Pharmacokinetics of Oral Minor Cannabinoids in Blood and Brain.

Introduction: Minor cannabinoids are increasingly being consumed in oral formulations (i.e., edibles, tinctures) for medical and nonmedical purposes. This study examined the pharmacokinetics (PKs) of cannabinoids tetrahydrocannabivarin (THCV), cannabichromene (CBC), cannabinol (CBN), and delta-8-tetrahydrocannabinol (D8-THC) after the first and last oral dose during a 14-day administration period. Materials and Methods: Sprague-Dawley rats (N=6 animals/dose, 50% female) were given an assigned dose of one of four cannabinoids (THCV=3.2-100 mg/kg, CBC=3.2-100 mg/kg, CBN=1-100 mg/kg, or D8-THC=0.32-10 mg/kg) or vehicle (medium-chain triglyceride oil) through oral gavage once daily for 14 days. Blood was collected 45 min and 1.5, 3, and 24 h following the first dose (day 1) and the last dose (day 14) of repeated oral cannabinoid treatment for PK analysis. Outcomes of interest included time to maximum concentration (Tmax), maximum concentration (Cmax), and area under the concentration versus time curve (AUClast). Dose-normalized (DN) Cmax and DN AUClast were also calculated. Brain tissue was collected 24 h post-administration of the first (day 1) and the last (day 14) dose of each cannabinoid to determine concentrations in brain. Results: All cannabinoids tested were detectable in plasma after single and 14-day repeated dosing. DN Cmax and DN AUClast were highest for D8-THC, followed by CBC, CBN, and THCV. There was no sex difference observed in cannabinoid kinetics. Accumulation of D8-THC in plasma was observed after 14 days of administration. THCV levels in plasma were lower on day 14 compared to day 1, indicating potential adaptation of metabolic pathways and increased drug elimination. Cannabinoids were detected in brain tissue 24 h post-administration of the first and the last dose of 17-100 mg/kg THCV, 3.2-100 mg/kg CBC, 10-100 mg/kg CBN, and 10 mg/kg D8-THC. Conclusions: THCV, CBC, CBN, and D8-THC produced detectable levels in plasma and translocated to brain tissue after the first dose (day 1) and the last dose (day 14) of repeated oral dosing. Examination of PKs of these minor cannabinoids in blood and brain provides a critical step for informing target dose ranges and dosing schedules in future studies that evaluate the potential effects of these compounds.

Evaluation of the Modulatory Effects of Minor Cannabinoids and Terpenes on Delta-9-Tetrahydrocannabinol Discrimination in Rats.

Introduction: Cannabis contains a multitude of phytocannabinoids and terpenes in addition to its main psychoactive constituent, delta-9-tetrahydrocannabinol (D9-THC). It is believed that the combination of minor cannabinoids and terpenes with D9-THC may impact the subjective and physiological effects of D9-THC. In this study, select minor cannabinoids (cannabigerol [CBG], cannabidivarin [CBDV], cannabichromene [CBC], tetrahydrocannabivarin [THCV], cannabigerolic acid [CBGa], and cannabidiolic acid [CBDa]) and terpenes (beta-caryophyllene and linalool) were evaluated for their potential to decrease the interoceptive effects of D9-THC using drug discrimination methods. Materials and Methods: Male and female rats (n=16; 50% female) were trained to discriminate D9-THC from vehicle. Following training, D9-THC was administered 45 min pre-session, followed by administration of a minor cannabinoid or terpene (or vehicle) 15 min pre-session. CBG, CBDV, CBC, and THCV were administered at doses of 3-30 mg/kg; CBGa and CBDa were administered at doses of 10-100 mg/kg; beta-caryophyllene and linalool were administered at doses of 10-30 mg/kg. Percentage of D9-THC responding (%) was calculated to assess changes to D9-THCs interoceptive effects. Results: CBG, CBDV, CBC, THCV, CBGa, CBDa, beta-caryophyllene, and linalool had little effect on percent D9-THC responding in either sex. No compounds lowered percent D9-THC responding to 50% or below. THCV, CBC, CBDa, and beta-caryophyllene in combination with D9-THC decreased response rates compared with D9-THC alone. Conclusions: The minor cannabinoids and terpenes examined in the current study did not alter the discriminative stimulus effects of D9-THC. These results suggest that these compounds are unlikely to lower the psychoactive effects of D9-THC in human users.

