Nicotine
In a human randomized controlled trial, nicotine augmented THC-induced “high” and heart rate [259]. In rodent behavioral studies, acute nicotine augmented THC discrimination and THC-induced hypothermia, antinociception, locomotor inactivity, anxiolysis, and place aversion [260]–[264]. Nicotine-potentiated THC discrimination was blocked by rimonabant and URB-597 (a FAAH inhibitor), suggesting nicotine potentiation is mediated by the release of AEA acting at CB1 [263]. CB2 is also involved—the CB2–selective agonist JWH133 induced antinociception in the mouse formalin test, and this effect was potentiated by nicotine [265]. Acute nicotine elicited marked increases in AEA in the amygdala, hypothalamus, and prefrontal cortex but decreased levels in the hippocampus; variations in 2-AG were less pronounced [266].
In a contrary study, intracelebellar microinfusion of nicotine attenuated THC-induced ataxia in mice. Microinfusion of synthetic subtype agonists indicated the involvement of α4β2 but not α7 nicotinic receptor subtypes [267]. Buczynski et al. [268] compared volitional self-administration (SA) versus forced nicotine exposure (FA) in the ventral tegmental area using in vivo microdialysis. SA but not FA increased AEA; both SA and FA increased 2-AG; these subtle changes were not seen in corresponding bulk brain tissue analysis of eCBs. Acute nicotine enhanced THC-induced c-Fos expression in various brain regions [264].
Chronic nicotine increased AEA levels in the limbic forebrain and increased AEA and 2-AG contents in rat brainstem, but decreased AEA and/or 2-AG contents in the hippocampus, the striatum and the cerebral cortex [258]. Chronic nicotine increased CB1 density in the prelimbic prefrontal cortex, ventral tegmental area, and the hippocampus [269]. Seven days of nicotine exposure increased brain CB1 densities in adolescent male rats and sensitized them to the locomotor-decreasing effects of THC and CP55,940 [270]. These changes were not seen in adult male rats. Chronic nicotine inhibited the development of tolerance to antinociceptive and hypothermic effects of THC [264].
Other plant products that exert cholinergic effects, such as calamus, Acorus calamus, have been admixed with cannabis to decrease cannabis-induced memory deficits, and “calm and center the effects of marijuana” [42]. Consistent with this, the synthetic cholinergic agent rivastigmine reversed memory deficits in rats induced by the synthetic cannabinoid WIN55,212-2 [271].