Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 hrs for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERTir), and the reduction in SERTir also was completely attenuated in MDMA preconditioned animals. Preconditioning with MDMA (10 mg/kg, i.p.) daily for 4 days provided neuroprotection against methamphetamineinduced 5-HT depletion, but not DA depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA induced hyperthermia in rats previously exposed to MDMA contributes towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute toward neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT produced by subsequent MDMA administration. The mechanisms underlying preconditioninginduced neuroprotection for MDMA remain to be determined.

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a popular drug of abuse with well-documented acute effects on serotonergic, dopaminergic, and cholinergic transmitter systems, as well as evidence of long-term disruption of serotoninergic systems in the rat brain. Recently, it was demonstrated that MDMA evokes a delayed and sustained increase in glutamate release in the hippocampus. The purpose of the present study was to determine the role of inflammatory mediators in the MDMA-induced increase in glutamate release, as well as the contribution of inflammatory pathways in the persistent neurochemical toxicity associated with repeated MDMA treatment. Treatment with the non-selective cyclooxygenase (COX) inhibitor ketoprofen and the COX-2 selective inhibitor nimesulide attenuated the increase in extracellular glutamate in the hippocampus evoked by repeated MDMA exposure (10 mg/kg, i.p., every 2 h); no attenuation was observed in rats treated with the COX-1 selective inhibitor piroxicam. Reverse dialysis of a major product of COX activity, prostaglandin E2, also resulted in a significant increase in extracellular glutamate in the hippocampus. Repeated exposure to MDMA diminished the number of parvalbumin-positive GABA interneurons in the dentate gyrus of the hippocampus, an effect that was attenuated by ketoprofen treatment. However, COX inhibition with ketoprofen did not prevent the long-term depletion of 5-HT in the hippocampus evoked by MDMA treatment. These data are supportive of the view that cyclooxygenase activity contributes to the mechanism underlying both the increased release of glutamate and decreased number of GABA interneurons in the rat hippocampus produced by repeated MDMA exposure.

Background: Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine. Methods: Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels. Results: Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats. Conclusions: Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain.

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3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse world-wide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. While MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT.

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

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