RTI-263, a biased neuropeptide S receptor agonist that retains an anxiolytic effect, attenuates cocaine-seeking behavior in rats.

Neuropeptide S (NPS) is a neuromodulatory peptide that acts via a G protein-coupled receptor. Centrally administered NPS suppresses anxiety-like behaviors in rodents while producing a paradoxical increase in arousal. In addition, NPS increases drug-seeking behavior when administered during cue-induced reinstatement. Conversely, an NPS receptor (NPSR) antagonist, RTI-118, decreases cocaine-seeking behavior. A biased NPSR ligand, RTI-263, produces anxiolytic-like effects and has memory-enhancing effects similar to those of NPS but without the increase in arousal. In the present study, we show that RTI-263 decreased cocaine seeking by both male and female rats during cue-induced reinstatement. However, RTI-263 did not modulate the animals' behaviors during natural reward paradigms, such as palatable food intake, feeding during a fasting state, and cue-induced reinstatement of sucrose seeking. Therefore, NPSR biased agonists are a potential pharmacotherapy for substance use disorder because of the combined benefits of decreased drug seeking and the suppression of anxiety.

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression.

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.

Sex-based changes in rat brain serotonin and behavior in a model of altitude-related vulnerability to treatment-resistant depression.

RATIONALE: Rates of depression and suicide increase with altitude. In our animal model, rats housed at moderate altitude vs. at sea level exhibit increased depressive symptoms in the forced swim test (FST) and lack of response to selective serotonin reuptake inhibitors (SSRIs). Depression and SSRI resistance are linked to disrupted serotonergic function, and hypobaric hypoxia may reduce the oxygen-dependent synthesis of serotonin. We therefore tested brain serotonin in rats housed at altitude. METHODS: Sprague-Dawley rats were housed at altitude (4,500 ft, 10,000 ft) vs. sea level for 7-36 days. Brain serotonin was measured by ELISA, or behavior evaluated in the FST, sucrose preference (SPT), or open-field tests (OFT). RESULTS: After 2 weeks at 4,500 ft or 10,000ft vs. sea level, serotonin levels decreased significantly at altitude in the female prefrontal cortex, striatum, hippocampus, and brainstem, but increased with altitude in the male hippocampus and brainstem. Female brain serotonin decreased from 7 to 36 days at 4,500 ft, but males did not vary. At 2 weeks and 24 days, females at altitude exhibit lower brain serotonin and increased depressive symptoms in the FST and SPT, with motor behavior unaltered. In males, serotonin, passive coping in the FST and OFT immobility increased with altitude at 2 weeks, but not at 24 days. Male SPT behavior did not change with altitude. CONCLUSIONS: Females may be more vulnerable to depressive symptoms at altitude, while males may be resilient. Chronic hypoxic stress at altitudes as low as 4,500 ft may cause a brain serotonin imbalance to worsen vulnerability to depression and SSRI resistance, and potentially worsen suicide risk.

Behavioral assessment of rimonabant under acute and chronic conditions.

Cannabinoid subtype 1 receptor (CB1R) antagonists were originally developed as anti-obesity agents. Unfortunately, SR1417116A (rimonabant), the first marketed inverse agonist of CB1R, produced CNS-related adverse effects including depression and suicidal ideation, and thus it was withdrawn from the market. These effects of rimonabant became evident in patients following chronic dosing. Standard preclinical toxicity studies failed to detect these adverse effects. The goal of these studies was to perform an integrated battery of behavioral assays to better understand the behavioral effects of rimonabant following both acute and chronic administration. In the present study, acute dosing with rimonabant in rats significantly decreased food consumption; decreased measures of locomotor activity; increased scratching, grooming and wet-dog shakes; and increased defecation. Subsequently, animals were tested using a chronic dosing regimen but prior to drug administration for that day. The highest dose of rimonabant tested significantly decreased marble burying behavior, presumably anxiolysis. There were also significant effects in social interaction after chronic dosing. Our results did not reveal significant rimonabant-induced anxiogenic behaviors. Future studies to characterize behavioral screens for anxiogenic effects of CB1 antagonists in rodents should further explore social interaction paradigms and potential comorbid factors of rimonabant dosing such as sex, age, and obesity.

Microinjection of urotensin II into the pedunculopontine tegmentum leads to an increase in the consumption of sweet tastants.

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 is unknown, they are thought to contribute to 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 of palatable solutions (sucrose). Second, if so, distinguish the impact of the caloric value by using saccharin, a zero calorie sweetener. Lastly, we tested the UII-mediated effects on perception of acoustic stimuli by measuring acoustic startle reflex (ASR). Male Sprague-Dawley rats were bilaterally cannulated into the PPTg, then placed under food restriction lasting the entire consumption experiment (water ad lib.). 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. During the saccharin experiment rats were tested in a contact lickometer which recorded each individual lick to give insight into the microstructure of the consumption behavior. 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. This significant increase persisted for days after the single administration of UII, but there was no generalized arousal or increase in water consumption between testing sessions. The effects on ASR were not significant. 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. The long-lasting effects seen after UII treatment support further research into the role of sensory processing on reward related-behaviors at the level of the PPTg cholinergic neurons.