Evaluating Potential Anxiolytic Effects of Minor Cannabinoids and Terpenes After Acute and Chronic Oral Administration in Rats.

Background: Cannabis and its primary psychoactive constituent delta-9-tetrahydrocannabinol (D9-THC) produce biphasic, dose-dependent effects on anxiety. In addition to D9-THC, cannabis contains other "minor" cannabinoids and terpenes with purported therapeutic potential for the treatment of anxiety. Empirical data on potential therapeutic effects of these compounds is limited. The current study evaluated the effects of selected minor cannabinoids and terpenes in a battery of tests sensitive to anxiolytic and anxiogenic drugs. Methods: In Experiment 1, adult male Sprague Dawley rats (N=7-8/group) were administered acute oral doses of one of five minor cannabinoids: delta-8-tetrahydrocannabinol (D8-THC; 10 mg/kg), tetrahydrocannabivarin (32 mg/kg), cannabidiolic acid (32 mg/kg), cannabidivarin (32 mg/kg), and cannabigerol (100 mg/kg), or one of five terpenes: D-limonene (17 mg/kg), ⍺-pinene (100 mg/kg), ⍺-terpineol (10 mg/kg), bisabolol (100 mg/kg), and ß-caryophyllene (17 mg/kg), or vehicle (medium-chain triglycerides [MCT] oil). Ethyl alcohol was tested as an active comparator. Thirty minutes post-administration, the marble burying test, the three-chamber social interaction test, and the novelty-induced hypophagia test were completed; motor activity was assessed throughout testing. Experiment 2 examined the potential anxiolytic effects of minor cannabinoids when administered chronically; rats administered MCT oil or minor cannabinoids in Experiment 1 continued receiving once-daily doses for 21 days and were assessed using the same test battery after 7, 14, and 21 days of administration. Results and Conclusions: When compared to vehicle, acute administration of bisabolol and D-limonene increased the amount of food consumed and bisabolol-, D-limonene-, ⍺-pinene-, and ß-caryophyllene decreased percent time spent in the outer zone in the novelty-induced hypophagia test, suggestive of an anxiolytic effect. Only ethanol increased social interaction. After acute administration, anxiogenic effects in the marble burying test were observed for D8-THC, but not for other minor cannabinoids and terpenes. Throughout chronic administration, only D8-THC displayed anxiogenic effects in the novelty-induced hypophagia test. The other cannabinoids did not show anxiolytic or anxiogenic effects in any of the tests at the doses or times tested. The minor cannabinoids and terpenes did not impair or stimulate general motor activity. These data provide a foundation for future studies investigating cannabinoid/terpene interactions.

Oral Cannabidiol does not alter Alcohol Seeking and Self-Administration in Baboons.

BACKGROUND: The cannabinoid cannabidiol (CBD) is currently under investigation as a pharmacotherapy for alcohol use disorder. The aim of the present study was to examine whether acute and chronic treatment with pure CBD would decrease alcohol seeking and consumption behaviors or alter drinking patterns in male baboons with extensive histories of daily alcohol intake (1 g/kg/day). METHODS: Seven male baboons self-administered oral alcohol (4% w/v) in a validated chained schedule of reinforcement (CSR) procedure that modeled periods of anticipation, seeking, and consumption. In Experiment 1, CBD (5-40 mg/kg) or vehicle (peanut oil, USP) was administered orally 15- or 90-minutes prior to the start of the session. In Experiment 2, oral doses of CBD (10-40 mg/kg) or vehicle were administered for 5 consecutive days during ongoing alcohol access under the CSR. In addition, behavioral observations were conducted to assess potential drug side effects (e.g., sedation, motor incoordination) following chronic CBD treatment immediately after the session and 24-hours after drug administration. RESULTS: Across both experiments, baboons self-administered an average of 1 g/kg/day of alcohol under baseline conditions. Administration of acute or chronic CBD (150-1200 mg total CBD dose/day) that encompassed the purported therapeutic dose range did not significantly reduce alcohol seeking, self-administration or intake (g/kg). Drinking patterns (i.e., number of drinks/bouts, bout duration, nor interdrink interval) also were not altered. There were no observable behavioral disruptions following CBD treatment. CONCLUSIONS: In sum, the current data do not support use of pure CBD as an effective pharmacotherapy to reduce ongoing excessive drinking.

