Assessment of the associative determinants of tolerance to the effects of cannabis extract on exploratory behavior in rats.

Abstract

Experimental evaluation of cannabis tolerance has lacked an associative learning approach, focusing primarily on physiological variables. The present study assessed acute effects, chronic tolerance, and contextual specificity, exploring a potential associative component underlying cannabis tolerance. Sixteen adult Sprague-Dawley rats of both sexes were assigned to two groups, one receiving vaporized administrations of cannabis and the other receiving the vehicle substance, in two different counterbalanced contexts. An initial measurement was performed to assess acute effects, followed by four measurements to evaluate the development of chronic tolerance, and a final measurement to test the context specificity of tolerance, comparing the responses to the usual administration context and a novel context. Ten behaviors were analyzed in an open field. Acute effects were observed in seven indicators, corresponding to greater exploration activity in the group that received the drug compared to the control group. In five of these, the data also showed the development of chronic tolerance to the effects of cannabis on exploration, which was indicated by a progressive decrease in exploratory activity in the drug group. However, no evidence of context specificity was found in any variables in which chronic tolerance was observed. We discuss factors that may be related to the lack of contextual specificity of cannabis tolerance. Together, our findings show that a single administration of cannabis induces acute effects, and repeated exposure leads to chronic tolerance, ultimately reducing exploratory behavior.

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Keywords: Cannabis, Contextual specificity, Tolerance, Acute effects, Associative learning

Highlights

•Cannabis tolerance has rarely been studied from an associative learning perspective.
•Acute effects, chronic tolerance, and contextual specificity of cannabis were assessed using exploration indices.
•Cannabis initially reduced exploration, but this effect diminished with repeated administration.
•Tolerance was not specific to the administration context in any exploratory index.
•Cannabis produced both acute effects and tolerance in exploratory behavior.

Article notes

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Received 2025 Mar 15; Revised 2025 May 5; Accepted 2025 May 6; Collection date 2025 Jun.

Author notes

1.Introduction

Cannabis is the most widely used illicit drug globally (Carliner et al., 2017, Manthey et al., 2021; United Nations Office on Drugs and Crime, 2022). In 2020, 209 million people used cannabis, with a 23 % increase in use over the past decade (United Nations Office on Drugs and Crime, 2022). The drug contains over 400 chemical compounds, including more than 100 cannabinoids, with Δ-9-tetrahydrocannabinol (∆9-THC) being its main psychoactive component, affecting various cognitive processes (Atakan, 2012, Bourque and Potvin, 2021, Filbey et al., 2014, Freeman et al., 2019).

Research has mainly focused on the drug’s pharmacodynamics and health risks (Vigil et al., 2022), particularly its acute effects, including impacts on motor control (González et al., 2005), cognition (Broyd et al., 2016), and its potential therapeutic use for some disorders (Adams and Martin, 1996, Castaño et al., 2017; Mauzay, 2021). A significant acute effect is changes in exploratory behavior (Abood and Martin, 1992, Hampson and Deadwyler, 1999; Hollister, 1998; Pertwee, 1995), with cannabis causing biphasic dose-dependent effects: low doses increase hyperactivity, while high doses reduce exploratory behavior (Bruijnzeel et al., 2016, Katsidoni et al., 2013).

Chronic tolerance to cannabis refers to the progressive reduction in its acute effects following repeated use, often requiring higher doses to achieve the same initial response (Ritchie and Roser, 2019; San Martín et al., 2017). This phenomenon has been observed in both humans and animals (Colizzi and Bhattacharyya, 2018, Mason et al., 2021, Nguyen et al., 2018). The opponent-process motivational theory (Solomon and Corbit, 1974) explains chronic tolerance, suggesting that the drug’s primary effect is counteracted by an opposing response, which strengthens with repeated use, reducing the net effect of the drug, therefore causing tolerance. However, this model cannot explain why chronic tolerance sometimes occurs and sometimes does not, as it does not account for the contextual specificity effect demonstrated in both humans (Birak et al., 2011, McCusker and Brown, 1990, Shapiro and Nathan, 1986) and animals (Crowell et al., 1981, González et al., 2016, Siegel and Larson, 1996).

The compensatory conditioned response theory developed by Shepard Siegel provides an associative explanation of chronic drug tolerance that addresses the limitation of the opponent-process motivational theory (Siegel et al., 2000). According to this theory, the effect of drug administration on the central nervous system is considered an unconditional stimulus (US) that elicits an unconditioned response (UR) that compensates for the effects of the US. For instance, whenever an organism is repeatedly exposed to the same environmental cues when administered a drug. These cues will become CS that will elicit compensatory conditioned responses (CCR), thus counteracting the effect of the US.

