed in either standard conditions or EE. In both adult male and female offspring, there was no effect of CMS on basal or activated HPA function. CMS significantly increased locomotor activity in an open-field in male offspring, though no effect was observed in females. In female offspring, CMS disrupted PPI; however there was no effect on male PPI. EE had a number of effects on HPA function and behavior but in most cases these were independent of the influence of CMS. EE significantly elevated basal cortisol levels in male offspring at pnd70, whereas in female offspring, EE interacted with CMS to elevate basal cortisol levels from pnd35 to pnd70. In female offspring, EE decreased locomotor activity. In males, EE enhanced PPI; however in female offspring EE disrupted PPI. In conclusion, while CMS had minimal effects on HPA function, there were significant long-term sex-specific effects on behavior. EE did not reverse the effects observed as a result of CMS, but rather modified HPA function and behavior independently of CMS. Further, there was significant interaction of CMS with EE that resulted in elevation of basal HPA function in female offspring. These data, combined with previous studies from our laboratory, suggest that acute phases of maternal stress in late pregnancy may have greater long-term effects on HPA function and related behaviors than prolonged chronic maternal stress.     

THC Prevents MDMA Neurotoxicity in Mice

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB₁ receptor antagonist AM251 and the CB₂ receptor antagonist AM630, as well as in CB₁, CB₂ and CB₁/CB₂ deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB₁ receptor antagonist AM251, neither in CB₁ and CB₁/CB₂ knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB₂ cannabinoid antagonist and in CB₂ knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB₁ receptor, although CB₂ receptors may also contribute to attenuate neuroinflammation in this process.     

Behavioral deficits induced by lead exposure are accompanied by serotonergic and cholinergic alterations in the prefrontal cortex

The effects of long-term lead (Pb) exposure producing a blood Pb concentration of lower than 20 μg/dL, i.e. below that associated with overt neurological deficits in occupationally exposed individuals, was studied in adult rats. In order to assess gender differences, we performed parallel behavioral experiments in male and female rats. Exposure to Pb acetate (50 ppm in drinking water) for 6 months induced motor and cognitive alterations, however these effects were gender- and task-dependent. Chronic lead exposure impaired spatial learning assessed in the Morris water maze test (MWM) in both genders, whereas it only induced hyperactivity in the open field and impaired motor coordination in the rotarod test, only in male rats. Hyperactivity in male rats was accompanied by an increase in extracellular level of acetylcholine in the prefrontal cortex. Extracellular dopamine concentration in the prefrontal cortex was unaffected by lead exposure whereas serotonin concentration in the same brain area was significantly decreased in both male and female rats exposed to lead. These results unveil new molecular mechanisms underlying neuropsychiatric alterations induced by chronic lead exposure.     

Abnormal social behaviors in mice lacking Fgf17

The fibroblast growth factor family of secreted signaling molecules is essential for patterning in the central nervous system. Fibroblast growth factor 17 (Fgf17) has been shown to contribute to regionalization of the rodent frontal cortex. To determine how Fgf17 signaling modulates behavior, both during development and in adulthood, we studied mice lacking one or two copies of the Fgf17 gene. Fgf17-deficient mice showed no abnormalities in overall physical growth, activity level, exploration, anxiety-like behaviors, motor co-ordination, motor learning, acoustic startle, prepulse inhibition, feeding, fear conditioning, aggression and olfactory exploration. However, they displayed striking deficits in several behaviors involving specific social interactions. Fgf17-deficient pups vocalized less than wild-type controls when separated from their mother and siblings. Elimination of Fgf17 also decreased the interaction of adult males with a novel ovariectomized female in a social recognition test and reduced the amount of time opposite-sex pairs spent engaged in prolonged, affiliative interactions during exploration of a novel environment. After social exploration of a novel environment, Fgf17-deficient mice showed less activation of the immediate-early gene Fos in the frontal cortex than wild-type controls. Our findings show that Fgf17 is required for several complex social behaviors and suggest that disturbances in Fgf17 signaling may contribute to neuropsychiatric diseases that affect such behaviors.     

