Effects of Sceletium tortuosum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Broad historical and current uses in addition to diverse activity on CNS targets may make Sceletium tortuosum a useful therapeutic in a variety of clinical settings. This study sought to more broadly characterize activity of Sceletium tortuosum and mesembrine in a number of common, rodent-based assays that model nociception, depression, anxiety, ataxia, and abuse liability. MATERIALS AND METHODS: Male Sprague-Dawley were administered Sceletium tortuosum extract products and behavioral responses were evaluated in the conditioned place preference (CPP), hot plate, forced swim, elevated plus, and rotarod tests. RESULTS AND CONCLUSIONS: Sceletium tortuosum does not cause preference or aversion in CPP. Mesembrine appears to have analgesic properties without abuse liabilities or ataxia. The Sceletium tortuosum fraction has antidepressant properties but does produce ataxia. The ataxia may limit its usefulness as an antidepressant unless the antidepressant activity is associated with one constituent and the ataxia is associated with a separate constituent.

The effect of Salvia divinorum and Mitragyna speciosa extracts, fraction and major constituents on place aversion and place preference in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Consumer use of botanicals has increased despite, in many instances, the paucity of research demonstrating efficacy or identifying liabilities. This research employed the place preference/aversion paradigm to characterize the psychoactive properties of Salvia divinorum extract (10, 30, 100mg/kg), salvinorin A (0.1, 0.3, 1.0mg/kg), Mitragyna speciosa MeOH extract (50, 100, 300 mg/kg), Mitragyna speciosa alkaloid-enriched fraction (12.5, 25, 75 mg/kg) and mitragynine (5, 10, 30 mg/kg) in rats. MATERIAL AND METHODS: Following apparatus habituation and baseline preference scores, male Sprague-Dawley rats were given eight counter-balanced drug versus vehicle conditioning trials followed by a preference test conducted under drug-free states. S(+)-amphetamine (1mg/kg) served as the positive control (in Exp. 2) and haloperidol (0.8, 1.0mg/kg) served as the negative control in both studies. RESULTS: Rats displayed place aversion to both Salvia divinorum and salvinorin A that exceeded that of haloperidol. Rats showed place preference to mitragynine that was similar to that of S(+)-amphetamine. This CPP effect was much less pronounced with the Mitragyna speciosa extract and its fraction. CONCLUSIONS: These findings suggest that both botanicals possess liabilities, albeit somewhat different, that warrant caution in their use.

In vitro structure-activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety-depression model.

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety-depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.

Strain vulnerability and resiliency in the chick anxiety-depression model.

Increasing research is focused on genetic contributions to variability in stress-related endophenotypes in humans and animal model simulations. The current study sought to identify strain vulnerabilities and resiliencies to an isolation-stressor in the chick anxiety-depression model. Nine different strains of socially raised chicks were tested in isolated or non-isolated conditions for 90 min in which distress vocalization (DVoc) rates were collected and then transformed to depression-like phase threshold (@ 25, 50, 75 and 95%) latencies. In general, chicks in the non-isolated condition displayed relatively low DVoc rates throughout the test session, despite some variability in initial rates. Chicks in the isolated condition displayed relatively high DVoc rates in the first 3 min, indicative of an anxiety-like state, which declined by approximately 50% within 10-25 min in all strains and remained stable thereafter, indicative of a depression-like state. Contrast effects revealed that, relative to all other strains, the Black Australorp strain displayed shorter and the Producrain displayed longer depression threshold latencies, respectively. Of the remaining strains, the Silver Laced Wyandotte displayed depression thresholds that best represent an intermediate stress response. These findings identify vulnerable and resilient strains for examining depression-related endophenotypes in the chick anxiety-depression model.

Brain-derived neurotrophic factor response in vulnerable and resilient genetic lines in the chick anxiety-depression model.

Altered BDNF-mediated synaptogenesis is a major contributor to stress-vulnerability and depression. This study sought to determine patterns of hippocampal BDNF expression in stress-vulnerable and -resilient strains in the chick anxiety-depression model. Socially raised Black Australorp and Production Red strains were tested at 5-6 days post hatch under either 30, 60, 90, or 120 min of social separation stress; chicks tested with 2 social companions for 120 min served as controls. Distress vocalizations were recorded throughout the test session and latency to behavioral despair calculated. Following tests, bilateral hippocampal sections were harvested and analyzed via ELISA for BDNF levels. Black Australorps had shorter latencies to behavioral despair than Production Reds reflecting greater stress vulnerability. No differences were detected in BDNF levels between a No-Test and Social group within or between strains. The stress resilient Production Reds showed stable BDNF levels across the isolation test period whereas the vulnerable Black Australorps showed an increase in hippocampal BDNF levels that peaked at 90 min and declined thereafter. These findings fit well with the notion that strain-dependent stress-vulnerability reflects, in part, poor homeostatic mechanisms controlling synaptogenesis.