Siegel's compensatory conditioned response model suggests that chronic drug tolerance is context-specific as demonstrated in several experiments (Poulos et al., 1981, Siegel, 1975, Siegel, 2001, Siegel, 2005, Siegel, 2008, Siegel, 2011, Siegel, 2016, Siegel et al., 2000). More specifically, it predicts that these phenomena will occur with greater magnitude in the presence of cues in which the drug is usually administered compared to new consumption contexts (González et al., 2019). This model has been successful in explaining chronic tolerance and contextual specificity of tolerance to different drugs, such as morphine (Siegel, 1975, Siegel, 1977), heroin (Siegel, 2016), ethanol (González et al., 2016), caffeine (Rozin et al., 1984), among others.

Siegel's model has not only been successful in explaining tolerance by cues or contexts associated with the drug effect but also withdrawal or craving (McCusker and Brown, 1990), and enigmatic overdose (Siegel, 2016) by consumption of the usual dose outside the usual context of administration. For example, McCusker and Brown's study demonstrates that contextual cues associated with alcohol consumption produce craving in individuals who regularly consume alcohol in social settings because CCRs are activated by drug cues, resulting in withdrawal symptoms if the drug is not present (González et al., 2019).

Despite the successes of this model, only one study has explored the association between a physical context and drug administration of a cannabinoid (for a review, see Ibáñez-Jiménez et al., 2023). Hill et al. (2004) used the cannabinoid agonist HU-210, which is 7 times stronger than THC, and found chronic tolerance but no contextual specificity of tolerance. To date, no study has examined the contextual specificity of tolerance to the primary psychoactive component of cannabis. Therefore, this study examined the acute effects, the development of chronic tolerance, and the contextual specificity of ∆9-THC-induced tolerance in rats, with the aim of understanding its impact on exploratory behavior and testing predictions derived from Siegel’s theory. Three hypotheses guided the experiment: 1) the first administration of cannabis extract will affect exploration in the Drug group compared to the Vehicle group, 2) repeated administration of cannabis extract will lead to tolerance to its effects on exploration, and 3) tolerance will be context-specific. Given the mixed findings in the literature (Bruijnzeel et al., 2016, Katsidoni et al., 2013), we did not formulate directional hypotheses regarding exploratory behavior.

2.Methods

2.1.Subjects

The subjects were 16 young adult Sprague-Dawley naïve rats, eight males and eight females. At the start of the experiment, all rats were 11 weeks old. Average weight at that time was 442.13 ± 37.91 g for males and 260.13 g ± 27.99 g for females. After ensuring that the groups had the same number of rats of each sex, male and female rats were separately assigned to each group using the Random UChile randomization tool (Random UChile, n.d.): Vehicle group (n = 8) and Drug group (n = 8). All procedures performed in the experiment were approved by the Institutional Animal Care and Use Committee of Universidad de Chile (19294-FCS-UCH-e2).

The number of subjects needed for detecting differences was determined using G*Power (Faul et al., 2007) based on effect sizes from similar studies and previous pilot work. For chronic tolerance, the effect size from Wakley et al. (2014), Cohen's f = 1.07) was used, and for contextual specificity, the effect size from Baptista et al. (1998), Cohen's f = 1.05) was employed. This led to a minimum of 6 subjects per group. However, to account for sex and physical context counterbalancing, a minimum of 8 subjects per group was established.

The animals were obtained from the biotherium of the Faculty of Chemical and Pharmaceutical Sciences at Universidad de Chile and were maintained in the biotherium of the Laboratorio de Psicología Experimental: Prof. Ronald Betancourt Mainhard of the Faculty of Social Sciences at Universidad de Chile. Experimental subjects were housed in same-sex and same-group pairs. The rats were kept throughout the experiment in home cages covered with a stainless-steel lid where food and water were placed on top. A 12/12 h light/dark cycle was followed on an 8 am/8 pm schedule. The temperature fluctuated between 20 and 24 °C.

One week before the start of the experiment, the rats were handled by the experimental personnel for at least 1 minute three times a week. At the beginning of the experiment, all rats weighed at least 160 g and had ad libitum access to water and food (Prolab RMH 3000 - Lab Diet®). Weights were monitored before the experiment, but no group weight differences were found.

2.2.Apparatus and materials

2.2.1.Open field

Four open fields (43.2 cm×43.2 cm×30.5 cm) were used to record exploration indices in rats. The walls were made of 15 mm thick transparent acrylic, and the floor was covered with matte black vinyl. The floor was digitally divided into a center (30.347 cm×30.347 cm) and peripheral zones (6.32 cm×43.2 cm) using EthoVision XT 16 software. Exploratory indices were recorded with Basler aca1920–155uc cameras equipped with Sony IMX174 sensors and f8mm lenses above the open fields. Data collection lasted 5 minutes per exposure. Distance-related indices (total, center, and periphery) and time-related indices (time in movement, immobility, center, and periphery) were measured with EthoVision XT 16 software. Non-exploratory behaviors, including rearing, grooming, and scratching, were manually scored.