An analysis of spontaneous behavior following acute MDMA treatment in male and female rats

3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused drug that impairs behavioral, emotional and cognitive functions in humans and animals. The aim of this study was to evaluate MDMA effects on the spontaneous behavioral repertoire of rats with a focus on the gender differences. MDMA was given subcutaneously in a single dose of 2.5, 5 and 10 mg/kg and the spontaneous behavior of male and female rats was studied using the open field test. Behavioral patterns (locomotion, rearing, floor-sniffing, air-sniffing, grooming, immobility and stereotypy) were registered in two sessions - 30 and 60 min following MDMA administration; each session lasting 5 min. We found that MDMA totally disrupted the structure and timing of spontaneous behavioral patterns in both genders; no evident differences were measured between either of the sessions. MDMA irrespective of the dosage produced hyperlocomotion, excessive floor-sniffing and almost absolute suppression of grooming and immobility. A biphasic effect of MDMA was found in rearing. Gender differences were present namely in rearing and sniffing stereotypy. This study also confirms that behavioral experiments should focus on more behavioral elements than only on e.g. locomotion and that the observer-based approach still gives the most reliable results.     

The effects of neonatal saline injections on behaviours in DBA/2 male mice

DBA/2 male mice were exposed to the injections of the saline (0.01 ml/g i.p.) on 1-th, 3-th, 5-th, 7-th, 9-th days after birth. Intact males were used as a control group. Adult saline-treated males displayed the increased number of crossed squares, entries in the centre and time spent in the centre during the open "field" test in comparison with intact animals. The time spent in the light compartment of the light-dark box was decreased in saline treated mice compared with intact animals. During the test of acoustic startle response the magnitude of startle reflex and prepulse inhibition didn't change the startle reflex. Saline administration in males did not affect corticosterone basal level. Sexual motivation was revealed to decrease in saline treated males. These data suggest that neonatal administration of saline induced a stable behavioral syndrome in adult DBA/2 male mice: hyperactivity, a decrease of open space fear and simultaneously an increase of some indices of anxiety.     

Verbal Memory Deficits Are Correlated with Prefrontal Hypometabolism in 18FDG PET of Recreational MDMA Users

Introduction

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users.

Methods

Brain glucose metabolism in rest was assessed using 2-deoxy-2-(¹⁸F)fluoro-D-glucose positron emission tomography (¹⁸FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. ¹⁸FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test.

Results

As previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex.

Conclusions

Verbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.     

四氧嘧啶诱发糖尿病模型效果的性别差异

目的了解性别因素对四氧嘧啶诱发糖尿病动物模型的影响,为提高动物模型的复制效率提供实验依据。方法分别给雌、雄比格犬和昆明小鼠注射不同剂量的四氧嘧啶,药后3、7、14、21 d测定血糖值,同时统计实验期间动物的死亡情况。结果给予同等剂量的四氧嘧啶,雌性比雄性动物的血糖升高更快,浓度更高。雌性犬四氧嘧啶的最适造模剂量为40 mg/kg,而雄性犬在此剂量下的模型成功率只有40%,二者差异极显著（70%VS40%,P〈0.01）;雄性犬的最适使用剂量为50 mg/kg,但在此剂量下有高达30%的雌性犬因高血糖而死亡。四氧嘧啶对小鼠的影响与犬基本一致,雌雄鼠的最佳剂量分别为200 mg/kg和250 mg/kg。结论雌性动物对四氧嘧啶的敏感性较雄性动物高,雄性动物在使用四氧嘧啶复制糖尿病模型时,其剂量通常需要较雌性动物高20%左右。     

Ketamine pretreatment exacerbated 3,4-methylenedioxymethamphetamine-induced central dopamine toxicity

Currently, joint use of ketamine and 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) represents a specific combination of polydrug abuse. Long-lasting and even aggravated central neuronal toxicity associated with mixing ketamine and MDMA use is of special concern. This study was undertaken to examine the modulating effects of ketamine treatment on later MDMA-induced dopamine and serotonin neurotoxicity. We found that repeated administration of ketamine (50 mg/kg x 7) at 1.5-h intervals did not render observable dopamine or serotonin depletion in catecholaminergic target regions examined. In contrast, three consecutive doses of MDMA (20 mg/kg each) at 2-h intervals produced long-lasting dopamine and serotonin depletions in striatum, nucleus accumbens and prefrontal cortex. More importantly, pretreatment with binge doses of ketamine (50 mg/kg x 7 at 1.5-h intervals) 12 h prior to the MDMA dosing regimen (20 mg/kg x 3 at 2-h intervals) aggravated the MDMA-induced dopaminergic toxicity. Nonetheless, such binge doses of ketamine treatment did not affect MDMA-induced serotonergic toxicity. These results, taken together, indicate that binge use of ketamine specifically enhances the MDMA-induced central dopaminergic neurotoxicity in adult mouse brain.     