Effects of oral Δ9-tetrahydrocannabinol and cannabidiol combinations on a sustained attention task in rats.

A well-documented side effect of cannabis and Δ9-tetrahydrocannabinol (THC) acute administration is deficits in cognition and attention. Cannabidiol (CBD), a nonintoxicating constituent of cannabis, may modulate THC's impairing effects. A goal of this study was to determine the effects of THC and CBD, alone and in combination, on performance in the rodent Psychomotor Vigilance Test (rPVT), a translational paradigm used to quantify sustained attention. Outcome measures in the rPVT include motor speed, premature responding, and lapses in attention. Sprague Dawley rats were trained to perform the rPVT to the acquisition criteria and then received oral doses (mg/kg) of THC (1-17.6), CBD (1-100), and combinations of THC + CBD in sesame oil prior to rPVT sessions, administered in a within-subject randomized design. Blood was collected from rats receiving selected doses of THC alone or THC + CBD for analysis of THC and its metabolites. THC alone produced significant decreases in accuracy and increases in lapses in attention at higher doses (10 mg/kg; ps < .05). The coadministration of CBD (10 mg/kg) with THC (3 or 10 mg/kg) caused greater impairments to sustained attention compared with administration of THC alone (ps < .05). The rPVT is a translational platform sensitive to detect impairments in attention associated with THC and other cannabis constituents. Further work is necessary to determine the mechanism of THC and CBD interactions on impairments in sustained attention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Δ9-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats.

Background: The use of place conditioning procedures and drug vapor exposure models can increase our understanding of the rewarding and aversive effects of vaped cannabis products. Currently there are limited data on the conditioned rewarding effects of vaporized Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis in rats, and no studies to date examining sex differences. Methods: Male and female Sprague-Dawley rats (N=96; 12 per sex/group) underwent place conditioning sessions immediately after exposure to THC or vehicle (propylene glycol [PG]) vapor. Locomotor activity was measured by beam breaks during conditioning sessions. THC vapor-conditioned rats received one of three THC vapor exposure amounts (low: 5 puffs of 100 mg/mL THC, medium: 5 puffs of 200 mg/mL THC, or high: 10 puffs of 200 mg/mL THC) and matched vehicle vapor (PG) exposure on alternate days for 16 daily sessions. A "no THC" control group of vehicle-conditioned rats received only PG vapor exposure each day. After the 8th and 16th conditioning sessions, untreated rats were tested for conditioned place preference (CPP) or aversion (CPA). Next, extinction tests and a THC vapor-primed reinstatement test were conducted. Results: THC vapor produced CPP and locomotor effects in an exposure dependent manner, and some sex differences were observed. Low THC vapor exposure did not produce CPP in males or females. Medium THC vapor exposure produced CPP in males, but not females. High THC vapor exposure produced CPP in both males and females. Medium and high THC vapor exposure amounts produced hyperactivity in female rats, but not male rats. CPP was more resistant to extinction in females than males. THC vapor reexposure (i.e., drug-prime) after extinction did not result in reinstatement of CPP for either sex. Conclusion: This study demonstrates conditioned rewarding effects of THC vapor in both male and female rats and provides evidence for sex differences in amounts of THC vapor that produce CPP and in time to extinction. CPA was not observed at any of the THC vapor exposure amounts tested. These data provide a foundation for future exploration of the conditioned effects of cannabis constituents and extracts using vapor exposure models.

Translational models of cannabinoid vapor exposure in laboratory animals.