2.2.2.Drug

An oil extract of Cannabis sativa spp. presenting a ratio of cannabidiol (CBD)/ ∆9-tetrahydrocannabinol (THC) < 1/ 400 mg/mL dissolved in ethanol was obtained from a local pharmaceutical company after sanitary approval from the Public Health Institute of Chile (ISP). Then, following established methods in the literature, ethanol was evaporated, and the THC was dissolved in propylene glycol to achieve the target concentration (Javadi-Paydar et al., 2018, Nguyen et al., 2016, 2020). Propylene glycol was sourced from Texas Industrial Solutions Advanced Lubricants, a nationally authorized distributor of pharmaceutical-grade material.

Cannabis was administered by vapor inhalation using a sealed vacuum controlled system that allowed a continuous airflow within each session (see Vaporizer). The Drug group received cannabis administrations of 400 mg/mL. In contrast, the Vehicle group was exposed to vaporization of the vehicle in which the cannabis was previously dissolved (i.e., propylene glycol), using a volume identical to that used to dissolve the drug.

The dose used, according to the protocol of Moore et al. (2021), is considered a high dose and was determined because the use of lower doses, according to the same protocol, failed to cause acute effects in pilots conducted in our laboratory.

2.2.3.Vaporizer

For vaporized delivery, a passive vaporization system called E-Vape™ Control System from La Jolla Alcohol Research, Inc. (La Jolla, CA, USA) was used. To deliver the scheduled series of puffs a Geek Vape Z cartridge of 0.4 ohms resistance and 60 W was employed. Airflow in the chamber was continuous throughout the session and controlled via a vacuum “pull” system that maintained a constant flow of ambient room air at approximately 1 L/min through an intake valve, as described in previous studies (Javadi-Paydar et al., 2018). Four chambers were used for the vaporized administration of both cannabis (in the Drug group) and the vehicle substance (in the Vehicle group). Each chamber was 42 cm long, 21 cm high, and 23 cm wide, separated by a noise-insulating glass side wall and a PVC ceiling and floor 59 cm long, 27 cm high, and 49.5 cm wide. After drug or vehicle administration, the chambers were cleaned using isopropyl alcohol to ensure they were not contaminated for the next session.

The vaporization system and the open field were in contiguous rooms. Experimental subjects were always transported in their home cages between each room.

2.2.4.Contexts

Two contexts, labeled A and B, were used to assess the contextual specificity of tolerance in both the open field and the vaporizing chamber. For the Drug group, Context A was associated with cannabis administration, and Context B with vehicle administration. The Vehicle group received the vehicle substance in both contexts.

Each context had distinct physical features, and these contexts were counterbalanced across subjects (See Fig. 1 for an illustration of the experimental contexts). One context included four cardboard walls with 2 cm thick black and white vertical stripes, LED lighting (two 59 cm strips) above both the vaporizing chamber and open field to ensure equal light intensity, and a constant 400 Hz tone emitted via two standard computer speakers. The other context featured 1.7 cm black and white horizontal stripes, dimmer lighting with only one of the two LED lights turned on, and white noise 6 dB above ambient noise. In both contexts, the floor was black—black vinyl covered the Plexiglas in the open field, and the vaporizing chamber floor was painted black. Additionally, the open field was equipped with a ceiling-mounted camera to record exploratory behavior.

This design allowed associative tolerance assessment through an intra-subject pseudo-conditioning control. The Drug group received the CS (context) - US (drug effect) pairing in one context and the CS (context) - vehicle exposure in another. The Vehicle group received the CS (context) - vehicle exposure in both contexts. The emergence of differential responses to the contexts during the contextual specificity test would provide evidence of conditioning (Robbins and Ehrman, 1992).

2.3.Procedure

2.3.1.Vaporized administration

During the 40-day experimental protocol, vaporized cannabis and/or vehicle were administered (See Figure S6 for a schematic representation of the experimental timeline). The Drug group received cannabis for 21 days (19 during training, 2 during the contextual specificity test), intercalated with 19 vehicle administrations during training. The administration protocol lasted 15 minutes for all subjects. For the Drug group, 16 puffs of cannabis vapor were administered (6 seconds per puff, 52-second intervals). The Vehicle group received 3 puffs of vehicle vapor (6 seconds per puff, 7-minute intervals). The difference in puffs between groups was due to matching the amount of vehicle for assessing the cannabis effects.

2.3.2.Training

Between days 1 and 38, all subjects received a daily administration session of cannabis or vehicle substance as appropriate for 15 min. The context of drug and vehicle administrations was counterbalanced across subjects.

On days 1, 2, 7, 8, 15, 16, 23, 24, 31, and 32, during the five minutes before (i.e., pre-vaporization measurement) and after vaporization (i.e., post-vaporization measurement) of either cannabis or vehicle, subjects were put into open fields to record exploratory indices. The exploratory behavior of four rats at a time was simultaneously recorded. On the remaining days of the protocol, rats were administered the drug and/or the vehicle depending on the group, without behavioral measurement.