The effect of chronic prepubertal administration of marihuana (delta-9-tetrahydrocannabinol) on the onset of puberty and the postpubertal reproductive functions in female rats

The effect of the main psychoactive component of marihuana, delta-9-tetrahydrocannabinol (THC) was investigated on the onset of puberty and on the reproductive function in female rats up to the seventy-fifth to eightieth day of life. The drug was administered i.p. at a dose of 1 microgram/kg/day between the twenty-second postnatal day and the day of vaginal opening (V.O.). The administration of THC caused a 2-day delay in V. O., and the number of ova on the day of first estrus was significantly lower in treated rats than in controls. No differences were observed in serum gonadotropin and prolactin (PRL) levels on the day of V. O. After puberty, alterations occurred in the neuroendocrine functions of animals receiving THC that persisted until adulthood: estrous cycles were irregular, the number of ova in animals killed 35-40 days after V. O. was reduced, and serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were decreased (diminution of serum FSH content was less expressed). An increase in serum PRL concentration could be demonstrated only in animals killed on the day of estrus. From these results, it might be concluded that THC administered to prepubertal rats--even in a very low dose--causes long-term irreversible alterations in reproductive functions. The importance of the fight against drug abuse is emphasized.     

Antioxidant effect of tetrahydrocurcumin in streptozotocin-nicotinamide induced diabetic rats

Oxidative stress has been suggested to be a contributory factor in development and complication of diabetes. In the present study, we have investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites of curcumin on antioxidants status in streptozotocin-nicotinamide induced diabetic rats. Oral administration of THC at 80 mg/kg body weight of diabetic rats for 45 days resulted in significant reduction in blood glucose and significant increase in plasma insulin levels. In addition, THC caused significant increase in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, reduced glutathione, vitamin C and vitamin E in liver and kidney of diabetic rats with significant decrease in thiobarbituric acid reactive substances (TBARS) and hydroperoxides formation in liver and kidney, suggesting its role in protection against lipid peroxidation induced membrane damage. These biochemical observations were supplemented by histopathological examination of liver and kidney section. The antidiabetic and antioxidant effects of THC are more potent than those of curcumin at the same dose. Results of the present study indicated that THC showed antioxidant effect in addition to its antidiabetic effect in type 2 diabetic rats.     

Sexual differentiation of mammalian frontal cortex

The pattern of distribution of the progesterone binding sites was examined in selected nuclei of the brain of male and female rat. In female rats the frontal cortex resulted to be the region with the highest concentration of 3H R5020 binding sites. However, in male rats the same region showed very little progestin binding activity. When female rats were androgenized via neonatal exposure to testosterone, the progestin binding activity of the frontal cortex became similar to that we observed in male rats. The present investigation indicates that sexual differentiation of the rat brain may include also brain regions not clearly involved in sex related functions like the frontal cortex.     

Evidence for a role of Hsp70 in the neuroprotection induced by heat shock pre-treatment against 3,4-methylenedioxymethamphetamine toxicity in rat brain

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') produces acute hyperthermia which increases the severity of the selective serotoninergic neurotoxicity produced by the drug in rats. Heat shock protein 70 (Hsp70) is a major inducible cellular protein expressed in stress conditions and which is thought to exert protective functions. MDMA (12.5 mg/kg, i.p.), given to rats housed at 22 degrees C, produced an immediate hyperthermia and increased Hsp70 in frontal cortex between 3 h and 7 days after administration. MDMA, given to rats housed at low ambient temperature (4 degrees C) produced transient hypothermia followed by mild hyperthermia but no increase in Hsp70 expression, while rats treated at elevated room temperature (30 degrees C) showed enhanced hyperthermia and similar expression of Hsp70 to that seen in rats housed at 22 degrees C. Fluoxetine-induced inhibition of 5-HT release and hydroxyl radical formation did not modify MDMA-induced Hsp70 expression 3 h later. Four- or 8-day heat shock (elevation of basal rectal temperature by 1.5 degrees C for 1 h) or geldanamycin pre-treatment induced Hsp70 expression and protected against MDMA-induced serotoninergic neurotoxicity without affecting drug-induced hyperthermia. Thus, MDMA-induced Hsp70 expression depends on the drug-induced hyperthermic response and not on 5-HT release or hydroxyl radical formation and pre-induction of Hsp70 protects against the long-term serotoninergic damage produced by MDMA.     

