The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

Abstract

Cannabinoid-1 receptors (CB 1 ) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB 1 (by AEA and 2-AG) and non-CB 1 (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine.

Acute and chronic modulation of striatal endocannabinoid‐mediated plasticity by nicotine

“…This is in line with previous findings from the ventral tegmental area showing enhanced levels of the eCBs arachidonoylethanolamide and 2-arachidonoyl-glycerol after nicotine self-administration (Buczynski et al 2013). It is also in agreement with previous studies showing that antagonists targeting nAChRs on dopaminergic terminals impair eCB-signaling (Partridge et al 2002).…”

“…On the opposite, activation of CB1Rs or inhibition of eCB metabolism enhances nicotine self-administration and expression of nicotine-induced place preference (Merritt et al 2008;Gamaleddin et al 2013). Interestingly, eCB levels are altered by acute and repeated nicotine exposure (Gonzalez et al 2002;Buczynski, Polis, & Parsons 2013), and the endogenous ligand for the nicotinic acetylcholine receptor (nAChR), acetylcholine, appears to regulate eCB-mediated plasticity in the striatum (eCB-LTD) (Partridge et al 2002;Adermark 2011). The striatal eCB system has repeatedly been linked to neuronal adaptations that form persistent drug-related habits and addictive behaviors.…”

Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure

“…We previously demonstrated that nicotine-induced VTA 2-AG formation is sensitized following CNE in a manner independent of the volitional nature of drug exposure [e.g., similar sensitization induced by either nicotine self-administration (SA) or response-independent administration] ( Fig. 1A) (14). To determine the signaling mechanisms influenced by this aberrant 2-AG response, we screened the remaining microdialysate aliquots from these same subjects for temporal changes in neurotransmitter content.…”

“…Potent and selective diacylglycerol lipase inhibitors are characterized and used in ex vivo electrophysiology and in vivo behavioral analyses to demonstrate that this mechanism plays a prominent role in the dysregulation of ventral tegmental dopamine neurons following nicotine exposure. (14).…”

“…Substantial evidence implicates eCB signaling in the etiology of nicotine addiction, and recent work demonstrates that chronic nicotine exposure (CNE) selectively enhances nicotineinduced increases in VTA 2-AG formation (14). The present study investigated the possible contribution of this effect to aberrant VTA DA cell excitation present following CNE (15).…”