Separate and combined effects of the GABAB agonist baclofen and Δ9-THC in humans discriminating Δ9-THC
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 GABAA and metabotropic GABAB receptors, and prior research has implicated both in the behavioral and physiological effects of cannabinoids. With respect to GABAB, a preclinical study found that Δ9-THC and baclofen both decreased open field locomotor activity in rodents, and the GABAB 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 GABAB 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 GABAB, has received less attention. There appears to be only a single clinical research study that has combined a GABAB 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 GABAB 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 GABAB receptor subtype in the clinical effects of Δ9-THC by assessing the separate and combined effects of Δ9-THC and the preferential GABAB 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.
Section snippets
Subjects
Adults with a history of cannabis use were recruited from the local community. Potential subjects completed demographic, drug-use history and medical history questionnaires, as well as medical screens. Individuals with current or past histories of Axis I or DSM-IV psychiatric disorder, including substance dependence disorders other than nicotine, were excluded from participating. Substance abuse was not an exclusion criterion. The Institutional Review Board of the University of Kentucky Medical
Drug-discrimination task
All subjects met the discrimination criterion, which took an average of 4.3 sessions (range = 4–6). During the final four sessions of the control phase, subjects reported an average of 0.0 (SEM = 0.0) percent Δ9-THC-appropriate responding on the drug-discrimination task during placebo sessions and 100.0 (SEM = 0.0) percent drug-appropriate responding during sessions when the training dose of Δ9-THC (i.e., 30 mg) was administered.
The two-factor, repeated-measure ANOVA revealed a significant main effect
Discussion
The aim of this study was to assess the separate and combined effects of the preferential GABAB agonist baclofen and Δ9-THC using drug-discrimination procedures. Δ9-THC functioned as a discriminative stimulus and dose-dependently occasioned drug-appropriate responding. The larger baclofen dose alone occasioned Δ9-THC-appropriate responding, and when combined with Δ9-THC, both baclofen doses significantly enhanced drug-appropriate responding. Similar potentiation of baclofen and Δ9-THC dose
Role of funding source
This research and the preparation of this manuscript were supported by grants from the National Institute on Drug Abuse (K02 DA031766 and R01 DA025605) awarded to Dr. Joshua Lile. These funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
Drs. Lile, Kelly and Hays designed the study. Dr. Lile wrote the protocol; managed literature searches and summaries of previous related work; undertook the statistical analysis and graphical representation of the data; and wrote the first draft of the manuscript. Dr. Hays provided medical management and oversight. All authors contributed to and have approved the final manuscript.
Conflict of interest
There are no conflicts of interest to declare.
Acknowledgements
We appreciate the pharmacy services of Dr. Steve Sitzlar of the University of Kentucky Investigational Drug Service. We also thank Beth Eaves, Cleeve Emurian, Dustin Lee, Jillian O’Rourke and Glenn Robbins for expert technical assistance.
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