Days 1 and 2 were used to assess the acute effects of cannabis on exploratory behavior. In contrast, days 7, 8, 15, 16, 23, 24, 31, and 32 were used to assess the development of chronic tolerance.

2.3.3.Contextual specificity test

Between days 39 and 40 of the experimental protocol, the Vehicle group was exposed for the first time to cannabis administration in both contexts. On the other hand, the Drug group was exposed to cannabis for the first time in the context where they had not previously received the drug (i.e., the novel context), while on one of the two test days, cannabis was also administered in the context where it had been consistently given during the training phase (i.e., the usual context). This design allowed for a within-subject comparison of responses across both contexts.

2.4.Coding

The scoring procedure ensured coders were blind to subject identity. A researcher renamed videos with random five-letter codes (e.g., yzzhj), and they were randomly assigned to one of nine coders.

Each video was scored twice by different coders. After the first round, videos were randomly reassigned. Subject identities were revealed only after the second coding for statistical analyses.

Inter-coder agreement was assessed using Cohen’s Kappa (κ =.85), indicating strong agreement (McHugh, 2012). Discrepancies were resolved through consensus discussion.

2.5.Data analysis

Statistical analyses were performed in StatSoft Statistica 12.5 software (TIBCO Software Inc., 2018), in which we implemented mixed ANOVAs for each of the exploratory indices measured. The comparisons between groups were planned comparisons aimed at evaluating each specific hypothesis. Type I errors were corrected using Hochberg's method for planned comparisons, and Tukey's HSD method was used for post hoc analyses. Cohen’s f was reported as the effect size for main effects and interactions, and ƞ2_p (partial eta squared) was used as the effect size for planned comparisons calculated using the Effect Size Calculators developed by Uanhoro (2017). The significance level was set at.05.

3.Results

3.1.Acute effects

The acute effects of drug administration were assessed by analyzing pre- and post-vaporization scores (Days 1 and 2) using a 2 × 2×2 mixed ANOVA. Factors included “group” as a between-subject variable and “pre-post” and “context” as within-subject variables. Planned comparisons examined both contexts' exploratory indices pre- and post-vaporization, expecting significant differences only in Context A post-vaporization (hypothesis 1). Results for all main effects, interactions, and planned comparisons not reported in this section are included in the Supplementary material (see Tables S1-S3 and Tables S11-S17).

The total distance traveled index showed a significant group x pre-post x context interaction, F(1, 14) = 6.75, p = .02, ƒ = 0.59. No group differences were found pre-vaporization, but they emerged in Context A post-vaporization, F(1, 14) = 8.27, p = .01, ƞ2_p = .37. Pre-post differences were significant in the Vehicle group in both contexts, but in the Drug group only in Context B (see Fig. 2A).

Fig. 2Acute effects on distance-related indices. Note. Distance traveled in cm/m is shown for three distance-related indices, considering the pre- and post-vaporization measurements of both groups, both in Context A (i.e., where the Drug group was exposed to cannabis) and Context B (i.e., where the Drug group received the vehicle substance). A) Scores on the total distance traveled index. B) Scores on the distance traveled index on the sides. C) Scores on the distance traveled index in the center. The bars represent the standard error of the mean. * indicates within-group differences in the Drug group, and † indicates within-group differences in the Vehicle group. The number of symbols reflects the level of statistical significance (e.g., *p < .05, **p < .01, ***p < .001).

The distance traveled on the periphery index showed a similar pattern, with a significant group x pre-post x context interaction, F(1, 14) = 5.26, p = .03, ƒ = 0.51. No group differences were found pre-vaporization, but significant differences appeared in Context A post-vaporization, F(1, 14) = 4.66, p = .04, ƞ2_p = .24. Pre-post differences were significant in the Vehicle group in both contexts, and in the Drug group only in Context B (see Fig. 2B).

The distance traveled in the center index did not show a significant group x pre-post x context interaction but did show group x context, F(1, 14) = 9.48, p = .008, ƒ = 0.72, and pre-post x context interactions, F(1, 14) = 6.01, p = .02, ƒ = 0.55. No group differences were found pre-vaporization, but post-vaporization differences emerged in Context A, F(1, 14) = 12.73, p = .003, ƞ2_p = .47. Additionally, post-vaporization differences were found in the Drug group between Context A and B, F(1, 14) = 14.97, p = .001, ƞ2p = ƞ2_p, as well as between the Drug group in Context A and the Vehicle group in Context B, F(1, 14) = 14.34, p = .002, ƞ2_p = .50 (see Fig. 2C).

For time in movement, a significant group x context interaction was found, F(1, 14) = 6.87, p = .02, ƒ = 0.60. No group differences were observed pre-vaporization, but post-vaporization differences emerged in Context A, F(1, 14) = 7.95, p = .01, ƞ2_p = .36. Pre-post differences were significant in the Vehicle group (both contexts) and the Drug group (only Context B) (see Fig. 3A).