Cannabis is one of the most frequently used psychoactive substances in the world. The most common route of administration for cannabis and cannabinoid constituents such as Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is via smoking or vapor inhalation. Preclinical vapor models have been developed, although the vaporization devices and delivery methods vary widely across laboratories. This review examines the emerging field of preclinical vapor models with a focus on cannabinoid exposure in order to (1) summarize vapor exposure parameters and other methodological details across studies; (2) discuss the pharmacological and behavioral effects produced by exposure to vaporized cannabinoids; and (3) compare behavioral effects of cannabinoid vapor administration with those of other routes of administration. This review will serve as a guide for past and current vapor delivery methods in animals, synergize findings across studies, and propose future directions for this area of research.

Cannabinoid tetrad effects of oral Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and female rats: sex, dose-effects and time course evaluations.

RATIONALE: The legalization of medicinal use of Cannabis sativa in most US states and the removal of hemp from the Drug Enforcement Agency (DEA) controlled substances act has resulted in a proliferation of products containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for oral consumption (e.g., edibles, oils, and tinctures) that are being used for recreational and medicinal purposes. OBJECTIVE: This study examined the effects of cannabinoids THC and CBD when administered orally on measures of pain sensitivity, body temperature, locomotor activity, and catalepsy (i.e., cannabinoid tetrad) in male and female Sprague Dawley rats. METHODS: Rats (N = 24, 6 per sex/drug group) were administered THC (1-20 mg/kg), CBD (3-30 mg/kg), or sesame oil via oral gavage. Thermal and mechanical pain sensitivity (tail flick assay, von Frey test), rectal measurements for body temperature, locomotor activity, and the bar-test of catalepsy were completed. A separate group of rats (N = 8/4 per sex) was administered morphine (5-20 mg/kg; intraperitoneal, IP) and evaluated for pain sensitivity as a positive control. RESULTS: We observed classic tetrad effects of antinociception, hypothermia, hyper- and hypolocomotion, and catalepsy after oral administration of THC that were long lasting (> 7 h). CBD modestly increased mechanical pain sensitivity and produced sex-dependent effects on body temperature and locomotor activity. CONCLUSIONS: Oral THC and CBD produced long lasting effects that differed in magnitude and time course when compared with other routes of administration. Examination of cannabinoid effects administered via different routes of administration, species, and in both males and females is critical to enhance translation.

Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking.

A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p's < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p's < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

Appetitive, antinociceptive, and hypothermic effects of vaped and injected Δ-9-tetrahydrocannabinol (THC) in rats: exposure and dose-effect comparisons by strain and sex.

Advances in drug vapor exposure systems have enabled evaluation of Δ-9-tetrahydrocannabinol (THC) vapor effects in laboratory animals. The purpose of this study was to 1) establish a range of parameters of THC vapor exposure in rats sufficient to produce a behavioral dose-effect curve in a battery of tasks sensitive to THC; and 2) to investigate sex differences in the effects of THC vapor exposure and THC injection (intraperitoneal, IP) on these behaviors in two strains of outbred rats. Male and female Sprague Dawley and Wistar rats (N = 22, 5-6/sex per group) received THC via passive vapor exposure (200 mg/mL; 5 conditions) and IP injection (1-20 mg/kg) in a within subject design. The effects of vaped and injected THC on appetite was determined using progressive ratio responding for food pellets. THC effects on nociception, measured using the tail withdrawal assay, and body temperature were also assessed during a 5-h test period for evaluation of time course of effects. Plasma THC concentrations were assessed after THC vapor and 10 mg/kg IP THC. THC vapor produced exposure-related increases and decreases in motivation to obtain food under the progressive ratio schedule. IP THC (3-20 mg/kg) reduced breakpoints. Vaped and injected THC produced exposure and dose-dependent antinociception and hypothermia. Sex and strain differences in THC effects were also observed. Plasma THC concentrations were higher after 10 mg/kg IP THC (152 ng/mL) compared to the highest vapor exposure condition tested (38 ng/mL), but magnitude of behavioral effects were comparable. THC vapor exposure produced reliable, dose orderly effects on food-maintained behavior, nociception, and body temperature that are comparable to effects of IP THC, although there were differences in the time course of behavioral outcomes.

Effect of different standard rodent diets on ethanol intake and associated allodynia in male mice.

