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Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.

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The pedunculopontine tegmentum (PPTg) plays a role in processing multiple sensory inputs and innervates brain regions associated with reward‐related behaviors. The urotensin II receptor, activated by the urotensin II peptide (UII), is selectively expressed by the cholinergic neurons of the PPTg. Although the exact function of cholinergic neurons of the PPTg are unknown, they are thought to modify the perception of reward magnitude or salience detection. We hypothesized that the activation of PPTg cholinergic neurons would alter sensory processing across multiple modalities (ex. taste and hearing). Here we had three aims: first, determine if cholinergic activation is involved in consumption behavior. Second, if so, distinguish the impact of the caloric value by using saccharin, a zero calorie sweetener. Lastly, we tested the perception of acoustic stimuli by measuring the acoustic startle reflex (ASR).Male Sprague‐Dawley rats were bilaterally cannulated into the PPTg, then housed in a contact lickometer and placed under food restriction lasting the entire consumption experiment (water ad lib.). The lickometer recorded each individual lick to give insight into the microstructure of the consumption behavior. Treatment consisted of a microinjection of either 1 μL of aCSF or 1 μL of 10 μM UII into the PPTg, and the rats were immediately given access to either sucrose or saccharin. For the remaining five days rats were allowed one hour access per day to the same sweet solution without any further treatments. ASR testing consisted of a baseline (no treatment), treatment day, and two additional days (no treatment). Immediately following the microinjection of UII, consumption of both saccharin and sucrose increased compared to controls. The significant difference in sucrose consumption lasted two days post‐treatment while saccharin consumption was significantly different for three days after treatment. The ASR was significantly increased the day after treatment in the rats treated with UII.Activating cholinergic PPTg neurons may lead to a miscalculation of the salience of external stimuli, implicating the importance of cholinergic input in modulating a variety of behaviors. This potential plastic change can give rise to further studies in the role of sensory processing on reward related‐behaviors at the level of the PPTg cholinergic neurons.Support or Funding InformationThe Howard T. Blane Director's Award in the Addictions (BDAA) from Research Institute on AddictionThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In recent years, cannabinoid subtype 1 receptor (CB1R) antagonists have been developed to treat obesity and metabolic syndrome. Unfortunately, rimonabant (SR141716A) the first marketed drug produced CNS‐related adverse effects including depression and suicidal ideation and was withdrawn from the market. Recent data suggest that blockade of peripheral CB1R receptors can mitigate symptoms associated with metabolic syndrome independent of CNS effects. Therefore, CNS‐sparing CB1R antagonists that have limited transport across the blood‐brain‐barrier are under development. We have developed several potent, selective and drug‐like small molecule inverse agonists of CB1R with vastly reduced brain exposure (e.g. RTI‐1092915). As part of an integrated drug discovery program it was deemed prudent to evaluate lead compounds for evidence of possible neuropsychiatric side effects.First, a behavioral battery was performed in rats to assess the effects of rimonabant after acute and chronic dosing regimens. Rimonabant (vehicle, 3, 10 mg/kg) was administered i.p. 30 minutes prior to the simultaneous assessment of locomotor activity, grooming, feeding, and defecation. Rimonabant significantly decreased food consumption, decreased measures of locomotor activity, increased scratching and wet‐dog shakes, and increased defecation. Subsequently, animals were dosed daily but were always tested in a drug‐free state, as not to test the acute effects of the drug on top of the background of chronic dosing. The highest dose of rimonabant tested significantly decreased marble burying behavior, presumably anxiolysis, while there were trends for anxiogenic effects in the light‐dark box. In an attempt to clarify these results, behavioral tests including forced swim test and preference in two‐bottle choice for sucrose were performed, however there was no effect of treatment. Chronic treatment with rimonabant also significantly attenuated weight gain in these animals despite having ad libitum food.A similar battery of behaviors was performed to directly compare rimonabant (10 mg/kg) to RTI‐ 1092915 (3 mg/kg; a dose previously shown to reduce alcoholic steatosis). There were no significant effects with RTI‐1092915 while rimonabant again acutely decreased food intake, weight gain and locomotor activity. The chronic dosing of rimonabant, but not RTI‐1092915, significantly decreased time spent near an intruder animal in a social interaction paradigm.Our preliminary data suggests that certain behaviors, either after acute or chronic dosing, could be used to distinguish peripherally restricted and CNS penetrant CB1R antagonists. Specifically, social interaction could be used to assess the negative impact of chronic treatment with centrally‐acting CB1R antagonists. Finally, RTI‐1092915 shows no or mitigated negative effects in the behaviors tested. Therefore, RTI‐1092915 may be a lead candidate to treat metabolic syndrome and liver diseases through inhibition of peripheral CB1R receptors.Support or Funding InformationNIH DK100414, AA023256This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.