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Meta-Analysis
. 2018 Aug 16;25(9):446-454.
doi: 10.1101/lm.046870.117. Print 2018 Sep.

Highway to Hell or Magic Smoke? The Dose-Dependence of Δ 9-THC in Place Conditioning Paradigms

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Free PMC article
Meta-Analysis

Highway to Hell or Magic Smoke? The Dose-Dependence of Δ 9-THC in Place Conditioning Paradigms

Rimas A Kubilius et al. Learn Mem. .
Free PMC article

Abstract

The prerequisites for responsible cannabis use are at the heart of current inquiries into cannabis decriminalization by policy makers as well as academic and nonacademic stakeholders at a global scale. Δ9-tetrahydrocannabinol (Δ9-THC), the prime psychoactive compound of the cannabis sativa, as well as cannabimimetics that resemble the pharmacological properties and psychological effects of Δ9-THC, lend themselves handsomely to the preclinical scrutiny of reward-related behavior because they carry marked translational value. Although a functional dichotomy of the psychological effects of Δ9-THC (rewarding versus aversive) has been abundantly reported in place conditioning (PC) paradigms, and might be best attributed to a dose-dependence of Δ9-THC, most PC studies with Δ9-THC feature no significant effects at all. Therefore, after decades of rigorous research, it still remains undetermined whether Δ9-THC generally exerts rewarding or aversive effects in rodents. Here, we set out to extrapolate the commonly alleged dose-dependence of the rewarding and aversive effects of Δ9-THC from the existing literature, at the behavioral pharmacological level of analysis. Specifically, our meta-analysis investigated: (i) the alleged bidirectional effects and dose-dependence of Δ9-THC in the PC test; (ii) methodological inconsistencies between PC studies; and (iii) other pharmacological studies on cannabinoids (i.e., dopamine release, anxiety, stress, conditioned taste aversion, catalepsy) to substantiate the validity of PC findings. Our findings suggest that: (i) Δ9-THC dose-dependently generates rewarding (1 mg/kg) and aversive (5 mg/kg) effects in PC; (ii) an inconsistent use of priming injections hampers a clear establishment of the rewarding effects of Δ9-THC in PC tests and might explain the seemingly contradictory plethora of nonsignificant THC studies in the PC test; and (iii) other pharmacological studies on Δ9-THC substantiate the dose-dependent biphasic effects of Δ9-THC in PC. A standardized experimental design would advance evidence-based practice in future PC studies with Δ9-THC and facilitate the pointed establishment of rewarding and aversive effects of the substance.

Figures

Figure 1.
Figure 1.
Schematic illustration of the PC paradigm. (A) 2-compartment apparatus. (B) 3-compartment apparatus. Conditioned place preference (CPP) is established by either significantly more time spent in the drug-paired compartment (DPC) after conditioning than before (i.e., test versus preexp. DPC) or significantly more time spent in the DPC than in the vehicle-paired compartment (VPC) during test (i.e., DPC versus VPC). Conditioned place aversion (CPA) is operationalized by either significantly less time spent in the DPC after conditioning than before (i.e., test versus preexp. DPC) or significantly less time spent in the DPC than in the VPC during test (i.e., DPC versus VPC). In a three-compartment setting, the time spent in the nonpaired compartment (NPC) is in most studies not included into the measurement of a CPP or CPA.
Figure 2.
Figure 2.
Prevalence and dose-dependency of CPP, CPA, and nonsignificant effects (NE) with Δ9-THC. (A) The majority of studies has been performed with doses ≤1 mg/kg, and failed to reveal any effect at all (NE). (B) Dose-dependent distribution of CPPs, aversions (CPA), and no significant effects (NE) with Δ9-THC [KW(3) = 24.12, (***) P < 0.0001, Kruskal–Wallis, followed by Dunn's multiple post hoc test]. (C) Studies with drug priming show a bias toward the development of CPP, whereas studies without drug priming often fail to reveal any effect [χ2(1) = 6.352, ($) P = 0.0117].
Figure 3.
Figure 3.
Other dose-dependent appetitive (green) and aversive (red) effects of Δ9-THC. Results of individual experiments/ groups are plotted as black dots (median values as black lines); statistics: Wilcoxon signed rank test (one-sided question), P < 0.05 versus median of CPA and CPP, respectively. Median values of CPPs (1 mg/kg), CPAs (5 mg/kg), and NEs (1 mg/kg; cf. Fig. 2B) are incorporated as green, red, and gray dashed lines, respectively; dose ranges of CPPs, CPAs, and NEs are illustrated in the respective (yet fainter) colors. # (red) p < 0.05 versus median of CPA, # (green) p < 0.05 versus median of CPP (Wilcoxon signed test).

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