Alcohol is the most ubiquitously consumed and misused mind-altering substance in the world. Various animal models exist to aid in our neurobiological understanding of alcohol addiction. One variable too often taken for granted and not consistently controlled is the "standard" chow diet rodents are maintained on. In this set of experiments, we sought to determine the effect of different commonly used diets on ethanol intake, ethanol preference, and mechanical pain sensitivity in a widely used mouse model of heavy alcohol drinking, the intermittent access to 20% alcohol model. We found that male mice kept on LabDiet 5001 (Diet 2 [LD5001]) and on Teklad Diet 7012 (Diet 3 [H7012]) consistently drank more ethanol than mice kept on Teklad Diet 2918 (Diet 1 [H2918]) as well as compared to mice on LabDiet 5V75 (Diet 4 [LD5V75]). In addition, water intake was consistently lower in mice kept on LabDiet 5001 (Diet 2 [LD5001]), and occasionally in mice kept on Teklad Diet 7012 (Diet 3 [H7012]), compared to the Teklad Diet 2918 (Diet 1 [H2918]) group. We found that male mice showed a strong mechanical allodynia following 8 weeks of intermittent ethanol drinking at 72 h of withdrawal, compared to water Control mice, regardless of the diet and hence of the different amount of ethanol consumed. Our data provide evidence that the type of rodent diet subjects are exposed to is an important variable to report and control, in all ethanol drinking studies.

Reward sensitivity deficits in a rat model of compulsive eating behavior.

Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week ("C Phase"), followed by 2 days of access to a highly palatable sucrose diet ("P Phase"). We first tested the sensitivity to d-Amphetamine's stimulatory, reward-enhancing, and primary rewarding effects using a locomotor activity assay, an intracranial self-stimulation (ICSS) procedure, and a conditioned place preference test, respectively. We then quantified DA release in the nucleus accumbens (NAc) shell after treatment with d-Amphetamine using in vivo microdialysis, quantified levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA using quantitative polymerase chain reaction (qPCR), and lastly, quantified baseline extracellular DA and function of DAT in vivo using quantitative "no-net-flux" microdialysis. Chow/Palatable rats displayed blunted d-Amphetamine-induced locomotor activity, insensitivity to d-Amphetamine potentiation of ICSS threshold, and decreased place preference for d-Amphetamine during the P Phase. We found that Chow/Palatable rats had blunted DA efflux following d-Amphetamine treatment. Furthermore, DAT mRNA was increased in Chow/Palatable rats during the P Phase. Finally, quantitative "no-net-flux" microdialysis revealed reduced extracellular baseline DA and DAT function in Chow/Palatable rats. Altogether, these results provide evidence of reduced reward system functioning and related neuroadaptations in the DA and DAT systems in this model of compulsive eating. Reward deficits, resulting from repeated overeating, may in turn contribute to the perpetuation of compulsive eating behavior.

Impulsive choice does not predict binge-like eating in rats.

Binge eating disorder is an addiction-like disorder characterized by recurrent, excessive food consumption within discrete periods of time, and it has been linked to increased trait impulsivity. Within impulsivity components, while impulsive action was shown to predict binge-like and addictive-like eating, the role of impulsive choice is instead unknown. The goal of this study was to determine if impulsive choice predicted, or was altered by binge-like eating of a sugary, highly palatable diet. We utilized a modified adjusting delay task procedure in free-fed rats to assess impulsive choice behavior, that is. the tendency to respond for a larger, delayed reward over a lesser, immediate reward. We found that baseline impulsive choice was not a predictor of binge-like eating in 1-h sessions of palatable diet operant self-administration. Furthermore, binge-like eating of the same palatable diet had no effect on later impulsive choice behavior. Thus, our data suggest that, unlike impulsive action, impulsive choice behavior does not predict binge-like eating in rats.

Trace Amine Associated Receptor 1 (TAAR1) Modulation of Food Reward.