Fig. 3Acute effects on time-related indices. Note. Time in seconds is shown for three time-related indices, considering pre- and post-vaporization measurements for both groups, both in Context A (i.e., where the Drug group was exposed to cannabis) and in Context B (i.e., where the Drug group received the vehicle substance). A) Scores on the movement time index. B) Scores on the immobility time index. C) Scores on the index of time spent in the center. The bars represent the standard error of the mean. * indicates within-group differences in the Drug group, † indicates within-group differences in the Vehicle group, and # indicates between-group differences between the Drug and Vehicle groups. The number of symbols reflects the level of statistical significance (e.g., *p < .05, **p < .01, ***p < .001).

Results mirrored the previous index for time in immobility, showing a significant group x context interaction, F(1, 14) = 6.87, p = .02, ƒ = 0.60. No group differences were found pre-vaporization, but significant differences appeared in Context A post-vaporization, F(1, 14) = 7.95, p = .01, ƞ2_p = .36. Pre-post differences were significant in the Vehicle group (both contexts) and the Drug group (only Context B) (see Fig. 3B).

For time in the center, a group x context interaction was found, F(1, 14) = 7.49, p = .01, ƒ = 0.63. No group differences were observed pre-vaporization, but post-vaporization differences appeared in Context A, F(1, 14) = 9.83, p = .007, ƞ2_p = .41. The Drug group spent more time in the center than the Vehicle group in Context A post-vaporization, but not in Context B (see Fig. 3C).

The exploratory index of time on the periphery showed no main effect or interaction above the significance threshold (all p-values >.05).

A significant group x pre-post x context interaction was found for grooming, F(1, 14) = 6.16, p = .02, ƒ = 0.56. No group differences pre-vaporization, but post-vaporization differences appeared in Context A, F(1, 14) = 10.43, p = .006, ƞ2_p = .42. Pre-post differences were significant only for the Drug group in Context A, F(1, 14) = 18.98, p < .001, ƞ2_p = .57 (see Fig. 4). Only a main pre-post effect was found for rearing, F(1, 14) = 18.73, p < .001, ƒ = 1.05, with no significant interactions. Finally, analysis was not possible for scratching as only 3 of 16 subjects exhibited this behavior.

Fig. 4Acute effects on non-exploratory activities. Note. The number of emissions of grooming behavior that subjects performed in the open field is shown according to the pre- and post-vaporization measurements of both groups, both in Context A (i.e., where the Drug group was exposed to cannabis) and Context B (i.e., where the Drug group received the substance vehicle). The bars represent the standard error of the mean. * indicates within-group differences in the Drug group. The number of symbols reflects the level of statistical significance (e.g., *p < .05, **p < .01, ***p < .001).

3.2.Chronic tolerance

Chronic tolerance was assessed using difference scores (DS) in indices showing acute cannabis effects. A 2 × 5×2 mixed ANOVA was used, with the variable "group" as a between-subjects factor and the variables "measurements" and "context" as within-subject factors. We hypothesized significant differences between groups in Context A during the initial but not in the final measurements (hypothesis 2). Non-reported effects are in Tables S4-S6 and Tables S18-S21.

For total distance traveled, a significant measurement x group x context interaction was found, F(4, 56) = 2.71, p = .03, ƒ = 0.33. Group differences appeared in Context A initially, F(1, 14) = 5.17, p = .03, ƞ2_p = .26, but disappeared by the second measurement, indicating tolerance. By the last measurement, differences reappeared with a lower DS in the Drug group, F(1, 14) = 5.03, p = .04, ƞ2_p = .26 (see Fig. 5A).

Fig. 5Chronic tolerance on distance-related indices. Note. Difference score (i.e., post-vaporization score - pre-vaporization score) on distance-related indices measured in cm/m in 5 time-spaced sessions in both Context A (i.e., where the Drug group was exposed to cannabis) and Context B (i.e., where the Drug group received the vehicle substance). A) Scores on the total distance traveled index. B) Scores on the distance traveled index on the sides. C) Scores on the distance traveled index in the center. Measurement 1 corresponds to days 1–2, Measurement 2 to days 7–8, Measurement 3 to days 15–16, Measurement 4 to days 23–24, and Measurement 5 to days 31–32 of the experimental protocol. The bars represent the standard error of the mean. * indicates within-group differences in the Drug group, and # indicates between-group differences between the Drug and Vehicle groups. Non-significant comparisons are labeled with their specific p-values. The number of symbols reflects the level of statistical significance (e.g., *p < .05, **p < .01, ***p < .001).

A similar interaction was found for distance traveled on the periphery, F(4, 56) = 3.15, p = .02, ƒ = 0.37. There was a non-significant tendency toward a difference in Context A, F(1, 14) = 3.69, p = .07, which disappeared in the second measurement. By the last session, the Drug group had a lower DS, F(1, 14) = 5.64, p = .03, ƞ2_p = .28 (see Fig. 5B).

