The cannabinoid receptor 2 agonist, ß-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice.

Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. ß-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load. In this study, we assessed changes in circulating cytokines across the lifespan, memory performance in young and aged mice, and the effects of BCP on memory function and cytokine load. The plasma levels of 12 cytokines were assessed in male Swiss-Webster mice at 3, 12, and 18 months of age using multiplexed flow cytometry. Working memory was compared in 3 and 12 month-old mice using spontaneous alternations. A dose-response function (100-300 mg/kg, subchronic administration) for BCP-induced memory restoration was determined in 3- and 12- month-old mice. Finally, the effects on cytokine levels of the peak memory enhancing dose of BCP were assessed in 18- month-old mice. Circulating levels of several cytokines significantly increased with age. Multilinear regression analysis showed that IL-23 levels were most strongly associated with age. Aged mice showed deficits in working memory and higher levels of IL-23, both of which were reversed by BCP treatment. BCP appears to reverse age-associated impairments in memory and modulates cytokine production. IL-23 may play a significant role in the aging process, and future research should determine whether it has utility as a biomarker for novel anti-aging therapeutics.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo.

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Effects of the second-generation "bath salt" cathinone alpha-pyrrolidinopropiophenone (α-PPP) on behavior and monoamine neurochemistry in male mice.

RATIONALE: Synthetic cathinones ("bath salts") are ß-ketone analogs of amphetamines, yet few studies have examined their potential neurotoxic effects. OBJECTIVE: In the current study, we assessed the persistent behavioral and neurochemical effects of exposure to the second-generation synthetic cathinone α-pyrrolidinopropiophenone (α-PPP). METHODS: Male, Swiss-Webster mice were exposed to α-PPP (80 mg/kg) using a binge-like dosing regimen (QID, q2h). Behavior was assessed 4-5 days after the dosing regimen, and neurochemistry was assessed the following day. Behavior was studied using the elevated plus maze, Y-maze, and novel object recognition tests. Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography. Additional experiments assessed the time courses of the effects of α-PPP on locomotor activity and core temperature using telemetry. RESULTS: Exposure to α-PPP significantly impaired performance in the Y-maze, decreased overall exploratory activity in the novel object recognition test, and resulted in regionally specific depletions in monoamine neurochemistry. In contrast, it had no significant effect on elevated plus maze performance or object discrimination in the novel object recognition test. The locomotor-stimulant effects of α-PPP were comparable to cocaine (30 mg/kg), and α-PPP (80 mg/kg) did not induce hyperthermia. CONCLUSIONS: α-PPP exposure results in persistent changes in exploratory behavior, spatial working memory, and monoamine neurochemistry. This research highlights potential dangers of α-PPP, including potential neurotoxicity, and suggests that the mechanisms underlying the persistent untoward effects of the cathinones may be distinct from those of the amphetamines.