Eating disorders and some forms of obesity are characterized by addictive-like, compulsive eating behavior which contains numerous similarities with compulsive drug use. Food intake is in part mediated by reward and reinforcement processes that can become dysregulated in these disorders. Additionally, impairments in inhibitory control regulation of reward-related responding can cause or further exacerbate binge and compulsive eating. Dysfunctions in two neurotransmitter systems in the mesocorticolimbic pathway, dopamine and glutamate, are thought to contribute to maladaptive eating behaviors. The trace amine associated receptor 1 (TAAR1) system is a promising therapeutic target for compulsive eating behavior due to the role of TAAR1 in synaptic transmission and in the modulation of dopaminergic and glutamatergic signaling. In support of this notion, the TAAR1 agonist RO5256390 was found to decrease the reinforcing effects of palatable food-cues and to reduce binge-like and compulsive-like eating of palatable food. Additionally, prolonged, intermittent access to palatable food was shown to downregulate TAAR1 in the prefrontal cortex, suggesting a potential role for TAAR1 signaling in inhibitory control processes. Research into the role of TAAR1 in addiction, including TAAR1's ability to modulate psychostimulant reward and reinforcement, bolsters support for TAAR1 agonism as a pharmacological treatment for compulsive eating and other addictive behaviors. This review summarizes the evidence for TAAR1 agonism as a promising therapeutic for compulsive eating behavior as well as the hypothesized mechanism responsible for these effects.

Neuropharmacology of compulsive eating.

Compulsive eating behaviour is a transdiagnostic construct observed in certain forms of obesity and eating disorders, as well as in the proposed construct of 'food addiction'. Compulsive eating can be conceptualized as comprising three elements: (i) habitual overeating, (ii) overeating to relieve a negative emotional state, and (iii) overeating despite adverse consequences. Neurobiological processes that include maladaptive habit formation, the emergence of a negative affect, and dysfunctions in inhibitory control are thought to drive the development and persistence of compulsive eating behaviour. These complex psychobehavioural processes are under the control of various neuropharmacological systems. Here, we describe the current evidence implicating these systems in compulsive eating behaviour, and contextualize them within the three elements. A better understanding of the neuropharmacological substrates of compulsive eating behaviour has the potential to significantly advance the pharmacotherapy for feeding-related pathologies.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

A behavioral and pharmacological characterization of palatable diet alternation in mice.

Obesity and eating disorders are widespread in Western societies. Both the increased availability of highly palatable foods and dieting are major risk factors contributing to the epidemic of disorders of feeding. The purpose of this study was to characterize an animal model of maladaptive feeding induced by intermittent access to a palatable diet alternation in mice. In this study, mice were either continuously provided with standard chow food (Chow/Chow), or provided with standard chow for 2days and a high-sucrose, palatable food for 1day (Chow/Palatable). Following stability of intake within the cycling paradigm, we then investigated the effects of several pharmacological treatments on excessive eating of palatable food: naltrexone, an opioid receptor antagonist, SR141716A, a cannabinoid-1 receptor antagonist/inverse agonist, and BD-1063, a sigma-1 receptor antagonist. Over successive cycles, Chow/Palatable mice showed an escalation of palatable food intake within the first hour of renewed access to palatable diet and displayed hypophagia upon its removal. Naltrexone, SR141716A, and BD-1063 all reduced overconsumption of palatable food during this first hour. Here we provide evidence of strong face and convergent validity in a palatable diet alternation model in mice, confirming multiple shared underlying mechanisms of pathological eating across species, and thus making it a useful therapeutic development tool.

Neuroscience of Compulsive Eating Behavior.

A systematic characterization of compulsivity in pathological forms of eating has been proposed in the context of three functional domains: (1) habitual overeating; (2) overeating to relieve a negative emotional state; and (3) overeating despite aversive consequences. In this review, we provide evidence supporting this hypothesis and we differentiate the nascent field of neurocircuits and neurochemical mediators of compulsive eating through their underlying neuropsychobiological processes. A better understanding of the neurobiological mechanisms that lead to compulsive eating behavior can improve behavioral and pharmacological intervention for disorders of pathological eating.

Pathological Overeating: Emerging Evidence for a Compulsivity Construct.

