A rapid method for evaluating the behavioral effects of phencyclidine-like dissociative anesthetics in mice

Abstract

A simple and rapid method for detecting the behavioral effects of phencyclidine and related dissociative anesthetics is described. Dissociative anesthetics such as phencyclidine (PCP) and dizolcipine, which bind with high affinities at N-methyl-D-aspartate (NMDA) coupled cation channels ("PCP receptors"), produced a dose-related increase in the percentage of mice that fell from a 1.5 cm deep circular arena mounted on a 60 cm platform. A similar behavior was not manifest by other classes of compounds examined including competitive NMDA antagonists, an antagonist at strychnine-insensitive glycine receptors, and sigma-receptor ligands with moderate to low affinities for PCP receptors. Pretreatment of mice with glycine reduced in a dose-dependent manner the percentage of falls elicited by a maximally effective dose of dizolcipine. This simple procedure may prove useful for both the rapid detection of dissociative anesthetics and evaluation of putative PCP antagonists.

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition

“…We confirmed that the antidepressant-like action of 4-Cl-KYN in the acute FST involves the glycine B site, since pretreatment with glycine prevented the effects at the same dose shown to increase concentrations of glycine in the brain (albeit by less than a 2-fold difference) and to reverse the behavioral effects of NMDA channel blockers (Trullas and Skolnick, 1990;Evoniuk et al, 1991;Javitt et al, 1999). In support, no off-site receptor targets were identified by the extensive receptor screening performed (Supplemental Figs.…”

“…; Evoniuk et al (1991); Javitt et al (1999)]. Whereas glycine administration alone did not change immobility time of saline-treated animals in the FST, it prevented the antidepressant-like effects of 4-Cl-KYN (25 mg/kg) in this paradigm (Fig.…”

“…In a separate cohort of animals, glycine [1.6 g/kg, i.p. ; Evoniuk et al (1991); Javitt et al (1999)] was administered 10 minutes prior to injection of saline or 4-Cl-KYN. Since a leading hypothesis of ketamine antidepressant action involves the activation of AMPA receptors (Maeng et al, 2008;Li et al, 2010;Autry et al, 2011), we also assessed the role of this receptor in the antidepressant effects of 4-Cl-KYN by pretreatment with the AMPA receptor antagonist NBQX (10 mg/kg) 5 minutes prior to injection of saline, ketamine, or 4-Cl-KYN, and assessed behavior 1 hour later in the FST.…”

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Compounds that trigger psychedelic-like effects and a dissociative-like state, which partly resembles the anesthetic state, are termed dissociative anesthetics (Evoniuk et al, 1991;Yamakura et al, 2000;Zorumski et al, 2016). Dissociation refers to the disruption of usually integrated functions, such as consciousness, memory, emotions, and behavior (Carlson et al, 2018).…”