For distance traveled in the center, significant measurement x group interaction, F(4, 56) = 3.40, p = .01.05, ƒ = 0.39 was found. The Drug group showed differences between Contexts in the first measurement, F(1, 14) = 8.27, p = .01, ƞ2_p = .37, but not in the Vehicle group. These differences disappeared in the second measurement and reversed in the fifth, F(1, 14) = 7.30, p = .01, ƞ2_p = .34 (see Fig. 5C).

A significant measurement x group x context interaction was found for both time in movement, F(4, 56) = 3.26, p = .01, ƒ = 0.38, and time in immobility, F(4, 56) = 3.26, p = .01, ƒ = 0.38. Planned comparisons showed significant group differences in the first measurement in Context A for time in movement, F(1, 14) = 5.30, p = .03, ƞ2_p = .27, and time in immobility, F(1, 14) = 5.29, p = .03, ƞ2_p = .27, but not in Context B. These differences disappeared in the second measurement (time in movement, F(1, 14) = 0.34, p = .56, ƞ2_p = .02; time in immobility, F(1, 14) = 0.34, p = .56, ƞ2_p = .02). By the last measurement, differences re-emerged in Context A but in the opposite direction of the acute effects (time in movement, F(1, 14) = 9.15, p < .009, ƞ2_p = .39; time in immobility, F(1, 14) = 9.15, p = .009, ƞ2_p = .39). No significant differences were observed in Context B (Figs. 6A, 6B).

Fig. 6Chronic tolerance on time-related indices. Note. Difference score (i.e., post-vaporization score - pre-vaporization score) on time-related indices measured in seconds in 5 time-spaced sessions in both Context A (i.e., where the Drug group was exposed to cannabis) and Context B (i.e., where the Drug group received the vehicle substance). A) Scores on the movement time index. B) Scores on the immobility time index. C) Scores on the time spent in the center index. Measurement 1 corresponds to days 1–2, Measurement 2 to days 7–8, Measurement 3 to days 15–16, Measurement 4 to days 23–24, and Measurement 5 to days 31–32 of the experimental protocol. The bars represent the standard error of the mean. # indicates between-group differences between the Drug and Vehicle groups. The number of symbols reflects the level of statistical significance (e.g., #p < .05, ##p < .01, ###p < .001).

For time in the center, a significant measurement x group interaction was found, F(4, 56) = 4.00, p = .006, ƒ = 0.44, but chronic tolerance could not be confirmed (Fig. 6C). Similarly, grooming did not show the expected interaction.

The acute effects observed earlier are confirmed using DS analysis, showing the development of tolerance to cannabis's acute effects in most exploratory indicators. From the second measurement onwards, the Drug group showed a reduction in exploration activity, while the Vehicle group maintained constant exploration. Considering that the DS analysis could mask the source of tolerance development (e.g., lower or higher activity in the pre- and post-vaporization measurements), a complementary analysis was performed with the raw data of all tolerance measurements, which revealed no significant pre-vaporization changes but significant post-vaporization changes in the Drug group (see Figures S1-S2, and Figure S5) and a trend in non-significant results (see Figures S3-S4).

3.3.Contextual specificity of tolerance

The contextual specificity of tolerance was assessed using the DS from experimental days 39–40 in indices previously showing chronic tolerance. A 2 × 2 mixed ANOVA was conducted with "group" as a between-subjects factor and "context" as a within-subject factor. Planned comparisons tested group differences in both contexts (hypothesis 3). No context × group interaction was found (all p > .05), but main effect of group was observed in all analyzed indices except distance traveled on the periphery (see Fig. 7A-7E). See Figure S7 for an analysis based on raw data. Results for all main effects and interactions not reported in this section are given in the Supplementary material (Tables S7-S9).

Fig. 7Contextual specificity of tolerance in indices with chronic tolerance. Note. The difference score (i.e., post-vaporization score - pre-vaporization score) in the assessment of the context specificity of tolerance for indices that previously showed the development of chronic tolerance is shown. Both groups received cannabis administration (the first administration being for the Vehicle group), either in the Usual context (i.e., where the Drug group had previously received the drug) and in the Novel context (i.e., where the Drug group had never received the drug). A) Scores on the total distance traveled index. B) Scores on the distance traveled on the sides index. C) Scores on distance traveled in the center index. D) Scores on the movement time index. E) Scores on the immobility time index. The bars represent the standard error of the mean.

These results suggest no contextual specificity of tolerance in any of the variables in which chronic tolerance was reported. We implemented a Bayesian Paired Samples T-Test to assess response similarity between the Usual Context and the Novel Context in the Drug group. The results show only anecdotal evidence in favor of the null hypothesis for all the indicators analyzed (van Doorn et al., 2021; see Table S10).

