Behavioral effects of the novel potent cannabinoid CB1 agonist AM 4054

Abstract

Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625 – 1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625 – 0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125 – 0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function.

Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task

“…Rats were held loosely by an experimenter, while a thin, flexible thermistor probe (Fisher Scientific, Pittsburgh, PA) was then inserted 6 cm into the animal’s rectum. Temperature was recorded when it ceased to fluctuate for at least 5 s. These methods have previously been used to measure temperature changes induced by cannabinoid receptor agonists (McLaughlin et al 2005, 2013). …”

Effects of a novel CB1 agonist on visual attention in male rats: Role of strategy and expectancy in task accuracy.

“…Performance was also not significantly different between levers, unlike in Experiment 1. The impairment may also emerge at only high doses; the effective dose of 0.16 mg/kg induces catalepsy (McLaughlin et al, 2013), as does 2.0 mg/kg AM 411 (McLaughlin, Lu et al, 2005), which produced similar effects on a sustained attention task (McLaughlin, Brown et al, 2005). We piloted higher doses (not shown) that frequently resulted in few or no trials completed.…”

“…Both experiments reported here utilized AM 4054 (9β-(Hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol; Bergman et al, 2008; Desai et al, 2013; Kangas et al, 2013; McLaughlin et al, 2013; Paronis et al, 2013; Thakur et al, 2013). This novel compound, an analog of AM 411, is highly potent and has approximately threefold binding preference for the CB1 receptor, compared with CB2.…”

Modulatory effects by CB1 receptors on rat spinal locomotor networks after sustained application of agonists or antagonists

“…Despite extensive studies carried out on the lamprey spinal cord (El Manira and Kyriakatos, 2010) indicating the modulatory role of CB1Rs on locomotor networks (Kettunen et al, 2005), the involvement of CB1Rs in mammalian locomotion remains unclear. While CB1R activation globally reduces in vivo locomotion in mammals Bosier et al, 2010;Chaouloff et al, 2011;McLaughlin et al, 2013), the mechanisms underlying this phenomenon are not readily resolved with motor behavior experiments. It is, however, clear that, even after a single injection of a CB1R agonist, decrease in locomotion occurs rapidly (Di Marzo et al, 2000) and can persist for many hours with concomitant changes in brain metabolic activity (Whitlow et al, 2002).…”