Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation

Background: Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals. The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD. Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD. In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear. Method: Male Sprague-Dawley rats received six 1.0 mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context. Immediately following memory retrieval (recall) rats received oral administration of low dose THC, high dose THC, CBD, CBD + low THC, CBD + high THC [as isolated phytochemicals and, in separate experiments, in combination with plant background material (BM)]. Rodents were tested for freezing response context re-exposure at 24 h and 7 days following training. Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM. Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning

Extract and Active Principal of the Neotropical Vine Souroubea sympetala Gilg. Block Fear Memory Reconsolidation

Background: Souroubea sympetala Gilg. is a neotropical vine native to Central America, investigated as part of a targeted study of the plant family Marcgraviaceae. Our previous research showed that extract of S. sympetala leaf and small branch extract had anxiolytic effects in animals and acts as an agonist for the GABAA receptor at the benzodiazepine binding site. To date, the potential effects of S. sympetala and its constituents on reconsolidation have not been assessed. Reconsolidation, the process by which formed memories are rendered labile and susceptible to change, may offer a window of opportunity for pharmacological manipulation of learned fear. Here, we assessed the effects of S. sympetala crude extract and isolated phytochemicals (orally administered) on the reconsolidation of conditioned fear. In addition, we explored whether betulin (BE), a closely related molecule to betulinic acid (BA, an active principal component of S. sympetala), has effects on reconsolidation of learned fear and whether BE may synergize with BA to enhance attenuation of learned fear. Method: Male Sprague–Dawley rats received six 1.0-mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context (but in the absence of foot shocks). Immediately following memory retrieval (recall), rats received oral administration of S. sympetala extract at various doses (8–75 mg/kg) or diazepam (1 mg/kg). In separate experiments, we compared the effects of BA (2 mg/kg), BE (2 mg/kg), and BA + BE (2 mg/kg BA + 2 mg/kg BE). The freezing response was assessed either 24 h later (day 3) or 5 days later (day 7). Effects of phytochemicals on fear expression were also explored using the elevated plus maze paradigm. Results: S. sympetala leaf extract significantly attenuated the reconsolidation of contextual fear at the 25- and 75-mg/kg doses, but not at the 8-mg/kg dose. Furthermore, BA + BE, but not BA or BE alone, attenuated the reconsolidation of learned fear and exerted an anxiolytic-like effect on fear expression

Cannabinoids: Revealing their complexity and role in central networks of fear and anxiety

The first aim of the present review is to provide an in-depth description of the cannabinoids and their known effects at various neuronal receptors. It reveals that cannabinoids are highly diverse, and recent work has highlighted that their effects on the central nervous system (CNS) are surprisingly more complex than previously recognized. Cannabinoid-sensitive receptors are widely distributed throughout the CNS where they act as primary modulators of neurotransmission. Secondly, we examine the role of cannabinoid receptors at key brain sites in the control of fear and anxiety. While our understanding of how cannabinoids specifically modulate these networks is mired by their complex interactions and diversity, a plausible framework(s) for their effects is proposed. Finally, we highlight some important knowledge gaps in our understanding of the mechanism(s) responsible for their effects on fear and anxiety in animal models and their use as therapeutic targets in humans. This is particularly important for our understanding of the phytocannabinoids used as novel clinical interventions

Sleep Changes in Adolescents Following Procedural Task Training

Recent research has suggested that some of the inter-individual variation in sleep spindle activity is due to innate learning ability. Sleep spindles have also been observed to vary following learning in both young and older adults. We examined the effect of procedural task acquisition on sleep stages and on sleep spindles in an adolescent sample. Participants were 32 adolescents (17 female) between the ages of 12 and 19 years. Spindle activity was examined in three different frequency ranges: 11.00 – 13.50 Hz (slow), 13.51 – 16.00 Hz (fast), and 16.01 – 18.50 Hz (superfast). No changes in spindle density were observed after successful learning of the pursuit rotor task. This result was in contrast to a number of studies reporting spindle density increases following successful learning. In the present study, participants who successfully learned the task showed no changes in their sleep stage proportions, but participants who were not successful showed a decrease in the proportion of Stage 2 and increases in both SWS and REM sleep. We suggest that these changes in the sleep stages are consistent with the two stage model of sleep and memory proposed by Smith et al. (2004)