4.Discussion

The experiment aimed to evaluate the acute effects, the development of chronic tolerance, and the contextual specificity of tolerance on seven exploratory indices and three non-exploratory activities using vaporized administrations of cannabis. The findings of the present experiment show that a cannabis extract with a CBD:THC ratio < 1/400 mg/mL produced acute effects on exploratory behavior in seven out of ten indices analyzed (total distance traveled, distance on the periphery, distance traveled on the center, time in movement, time in immobility, time in the center, and grooming). These effects were associated with the maintenance of exploratory activity levels post-vaporization in the Drug group, in contrast to the Vehicle group, which showed a significant decrease in the same indices following vaporization of the vehicle substance. These effects may be explained by habituation, where typical initial exploration decreases over time (Bolivar et al., 2000). The Drug group’s-maintained activity in Context A (where cannabis was administered) suggests that cannabis may inhibit this habituation or briefly increase locomotor activity (Bruijnzeel et al., 2016, Schramm-Sapyta et al., 2007). It is also possible that vapor exposure in the Vehicle group was stressful (Baglot et al., 2021), which cannabis exposure might have alleviated.

In addition, results show that chronic tolerance to the effects of cannabis developed in five of those seven indices (total distance traveled, distance traveled on the periphery, distance traveled in the center, time in movement, and time in immobility), measured as the progressive decrease in the differences between groups in the indices evaluated. Our results showed that the Vehicle group increased responses from measurements 1–2, which contradicts habituation interpretation, suggesting that the initial reduction in exploration was more likely due to stress from vapor exposure rather than habituation (Baglot et al., 2021). The Drug group showed decreased exploration from measurement 3 onward, indicating tolerance development rather than attenuation of habituation inhibition. In sum, chronic consumption progressively decreases exploration in the Drug group, reaching characteristics of less exploratory behavior. Lastly, no contextual specificity of tolerance was observed in any of these exploratory indices.

Only one study has examined the associative component of cannabinoid tolerance (Hill et al., 2004). Unlike our experiment, it used female rats, HU-210 instead of cannabis extract, intraperitoneal administration, and a different experimental design but also measured exploratory activity. While Hill et al. found cannabis reduced exploratory behavior (i.e., hypolocomotion), our results suggest that cannabis administration increases exploratory behavior following vaporization, compared to the control group. Both studies, however, observed tolerance development after repeated administration and found no contextual specificity of tolerance. A key methodological difference between studies lies in the age of the animals employed. Hill et al. used 14-month-old rats which, according to Ghasemi et al. (2021), correspond to mature adulthood. In contrast, our study employed 11-week-old rats, a developmental stage considered emerging adulthood. This age disparity may help explain the divergent acute effects on exploratory behavior observed between the two studies. Supporting this interpretation, Schramm-Sapyta et al. (2007) reported age-related differences in the locomotor effects of THC, with adolescent rats exhibiting a slight increase in activity—consistent with our findings. Finally, the use of both male and female rats in this study may also contribute to the difference in effects compared to Hill et al. (2004); however, this explanation cannot be adequately assessed due to the limited number of subjects used in this study.

Our experiment found no contextual specificity of tolerance, contradicting the compensatory conditioned response theory (Siegel et al., 2000). While this model explains tolerance for many drugs, our results suggest cannabis tolerance is not context specific. This aligns more with the opponent-process theory (Solomon and Corbit, 1974). This non-associative model explains tolerance through two processes: the primary state elicited by the drug, which in this case is indicated by greater exploration in the Drug group during the measurement of acute effects and, subsequently, the opponent reaction that would be linked to the opposite effects, which in this case would be a decrease in exploratory activity not specific to the usual context of administration, as suggested by our data. Another theory that could explain the results obtained is Baker and Tiffany's (1985) explanation of tolerance as habituation, which uses associative and non-associative routes to explain the tolerance process, following the habituation model proposed by Wagner (1976). The non-associative route of the model could explain the results obtained. The model posits that self-generated priming, through previous exposure to the drug, leads to a representation of the effects of the drug in short-term memory, reducing its effects (see Prados et al., 2020; Sal et al., 2021). In the case of our experiment, the route of administration through several puffs of cannabis vapor may lead to the first puff of drug activating the drug representation via self-generated priming, which has been found to decrease the associability of a cue or context (Baker and Tiffany, 1985) and could explain the lack of context specificity.

Several factors may explain the absence of context specificity of tolerance. First, the number of context-drug pairings, though consistent with prior studies (González et al., 2016, Siegel and Larson, 1996), may have been insufficient. Second, the contexts—despite differences in sound, lighting, and wall patterns—may not have been sufficiently distinct, possibly due to vapor obscuring visual cues. More salient features like odors or textures could be considered (Burn, 2008). Third, cannabis may impair attention, memory, and learning (Kroon et al., 2021), affecting discrimination between contexts (Mishima et al., 2001). Finally, differences in metabolism and half-life compared to drugs like morphine (Hinson and Siegel, 1983) may have disrupted conditioning processes (Hill et al., 2004). Finally, intraadministration associations—in which early drug effects act as internal cues—may overshadow environmental stimuli, limiting context-drug associations and thus context specificity (Kim et al., 1999).

