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Published in final edited form as: Behav Brain Res. 2024 Oct 24;477:115315. doi: 10.1016/j.bbr.2024.115315

Effects of repeated voluntary oral consumption of synthetic delta-9-tetrahydrocannabinol on locomotor activity and cannabinoid receptor 1 expression

Dylan A Laux a, C Azuma Miki a, Mary E Cain a
PMCID: PMC11570332  NIHMSID: NIHMS2032793  PMID: 39461370

Abstract

As cannabis legalization expands, preclinical studies continue to investigate the impact of repeated exposure to delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in the plant. With the increasing popularity of cannabis infused foods, the rise of THC in medicinal applications have also expanded. The present study addresses a critical gap in existing literature by investigating the behavioral and neurobiological effects of low-dose edible THC in a preclinical rodent model. Adult male rats were administered synthetic-THC (Dronabinol) (0.0625mg/kg, 0.125mg/kg, and 0.25mg/kg) or vehicle (sesame oil) through edible cookies, 90min prior to eight locomotor sessions. Locomotor activity significantly increased in both 0.0625mg/kg and 0.25mg/kg THC groups, indicating a dose-dependent relationship. Repeated 0.25mg/kg THC administration dose-dependently reduced cannabinoid receptor 1 expression in the hippocampus. The observed neurobiological change from low dose oral THC advances our understanding of repeated cannabis use. These findings also emphasize the importance of refining rodent models for translational relevance.

Keywords: Delta-9-Tetrahyrocannabinol (THC), Dronabinol, Cannabinoid Receptor 1 (CB1), Hippocampus, Edibles, Locomotor activity

Introduction

With the accelerating legalization of cannabis across the United States, an expansive body of clinical and pre-clinical research has emerged, predominantly focused on deciphering the complexities of cannabinoids. Presently, the field has knowledge of over 100 cannabinoids within the cannabis plant, including the psychoactive delta-9-tetrahydrocannabinol (THC) (Rosenberg et al., 2015). With increased legalization and acceptance of cannabis, foods that are infused with cannabis (edibles) have been increasing in popularity. For example, in Canada, edible use has increased from 40% of users in 2018 to 54% of users in 2023 while inhalation has decreased from 80% of users in 2018 to 60% in 2023 (Health Canada, 2024). Because oral THC metabolism and effects differ significantly from those of inhaled or injected forms in humans (Grotenhermen, 2003; Hložek et al., 2017), preclinical studies assess behavioral effects across a range of THC doses (Carrica et al., 2023; Kruse et al., 2019; Moore & Weerts, 2022). When taking THC orally, first-pass metabolism occurs in the liver, where THC is metabolized to 11-OH-THC, and other metabolites. 11-OH-THC is considered to have stronger psychoactive effects than THC, providing evidence for differences in strength and duration of intoxication between eating and smoking cannabinoids (Grotenhermen, 2003).

Preclinical models studying the effects of oral THC in behavioral paradigms have resulted in contrasting effects between age, sex, and dosage differences (Hložek et al., 2017; Kruse et al., 2019; Moore & Weerts, 2022). However, these studies have predominantly focused on the effects of a high dose range (1–20mg/kg), overlooking the behavioral and neurobiological effects of low doses, which could potentially be a better representation of human clinical use (FDA, 2024; O’Donnell et al., 2022). In the United States synthetically produced cannabinoid products have been developed and standardized for prescribed medicinal use. Legally, these products are consumed orally at the amount of 2.5–10mg of THC per dose (FDA, 2024; O’Donnell et al., 2022). However, human research is often confounded by non-naive participants. Therefore, animal models of voluntary oral consumption of THC at a wide range of doses are needed to understand the behavioral and neurobiological effects of the drug.

Preclinical research utilizing injections of THC (0.5–30mg/kg) observes a clear biphasic relationship to drug dose and locomotion, where low doses produce increased locomotion, and high doses decreased movement (Smirnov & Kiyatkin, 2008; Taffe et al., 2015; Wakley et al., 2014). Comparatively, animal studies with either experimenter delivered (Hložek et al., 2017; Moore & Weerts, 2022) or voluntary (Kruse et al., 2019) oral THC (1–10mg/kg) have produced mixed results on locomotion across doses ranging from 1–10mg/kg. While results do not seem to vary between experimenter delivered versus voluntary consumption of oral THC, it is an important premise for preclinical models to represent human drug consumption patterns as closely as possible. To address these gaps in literature for oral administration paradigms, we employed an established preclinical model of edible THC (Carrica et al., 2023; Nelson et al., 2019; Sangiamo et al., 2023), to investigate a behavioral and neurobiological effect of repeated voluntary consumption of low-dose oral THC.

