Profiling of behavioral effects evoked by ketamine and the role of 5HT2 and D2 receptors in ketamine-induced locomotor sensitization in mice

Galvanho, Jefferson P.; Manhães, Alex C.; Carvalho-Nogueira, Ana Cristina C.; Silva, Joyce de M.; Filgueiras, Cláudio C.; Abreu‐Villaça, Yael

doi:10.1016/j.pnpbp.2019.109775

Cited by 13 publications

(8 citation statements)

References 92 publications

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“…2B), consistent with our conclusion that the restoration of reward behavior by psilocybin was independent of 5-HT2AR activation. As in previously published reports (6,20), pretreatment with ketanserin induced hypolocomotion, directly and/or by enhancing the effects of psilocybin (SI Appendix, Fig. S2), confirming its activity at the given dose.…”

Section: Neurosciencesupporting

confidence: 88%

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Hesselgrave

Troppoli

Wulff

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

234

145

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Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus—a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. We conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR–independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.

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Section: Neurosciencesupporting

confidence: 88%

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Hesselgrave

Troppoli

Wulff

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

234

145

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“…Previous studies have found that repeated ketamine with 20 or 30 mg/kg (i.p.) could induce locomotor sensitization in rats 32,33 . Our results showed 2‐FDCK increased locomotor activity on the first day and induced expression of locomotor sensitization following the 2 weeks of withdrawal with the dose of 30 mg/kg, which was similar to ketamine.…”

Section: Discussionsupporting

confidence: 64%

2‐Fluorodeschloroketamine has similar abuse potential as ketamine

et al. 2022

Addiction Biology

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2‐Fluorodeschloroketamine (2‐FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2‐FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2‐FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self‐administration and drug discrimination using ketamine as a reference. 2‐FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2‐FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2‐FDCK and ketamine induced locomotor sensitization after withdrawal. 2‐FDCK readily induced self‐administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2‐FDCK dose‐dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2‐FDCK has an abuse potential comparable with ketamine.

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“…To delineate changes in the lipidome of the brain after ketamine exposure, we initially performed untargeted lipidomic analysis of the brains of mice that received an intraperitoneal (i. p.) injection of 15 mg/kg ketamine or saline for 7 consecutive days. The dose of 15 mg/kg ketamine in mice is almost equivalent to recreational use in humans and is similar to the dose applied in other animal studies [29][30][31] . The PFC, nucleus accumbens (NAc), CPu (dorsal striatum), and hippocampus (Hipp), which are critically involved in various stages of the addiction cycle 32 , were collected for untargeted lipidomic analysis using liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS).…”

Section: Resultsmentioning

confidence: 54%

Endocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice

Wang

et al. 2020

Nat Commun

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The abuse potential of ketamine limits its clinical application, but the precise mechanism remains largely unclear. Here we discovered that ketamine significantly remodels the endocannabinoid-related lipidome and activates 2-arachidonoylglycerol (2-AG) signaling in the dorsal striatum (caudate nucleus and putamen, CPu) of mice. Elevated 2-AG in the CPu is essential for the psychostimulant and reinforcing effects of ketamine, whereas blockade of the cannabinoid CB1 receptor, a predominant 2-AG receptor, attenuates ketamine-induced remodeling of neuronal dendrite structure and neurobehaviors. Ketamine represses the transcription of the monoacylglycerol lipase (MAGL) gene by promoting the expression of PRDM5, a negative transcription factor of the MAGL gene, leading to increased 2-AG production. Genetic overexpression of MAGL or silencing of PRDM5 expression in the CPu robustly reduces 2-AG production and ketamine effects. Collectively, endocannabinoid signaling plays a critical role in mediating the psychostimulant and reinforcing properties of ketamine.

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Profiling of behavioral effects evoked by ketamine and the role of 5HT2 and D2 receptors in ketamine-induced locomotor sensitization in mice

Cited by 13 publications

References 92 publications

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

2‐Fluorodeschloroketamine has similar abuse potential as ketamine

Endocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice

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