The open field test is widely used to assess anxiety in rodents, with center time as a key indicator (Lezak et al., 2017, Prut and Belzung, 2003). In this study, cannabis produced no clear anxiolytic or anxiogenic effects. Slight, non-significant changes in center time and peripheral activity after cannabis administration suggest a general maintenance of exploration rather than anxiety modulation. Future studies should include additional anxiety-related measures and assess dose-dependent effects. Finally, findings underscore the need for further research on cannabis tolerance, including populations with prenatal exposure. Despite increasing rates of gestational cannabis use, its impact on offspring remains unclear (Cupo et al., 2024; Singh et al., 2020). Therefore, future studies could explore whether such exposure influences the development or context specificity of tolerance (Ramírez et al., 2022).

CRediT authorship contribution statement

Vergés Alvaro: Writing – review & editing, Supervision. Ibáñez-Jiménez Esperanza: Writing – review & editing, Investigation, Conceptualization. Laborda Mario A.: Writing – review & editing, Writing – original draft, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. Quezada-Scholz Vanetza E.: Writing – review & editing, Supervision, Conceptualization. Ramírez Simón: Writing – review & editing, Investigation, Conceptualization. Aguilar Camila: Writing – review & editing, Investigation, Conceptualization. Alfaro Felipe: Writing – review & editing, Investigation, Conceptualization. Badilla Jonathan: Writing – review & editing, Investigation, Conceptualization. Bustamante Javier: Writing – review & editing, Supervision. Bertin Francisca: Writing – review & editing, Investigation, Conceptualization. Fuentealba José A.: Writing – review & editing, Supervision. Varas Felipe I.: Writing – review & editing, Writing – original draft, Visualization, Investigation, Formal analysis, Data curation, Conceptualization. Angulo Rocío: Writing – review & editing, Supervision. Miguez Gonzalo: Writing – review & editing, Supervision, Methodology, Funding acquisition, Formal analysis, Conceptualization.

Ethics approval

All procedures performed in the experiment were approved by the Institutional Animal Care and Use Committee of the Universidad de Chile, protocol 19294-FCS-UCH-e2.

Consent for publication

All the authors expressly consent to the publication of the work.

Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGPT to improve the readability and language of the manuscript. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Funding

This research was funded by the project ANID-Fondecyt 1191619, which was granted to MAL. In addition, the authors are grateful to the National Agency for Research and Development of Chile (ANID-Chile) for supporting the work of the Research Group in Experimental Psychology and Psychopathology, Department of Psychology, Faculty of Social Sciences, Universidad de Chile. Project ANID-Fondecyt 1220797 supported GM, project ANID-Fondecyt 11170143 supported VEQ-S, project ANID-Fondecyt Postdoctorado 3200226 supported FA, project ANID-Fondecyt Postdoctorado 3210212 supported FB, project ANID-Fondecyt 11200561 supported JBustamante, and project ANID-Fondecyt 1201679 supported AV.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank Catalina Fuentealba, Antonia Mardonez, Paulina Pino, and anonymous reviewers for their comments on earlier versions of the manuscript. The authors are very grateful to Mauro Iturriaga for his assistance implementing the experiment. We also thank Francisca Droguett, Catalina Fuentealba, Matías González, Pilar Herrera, Antonia Mardonez, Paulina Pino, Viviana Sáez, and Laura Velásquez for their collaboration in the manual coding required for the experiment. Finally, we thank Sophie De Bona for her assistance in preparing the extract used in the experiment.

Footnotes

Footnote Group

Appendix A.Supplementary material

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

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References

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Associated Data

Supplementary Materials

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Studies

Conditions

Cannabinoids and active compounds

Related research

Abstract

Untitled section

Highlights

Article notes

Untitled section

Author notes

1.Introduction

2.Methods

2.1.Subjects

2.2.Apparatus and materials

2.2.1.Open field

2.2.2.Drug

2.2.3.Vaporizer

2.2.4.Contexts

2.3.Procedure

2.3.1.Vaporized administration

2.3.2.Training

2.3.3.Contextual specificity test

2.4.Coding

2.5.Data analysis

3.Results

3.1.Acute effects

3.2.Chronic tolerance

3.3.Contextual specificity of tolerance

4.Discussion

CRediT authorship contribution statement

Ethics approval

Consent for publication

Declaration of Generative AI and AI-assisted technologies in the writing process

Funding

Declaration of Competing Interest

Acknowledgments

Footnotes

Footnote Group

Appendix A.Supplementary material

Data availability

References

Untitled section

References

Associated Data

Supplementary Materials

Data Availability Statement

Additional materials