Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug used and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized ⌬ 9-tetrahydrocannabinol-rich (CAN THC) or cannabidiol-rich (CAN CBD) whole-plant cannabis extracts. Male Sprague-Dawley rats were trained to nose-poke for discrete puffs of CAN THC , CAN CBD , or vehicle (VEH) in daily 1 h sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CAN THC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared with CAN CBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CAN THC administration decreased hippocampal CB1 receptor binding. Removal of CAN THC reinforcement (but not CAN CBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors.

In recent years, lipids have come to the foreground as signaling mediators in the central nervous system (CNS) 1,2 . While classical neurotransmitters are stored in synaptic vesicles and released on fusion with the plasma membrane of neurons, due to their lipophilic nature, lipids readily diffuse through membranes and are not stored in vesicles. It is, therefore, generally accepted that signaling lipids are produced 'on demand' and are rapidly metabolized to terminate their biological action 3 . In particular, NAEs, including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA) and the endocannabinoid anandamide (N-arachidonoylethanolamine, AEA) have emerged as key lipid signaling molecules. Genetic deletion or pharmacological inhibition of the main NAE hydrolytic enzyme, fatty acid amide hydrolase (FAAH), revealed elevated anandamide, PEA and OEA levels in brain and implicated these molecules in the modulation of various physiological processes such as pain, stress, anxiety, appetite, cardiovascular function and inflammation [4][5][6][7] . The physiological effects resulting from perturbation of the production of anandamide and other NAEs in living systems are, however, poorly studied, partly because of a lack of pharmacological tools to modulate their biosynthetic enzymes 8 . NAPE-PLD is generally considered a principal NAE biosynthetic enzyme 9,10 . Biochemical and structural studies have demonstrated that NAPE-PLD is a membrane-associated, constitutively active zinc hydrolase with a metallo-β-lactamase fold 11 . The enzyme generates a broad range of NAEs by hydrolysis of the phosphodiester bond between the phosphoglyceride and the NAE in N-acylphosphatidylethanolamines (NAPEs) 12 . Knockout (KO) studies have shown that the Ca 2+ -dependent conversion of NAPE to NAEs bearing both saturated and polyunsaturated fatty acyl groups are fivefold reduced in brain lysates from mice that genetically lack Napepld 13 . In accordance, reduced levels of saturated and mono-unsaturated NAEs were observed in the brains of NAPE-PLD KO mice [13][14][15] . Anandamide levels were not reduced in the transgenic model reported by Leung et al., which suggested the presence of compensatory mechanisms 13 . Indeed, multiple alternative biosynthetic pathways for anandamide have been discovered since 10 .

Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague–Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction.

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