Pharmacological elevation of anandamide impairs short-term memory by altering the neurophysiology in the hippocampus

Abstract

In rodents, many exogenous cannabinoid agonists including Δ9-THC and WIN 55,212-2 (WIN-2) have been shown to impair short-term memory (STM) by inhibition of hippocampal neuronal assemblies. However, the mechanisms by which endocannabinoids such as anandamide and 2-arachidonylglycerol (2-AG) modulate STM processes are not well understood. Here the effects of anandamide on performance of a Delayed Non-Match to Sample (DNMS) task (i.e., STM task) and concomitant hippocampal ensemble activity were assessed following administration of either URB597 (0.3, 3.0mg/kg), an inhibitor of the Fatty Acid Amide Hydrolase (FAAH), AM404 (1.5, 10.0mg/kg), a putative anandamide uptake/FAAH inhibitor, or R-methanandamide (3.0, 10.0mg/kg), a stable analogue of anandamide. Principal cells from hippocampal CA3/CA1 were recorded extracellularly by multi-electrode arrays in Long-Evans rats during DNMS task (1–30s delays) performance and tracked throughout drug administration and recovery. Both R-methanandamide and URB597 caused dose- and delay-dependent deficits in DNMS performance with suppression of hippocampal ensemble activity during the encoding (sample) phase. R-methanandamide induced effects were not reversed by capsaicine excluding a contribution of TRPV-1 receptors. AM404 produced subtle deficits at longer delay intervals but did not alter hippocampal neuronal activity during task-specific events. Collectively, these data indicate that endocannabinoid levels affect performance in a STM task and their pharmacological elevation beyond normal concentrations is detrimental also for the underlying physiological responses. They also highlight a specific window of memory processing, i.e. encoding, which is sensitive to cannabinoid modulation.

Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats

“…Their behavioral procedure is sensitive to impairment by THC, and these impairments correlate with suppressed hippocampal cell firing around the time of the sample response, presumably representing disrupted encoding of the sample (Hampson and Deadwyler 2000). Goonawardena et al (2011) found that treatment with methanandamide or URB597 (3 mg/kg) produced THC-like effects on memory and hippocampal cell firing. It is unclear why URB597 produced impairments in their procedure but not ours, but one possibility is the use of Long-Evans rats in their study versus Sprague-Dawley rats in ours.…”

“…Goonawardena et al (2011) used a delayed nonmatching-to-position procedure that was similar to the one used in the present study, but used retractable levers instead of lighted nosepoke holes to present the samples and record the responses. Their behavioral procedure is sensitive to impairment by THC, and these impairments correlate with suppressed hippocampal cell firing around the time of the sample response, presumably representing disrupted encoding of the sample (Hampson and Deadwyler 2000).…”

“…In rodents, memory has also been shown to be impaired by administration of exogenous anandamide, but only when its degradation by FAAH is prevented (Goonawardena et al 2011; Lichtman et al 1995; Mallet and Beninger 1996; 1998; Varvel et al 2006). Surprisingly, inhibition or genetic deletion of FAAH, which substantially increases endogenous levels of anandamide, has been found to enhance rather than impair memory in rodents trained with procedures involving aversively-motivated behavior (i.e., water maze: Varvel et al, 2006, 2007; or passive-avoidance of a context associated with footshock: Hasanein and Teimuri Far 2015; Mazzola et al 2009; Morena et al 2014).…”

“…Surprisingly, inhibition or genetic deletion of FAAH, which substantially increases endogenous levels of anandamide, has been found to enhance rather than impair memory in rodents trained with procedures involving aversively-motivated behavior (i.e., water maze: Varvel et al, 2006, 2007; or passive-avoidance of a context associated with footshock: Hasanein and Teimuri Far 2015; Mazzola et al 2009; Morena et al 2014). However, memory-related studies with appetitively-motivated procedures have mostly shown impairment rather than enhancement after treatment with a FAAH inhibitor (Basavarajappa et al 2014; Busquets-Garcia et al 2011; Goonawardena et al 2011; Seillier et al 2010; these studies all used URB597). There have been fewer studies involving MGL inhibition.…”

Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459

“…This pertains not only to short-term memory (Goonawardena et al , 2010a, 2010b, 2011a, 2011b) but also to the consolidation process underlying long-term memory formation (Clarke et al , 2008; Robinson et al , 2008, 2010). Memory consolidation, however, is critically dependent on the occurrence of regular sleep patterns (Brankack et al , 2009; Platt and Riedel, 2011).…”