Methylenedioxymethamphetamine (MDMA; Ecstasy) suppresses IL-1beta and TNF-alpha secretion following an in vivo lipopolysaccharide challenge

In this study we examined the effects of methylenedioxymethamphetamine (MDMA) administration on responsiveness to an in vivo immune challenge with lipopolysaccharide (LPS; 100 microg/kg; i.p.). LPS produced an increase in circulating IL-1beta and TNF-alpha in control animals. MDMA (20 mg/kg; i.p.) significantly impaired LPS-induced IL-1beta and TNF-alpha secretion. The suppressive effect of MDMA on IL-1beta secretion was transient and returned to control levels within 3 hours of administration. In contrast, the MDMA-induced suppression of TNF-alpha secretion was evident for up to 12 hours following administration. In a second study we examined the effect of co-administration of MDMA (5, 10 and 20 mg/kg; i.p.) on LPS-induced IL-1beta and TNF-alpha secretion, and demonstrated that all three doses potently suppressed LPS-induced TNF-alpha secretion, but only MDMA 10 and 20 mg/kg suppressed LPS-induced IL-1beta secretion. In addition, serum MDMA concentrations displayed a dose-dependent increase, with the concentrations achieved following administration of 5 and 10 mg/kg being in the range reported in human MDMA abusers. In order to examine the possibility that the suppressive effect of MDMA on IL-1beta and TNF-alpha could be due to a direct effect of the drug on immune cells, the effect of in vitro exposure to MDMA on IL-1beta and TNF-alpha production in LPS-stimulated diluted whole blood was evaluated. However IL-1beta or TNF-alpha production were not altered by in vitro exposure to MDMA. In conclusion, these data demonstrate that acute MDMA administration impairs IL-1beta and TNF-alpha secretion following an in vivo LPS challenge, and that TNF-alpha is more sensitive to the suppressive effects of MDMA than is IL-1beta. However the suppressive effect of MDMA on IL-1beta and TNF-alpha could not be attributed to a direct effect on immune cells. The relevance of these findings to MDMA-induced immunomodulation is discussed.     

Prenatal Stress Enhances Excitatory Synaptic Transmission and Impairs Long-Term Potentiation in the Frontal Cortex of Adult Offspring Rats

The effects of prenatal stress procedure were investigated in 3 months old male rats. Prenatally stressed rats showed depressive-like behavior in the forced swim test, including increased immobility, decreased mobility and decreased climbing. In ex vivo frontal cortex slices originating from prenatally stressed animals, the amplitude of extracellular field potentials (FPs) recorded in cortical layer II/III was larger, and the mean amplitude ratio of pharmacologically-isolated NMDA to the AMPA/kainate component of the field potential—smaller than in control preparations. Prenatal stress also resulted in a reduced magnitude of long-term potentiation (LTP). These effects were accompanied by an increase in the mean frequency, but not the mean amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in layer II/III pyramidal neurons. These data demonstrate that stress during pregnancy may lead not only to behavioral disturbances, but also impairs the glutamatergic transmission and long-term synaptic plasticity in the frontal cortex of the adult offspring.     

Effects of repeated doses of MDMA ("ecstasy") on cell-mediated immune response in humans.

Cell-mediated immune response after the administration of two repeated doses of 100 mg 3,4-methylenedioxymethamphetamine (MDMA) at 4-hour and 24-hour intervals was evaluated in two randomised, double-blind and cross-over clinical trials conducted in healthy male MDMA consumers. MDMA produced a time-dependent decrease in the CD4/CD8 T-cell ratio due to a decrease in the number of CD4 T-helper cells, a decrease in the functional responsiveness of lymphocytes to mitogenic stimulation, and a simultaneous increase in natural killer cells. In case of two 100 mg MDMA doses given 4 hour apart, immune alterations produced by the first dose were strengthened by the second one. At 24 hours after treatment, statistically significant residual effects were observed for all the altered immune parameters after the administration of two MDMA doses if compared to single dose and placebo. In the second clinical trial, the second 100 mg MDMA dose given 24 hours after the first dose produced immunological changes significantly greater than those induced by the initial drug administration and which seemed to show a delayed onset. Significant residual effects were observed for all the immune parameters as late as 48 hours after the second dose. These results show that repeated administration of MDMA with both a short and a long time interval between doses extends the critical period following MDMA administration, already observed after a single dose, in which immunocompetence is severely compromised.     

Preferential Potentiation of the Effects of Serotonin Uptake Inhibitors by 5-HT1A Receptor Antagonists in the Dorsal Raphe Pathway: Role of Somatodendritic Autoreceptors

Abstract: 5-HT_1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HT_ext) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT_1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HT_ext during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 µmol/L citalopram in the dorsal or median raphe nucleus reduced 5-HT_ext in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HT_ext induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT_1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT_1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.