In both human and preclinical literature, repeated use of THC can significantly reduce the number of cannabinoid receptor 1 (CB1) expressed throughout the brain (Kruse et al., 2019; Lazenka et al., 2014; Villares, 2007). While it is known that CB1 plays a critical role in neuronal development, CB1 also helps institute synaptic connections and maintain gene expression (Kano et al., 2009). In the current experiment, we determined if repeated oral synthetic THC, in the form of Dronabinol, alters CB1 expression.

The present short communications study was designed to determine the effects of repeated low dose oral THC on locomotor behavior and CB1 expression within the CA1 region of the hippocampus and nucleus accumbens (NAc) core and shell. We hypothesized that repeated voluntary consumption of low doses of THC would increase locomotor activity regardless of dose. Further, we hypothesized that THC would not alter CB1 expression in the CA1 region of the hippocampus or in the NAc core or shell.

Methods

47 adult male Long-Evans rats (Charles River Laboratories) were pair-housed in opaque cages, filled with rodent bedding, and had ad libitum access to food and water. This housing arrangement was maintained in a temperature and humidity-controlled colony room, operating on a 12-hour reverse light-dark cycle with lights turning on at 6am. All experimental procedures adhered to the Institutional Animal Care and Use Committee at Kansas State University and complied with NIH guidelines for the ethical treatment of laboratory animals.

Contents of 10mg capsules Dronabinol (Pharmaceutics International, Inc.) were extracted via a 1ml syringe and 20g needle. Subsequently, the extracted substance was diluted into three doses, 0.0625mg/kg, 0.125mg/kg and 0.25mg/kg with sesame oil (Spectrum) (Nelson et al., 2019; Sangiamo et al., 2023).

Drug or vehicle (sesame oil) was applied according to animal weight to half of a Mini-Oreo™ wafer without cream filling and allowed to absorb for 30 minutes (modified from: Carrica et al., 2023; Nelson et al., 2019; Sangiamo et al., 2023). These treated cookies were then placed in individual opaque cage liners with rodent bedding. Animals were allowed to voluntarily consume the cookie for up to 60 minutes and were returned to their home cage prior to behavioral tests. All rats ate the entire cookie and drug dose within the first 10 minutes of availability. For each rat, immediately following cookie consumption, a 60-minute timer was started for timing of behavioral testing.

Drug administration began with 2 habituation days, where animals received a plain cookie with only vehicle (sesame oil) applied for conditioning to cookie consumption. The following 16 days, animals received one cookie per day between the hours of 8–10am. For the drug conditions, synthetic THC cookies were administered every other day, with vehicle cookies given to all animals on alternate days. A total of 8 locomotor sessions were conducted 60 minutes after a rat consumed their cookie, exclusively on days when the drug was administered. The locomotor sessions were 90 minutes and occurred in six identical chambers (Coulbourn Instruments, TruScan 2.01), described previously (Garcia et al., 2017).

Immediately following the final locomotor session, rats were deeply anaesthetized using Fatal Plus (pentobarbital sodium) and transcardially perfused with 0.9% saline and 4% paraformaldehyde. Brains were extracted, post-fixed in 4% paraformaldehyde for 24 hours, and then transferred to a 20% sucrose solution for three days at 4°C. The brains were frozen at −80°C, and 40 μm slices were obtained from the dorsal hippocampus and NAc. A randomly selected subset of animals from each condition (N=7 per condition) was used for immunohistochemical results validated by power analysis via G*Power 3.1.9.7. Chromogenic immunohistochemical staining was employed to visualize CB1 expressing cells by utilizing a rabbit anti-cannabinoid 1 receptor/CB1 primary antibody (abcam-ab23703). Subsequent steps included incubation in biotinylated secondary antibody, avidin-biotin complex, and visualization using a 3’3’ diaminobenzidine solution. The reaction was terminated, and slices were stored in PBS at 4°C until mounting on charged slides and cover-slipping with Permount. Images were captured via Olympus BX41 light microscope and SPOT 5.1 Advanced Software at 20X magnification for anterior, middle, and posterior regions of each area of interest. CB1 positively labeled cells were then averaged across the three images for statistical analysis conducted in FIJI from ImageJ2. To determine if THC dose altered the total distance traveled (cm) across all sessions, a one-way ANOVA combined the mean total distance traveled (cm) across all eight sessions. To determine if the total distance traveled differed between sessions 1 and 8, a repeated-measures ANOVA, incorporating THC dose, session, and their interaction, was used. Separate one-way ANOVAs examined the influence of THC dose on CB1 expression in each region. Post-hoc comparisons were performed using Tukey’s honestly significant difference (HSD) test to identify specific group differences. The significance level for all statistical tests was set at α = 0.05. JMP Pro 16 (SAS Institute Inc., Cary, NC, USA) was used for all statistical analyses.