Compulsive eating behavior is a transdiagnostic construct that is characteristic of medical and psychiatric conditions such as forms of obesity and eating disorders. Although feeding research is moving toward a better understanding of the proposed addictive properties of food, the components and the mechanisms contributing to compulsive eating are not yet clearly defined or understood. Current understanding highlights three elements of compulsive behavior as it applies to pathological overeating: (1) habitual overeating; (2) overeating to relieve a negative emotional state; and (3) overeating despite aversive consequences. These elements emerge through mechanisms involving pathological habit formation through an aberrant learning process, the emergence of a negative emotional state, and dysfunctions in behavioral control. Dysfunctions in systems within neurocircuitries that comprise the basal ganglia, the extended amygdala, and the prefrontal cortex result in compulsive eating behaviors. Here, we present evidence to relate compulsive eating behavior and addiction and to characterize their underlying neurobiological mechanisms. A major need to improve understanding of compulsive eating through the integration of complex motivational, emotional, and cognitive constructs is warranted.

The Trace Amine-Associated Receptor 1 Agonist RO5256390 Blocks Compulsive, Binge-like Eating in Rats.

Compulsive, binge eating of highly palatable food constitutes a core feature of some forms of obesity and eating disorders, as well as of the recently proposed disorder of food addiction. Trace amine-associated receptor 1 (TAAR1) is a highly conserved G-protein-coupled receptor bound by endogenous trace amines. TAAR1 agonists have been shown to reduce multiple behavioral effects of drugs of abuse through their actions on the mesocorticolimbic system. In this study, we hypothesized that TAAR1 may have a role in compulsive, binge-like eating; we tested this hypothesis by assessing the effects of a TAAR1 agonist, RO5256390, in multiple excessive feeding-related behaviors induced by limiting access to a highly palatable diet in rats. Our results show that RO5256390 blocked binge-like eating in rats responding 1 h per day for a highly palatable sugary diet. Consistent with a palatability-selective effect, drug treatment selectively reduced the rate and regularity of palatable food responding, but it did not affect either baseline intake or food restriction-induced overeating of the standard chow diet. Furthermore, RO5256390 fully blocked compulsive-like eating when the palatable diet was offered in an aversive compartment of a light/dark conflict box, and blocked the conditioned rewarding properties of palatable food, as well as palatable food-seeking behavior in a second-order schedule of reinforcement. Drug treatment had no effect on either anxiety-like or depressive-like behavior, and it did not affect control performance in any of the tests. Importantly, rats exposed to palatable food showed decreased TAAR1 levels in the medial prefrontal cortex (mPFC), and RO5256390 microinfused into the infralimbic, but not prelimbic, subregion of the mPFC-reduced binge-like eating. Altogether, these results provide evidence for TAAR1 agonism as a novel pharmacological treatment for compulsive, binge eating.

Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons.

Contexts associated with opioid reward trigger craving and relapse in opioid addiction. Effects of reward-context associative learning on nucleus accumbens (NAc) dendritic morphology were studied using morphine conditioned place preference (CPP). Morphine-conditioned mice received saline and morphine 10 mg/kg subcutaneous (s.c.) on alternate days. Saline-conditioned mice received saline s.c. each day. Morphine-conditioned and saline-conditioned groups received injections immediately before each of eight daily conditioning sessions. Morphine homecage controls had no CPP training, but received saline and morphine in the homecage concomitantly with the morphine-conditioned group. Morphine conditioning produced greater place preference than saline conditioning. Mice were sacrificed 1 day after CPP expression. Dendritic changes were studied using Golgi-Cox staining and digital tracing of NAc core and shell neurons. In the NAc core, morphine homecage administration increased spine density, while morphine conditioning increased dendritic complexity, as defined by increased dendritic count, length and intersections. Place preference positively correlated with dendritic length and intersections in the NAc core. The core may mediate reward consolidation and determine how context-related signals from the shell lead to motor behavior. The combination of drug and conditioning in the morphine-conditioned group produced unique morphological effects different from the effects of drug or conditioning procedures by themselves. An additional study found no differences in neuron morphology between saline-conditioned mice, trained as described earlier, and mice that were not conditioned, but received saline in the homecage. The unique effect of morphine reward learning on NAc core dendrites reflects a brain substrate that could be targeted for therapeutic intervention in addiction.