Separate and combined effects of the GABA_B agonist baclofen and Δ⁹-THC in humans discriminating Δ⁹-THC

Abstract

Background

Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ⁹-THC. The aim of the present study was to determine the potential involvement of the GABA_B receptor subtype by assessing the separate and combined effects of the GABA_B-selective agonist baclofen and Δ⁹-THC using pharmacologically specific drug-discrimination procedures.

Methods

Eight cannabis users learned to discriminate 30 mg oral Δ⁹-THC from placebo and then received baclofen (25 and 50 mg), Δ⁹-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected.

Results

Δ⁹-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ⁹-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ⁹-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ⁹-THC-like subjective responses when administered alone.

Conclusions

These results suggest that the GABA_B receptor subtype is involved in the abuse-related effects of Δ⁹-THC, and that GABA_B receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA_A) to determine the contribution of the different GABA receptors in the effects of Δ⁹-THC, and by extension cannabis, in humans.

Introduction

In a previous study we investigated the potential involvement of γ-aminobutyric acid (GABA) in the discriminative-stimulus effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in humans by administering the GABA reuptake inhibitor tiagabine in subjects trained to discriminate oral Δ⁹-THC (Lile et al., 2012). Tiagabine alone occasioned Δ⁹-THC-appropriate responding, and significantly enhanced drug-appropriate responding when combined with Δ⁹-THC. Similar potentiation was observed on self-report and performance measures. Those results were consistent with observations from another experiment in which the CB agonist nabilone was administered alone and in combination with Δ⁹-THC (Lile et al., 2011). The leftward/upward shift in the dose–effect curves across several cannabinoid-sensitive measures following tiagabine administration, and the similarity to the results obtained with nabilone, indicate that GABA is involved in the behavioral effects of cannabinoids in humans. Because tiagabine modulates GABA activity by blocking reuptake transporters, thereby producing global elevations in GABA levels, the contribution of specific receptor subtypes could not be determined in our previous study.

There are two well characterized GABA receptor subtypes, ionotropic GABA_A and metabotropic GABA_B receptors, and prior research has implicated both in the behavioral and physiological effects of cannabinoids. With respect to GABA_B, a preclinical study found that Δ⁹-THC and baclofen both decreased open field locomotor activity in rodents, and the GABA_B antagonist CGP 35348 reversed the locomotor-decreasing effects of both drugs (Romero et al., 1996). In addition, baclofen augmented the catalepsy produced by Δ⁹-THC in rodents (Pertwee et al., 1988). Preclinical studies that have tested cannabinoid and GABA_B agonists separately have demonstrated overlap in their pharmacological profiles; specifically, these drugs are anxiolytic (Moreira and Wotjak, 2010, Pilc and Nowak, 2005), induce hypothermia (Frosini et al., 2004, Wenger and Moldrich, 2002), impair memory processes (Castellano et al., 2003, DeSousa et al., 1994), and produce peripheral antinociception (Dario et al., 2007, Hohmann, 2002).

GABA participation in the effects of cannabinoids in humans, particularly GABA_B, has received less attention. There appears to be only a single clinical research study that has combined a GABA_B agonist (baclofen) with a cannabinoid under controlled laboratory conditions (Haney et al., 2010). In that study, daily cannabis users were maintained on 60 and 90 mg/day of baclofen (20 and 30 mg, t.i.d.) and then received active (3.3% Δ⁹-THC) and placebo cannabis. Baclofen significantly decreased self-reported ratings of High and Want Marijuana, but did not impact cannabis self-administration in a relapse model of cannabis use. In addition, a case study of six male patients with cannabis dependence suggested that 40 mg/day baclofen treatment reduced the signs and symptoms of cannabis withdrawal and facilitated abstinence (Nanjayya et al., 2010). Further clinical research with GABA_B compounds is warranted given the important objective of identifying medications to manage cannabis-use disorders (Vandrey and Haney, 2009).

The purpose of this experiment was therefore to determine the potential involvement of the GABA_B receptor subtype in the clinical effects of Δ⁹-THC by assessing the separate and combined effects of Δ⁹-THC and the preferential GABA_B agonist baclofen using drug-discrimination procedures. The discriminative-stimulus effects of a drug are concordant with the central actions of a drug at the receptor level, and are therefore pharmacologically specific (Holtzman and Locke, 1988). For example, in previous studies in which human subjects learned to discriminate Δ⁹-THC, the cannabinoid agonist nabilone, but not methylphenidate, triazolam or hydromorphone, occasioned drug-appropriate responding, whereas each of these drugs increased positive drug–effect questionnaire ratings (Lile et al., 2009, Lile et al., 2010). In the present study, findings from the drug discrimination task were supplemented by testing the subject-rated, psychomotor performance, cardiovascular and thermoregulatory effects of baclofen and Δ⁹-THC separately and in combination.