Results

Locomotor Activity

Taking the mean distance from all 8 sessions combined, THC significantly increased the distance traveled (cm) when compared to the control group. The ANOVA resulted in a main effect of THC Dose on distance traveled (cm)when all 8 locomotor sessions were averaged together, F(3, 381) = 7.05, p < .001. Post-hoc comparisons revealed that 0.0625mg/kg and 0.25mg/kg THC groups had significantly further distance traveled than the control group (p < .001; Figure 1A).

Figure 1.

Figure 1.

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A) Mean total distance traveled (cm +/− SEM) of all 8 locomotor sessions averaged together. * Represents significant (< .05) effect relative to control group. B) Total distance traveled (cm +/− SEM) comparing in session one versus eight. * Represents significant (< .05) effect between session one and eight. # Represents significant (< .05) effect of THC dose compared to control.

The ANOVOA to determine if the total distance traveled differed between sessions 1 and 8, resulted in significant main effects of session, F(1,95) = 50.49, p < .001, and THC dose, F(3,95) = 3.11, p = 0.030, despite having no session by drug interaction (p = 0.913). Post hoc analysis indicated that distance traveled was higher in the first session than the final session (p < .001) and 0.25mg/kg THC had significantly further distance traveled than the control group (p = .025) Figure 1B).

CB1 Expression

The ANOVA results indicated a significant effect of THC Dose on CB1-labeled cell counts within the CA1 region of the hippocampus, F(3, 23) = 3.43, p = 0.032 (Figure 2A) with the highest dose significantly (p = 0.022) decreasing expression compared to the control condition. Neither NAc core (p = 0.500) or shell (p = 0.869) showed a reduction in CB1 expression (Figure 3A&B).

Figure 2.

Figure 2.

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A) CB1 positively labeled cells (+/− SEM) within the CA1 region of the hippocampus. * Represents significant (< .05) effect relative to Control group. B) Representative image of the dorsal Hippocampus. Repeated oral consumption of 0.25 mg/kg THC significantly reduced CB1 expression.

Figure 3.

Figure 3.

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CB1 positively labeled cells (+/− SEM) within the NAc. A) NAc Core, B) NAc Shell. THC did not alter CB1 expression in either region.

Discussion

Our study aimed to address the behavioral and neurobiological effects of repeated low-dose edible THC. The results of our study revealed a significant main effect of THC dose on locomotor activity when averaging all sessions together, with both the lower and higher THC doses inducing significantly further distance traveled than the control group. Previous literature with THC administered via injection has observed that low doses of THC induce hyperlocomotion, and high doses create hypolocomotion (Smirnov & Kiyatkin, 2008; Taffe et al., 2015; Wakley et al., 2014). Our results display increased locomotion from low doses of edible THC, which closely replicate results found in studies using injections of THC. While our results replicate increased locomotor activity with low doses of oral THC, we did not find a decrease in locomotion at our highest dose, giving reason to further explore a broader range of doses of oral THC and behavioral effects. Further, there was a marginally significant (p = 0.066) increase in locomotor activity with the 0.125mg/kg dose, displaying a correlative trend in increased locomotion across all low doses of THC. It is important to note that our study utilized a range of lower doses compared to previous oral THC preclinical studies (Carrica et al., 2023; Kruse et al., 2019; Moore & Weerts, 2022).

Several discrepancies between studies may be impacting the results of the locomotor effects induced by THC ingestion. Metabolic differences between inhalation and ingestion of THC, time of edible administration and behavioral testing, open access to consume the drug versus forced consumption comparisons, and form of oral THC administration are all confounds between studies making them difficult to compare. Our methodology utilized an established preclinical model of edible THC (Carrica et al., 2023; Nelson et al., 2019; Sangiamo et al., 2023) to explore the behavioral and neurobiological effects of repeated low-dose oral THC, modifying the approach to more accurately reflect human consumption dosing and address the translation gap. In future studies, the use of a diverse dose range, encompassing low, medium, and high doses, may allow for a comprehensive exploration of THC’s effects on locomotor activity. Interestingly, a comparison between the first and final locomotor sessions demonstrated a significant main effect of session, with distance traveled higher in the first session than the final session. We also found a significant drug effect, indicating that THC’s effect on locomotion does not habituate across eight sessions. These results may positively contribute to the use of low-dose oral THC, indicating no behavioral changes after repeated exposure to doses below 0.25mg/kg. Further, it is important to note the present study only examined behavioral and neurobiological changes induced by low doses or oral THC in adult male rats. Previous literature has suggested significant age and sex differences of oral THC in behavioral tasks (Kruse et al., 2019; Moore & Weerts, 2022; Wakley et al., 2014). Therefore, future studies should investigate effects of low-dose oral THC in females as well as adolescents.

In this short report, we were unable to measure THC and relevant metabolites in the blood. While this is an important focus for future work, previous studies have shown that blood THC metabolite concentrations do not accurately reflect the drug’s impairment properties (McCartney et al., 2022). However, our ability to replicate prior work with changes in CB1 expression in the hippocampus confirms that our doses of THC were crossing the blood brain barrier and active within the central nervous system. Repeated administration of THC dose-dependently reduced CB1 expression in the CA1 region of the hippocampus. While these results replicate previous findings (Lazenka et al., 2014), our study extends this literature by using a much lower dose range. Similarly, our study demonstrated no change in CB1 expression within the NAc core or shell after repeated, oral THC, replicating previous research (Kruse et al., 2019). There is no literature correlating CB1 expression and functioning to locomotion. Future studies should target CB1 expression within the ventromedial hypothalamus and cerebellum to gain a better understanding of CB1 receptors modulating locomotor behavior and examine how our model impacts hippocampal-dependent behaviors.

While our study contributes valuable insights into the behavioral and neurobiological effects of low-dose edible THC, several limitations should be considered. The present experiment investigates a preclinical model of voluntary consumption of low doses of oral THC. Human studies on the adverse effects of oral THC often use pure, synthetic analogs of THC, such as dronabinol (Marinol). These investigations showed that oral THC has a dose-dependent decline in attention, memory, and psychomotor performance (Curran et al., 2002). However, it’s crucial to recognize that these findings have limited applicability to recreational cannabis products. Contrary to prescribed medical grade products, recreational cannabis products are non-standardized, and often contain unknown amounts of THC, cannabidiol (CBD), and other phytocannabinoids (Lucas et al., 2018). Importantly, THC combined with CBD has differential effects in both behavioral and neurobiological investigations (Fadda et al., 2004; Hudson et al., 2019). Therefore, the findings of this experiment should be limited to the understanding for animal models of voluntary, oral, synthetic THC at low doses only. Additional studies are needed to build a greater understanding of oral and experimenter administered cannabis plant-derived products and dosing in preclinical models.

In conclusion, our study provides a comprehensive exploration of the behavioral and neurobiological effects of low-dose edible THC, addressing a critical gap in the existing literature. The observed dose-dependent relationship between THC and locomotor activity, coupled with alterations in CB1 receptor expression, adds valuable information to the growing body of cannabinoid research. Future studies should aim to refine our understanding of the translational relevance of rodent models and address potential confounds, ultimately advancing our knowledge of the therapeutic and behavioral implications of cannabis use.

Highlights:

  • Oral THC modulates locomotion in early sessions but does not persist over multiple days

  • Down-regulation of CB1 receptors is seen after repeated low-dose oral THC

  • Model replicates oral THC can be voluntarily consumed in rats for multiple weeks

Funding:

This work was supported by the National Institutes of Health [P20GM113109].

Footnotes

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Data Availability:

Data is available upon request

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Data Availability Statement

Data is available upon request

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