Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at 1 and 2/3 Subtypes

Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 09/2009; 332(1):4-16. DOI: 10.1124/jpet.109.158303
Source: PubMed


Abuse-liability-related effects of subtype-selective GABA(A) modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at alpha(1)-, alpha(2)-, alpha(3)-, and alpha(5)-containing GABA(A) receptors, whereas 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) has weaker partial agonist efficacy at alpha(2) and alpha(3) and none at alpha(1) and alpha(5) subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032-0.1 mg/kg) and TPA023 (0.0032-0.32 mg/kg) was compared with lorazepam (0.01-0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self-injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [(11)C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the alpha(1) subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced alpha(2/3) subtype efficacy.

19 Reads
  • Source
    • "All had experience with one (PY) to five (YO) such studies of novel GABA-A allosteric modulators (Ator et al., 2010). Two baboons (GD, PY) had also served in an intravenous self-administration procedure in which they had experience with cocaine and five or six sedative/ anxiolytic compounds (Ator et al., 2010), and PY had experience with oral ethanol self-administration. Otherwise, GD, SHA, and YO had experience with bolus i.g. "
    [Show abstract] [Hide abstract]
    ABSTRACT: (±)-3,4-Methylenedioxymethamphetamine HCl (MDMA, "Ecstasy") is a popular drug of abuse. We aimed to characterize the behavioral effects of intragastric MDMA in a species closely related to humans and to relate behavioral effects to plasma MDMA and metabolite concentrations. Single doses of MDMA (0.32 - 7.8 mg/kg) were administered via an intragastric catheter to adult male baboons (N=4). Effects of MDMA on food-maintained responding were assessed over a 20-h period, while untrained behaviors and fine-motor coordination were characterized every 30 min until 3 h post-administration. Levels of MDMA and metabolites in plasma were measured in the same animals (N=3) following dosing on a separate occasion. MDMA decreased food-maintained responding over the 20-h period, and systematic behavioral observations revealed increased frequency of bruxism as the dose of MDMA was increased. Drug blood level determinations showed no MDMA after the lower doses of MDMA tested (0.32-1.0 mg/kg) and modest levels following higher MDMA doses (3.2-7.8 mg/kg). High levels of 3,4-dihydroxymethamphetamine (HHMA) were detected after all doses of MDMA, suggesting extensive first-pass metabolism of MDMA in the baboon. The present results demonstrate that MDMA administered via an intragastric catheter produced behavioral effects that have also been reported in humans. Similar to humans, blood levels of MDMA following oral administration may not be predictive of the behavioral effects of MDMA. Metabolites, particularly HHMA, may play a significant role in the behavioral effects of MDMA.
    Journal of Pharmacology and Experimental Therapeutics 03/2013; 345(3). DOI:10.1124/jpet.113.203729 · 3.97 Impact Factor
  • Source
    • "Drug history, including the type of drug used for self-administration training, has been shown to be a major determinant of the reinforcing effects of benzodiazepines (Nelson et al, 1983; Bergman and Johanson, 1985; Falk and Tang, 1989). Therefore, we examined self-administration of the different a1-sparing compounds described above in monkeys trained to self-administer either a benzodiazepine agonist (midazolam), or the psychomotor stimulant cocaine, in order to match the training conditions of Ator et al (2010). For comparisons across the two baseline conditions, we also included tests with non-selective benzodiazepine full agonists (midazolam, lorazepam) and a non-selective benzodiazepine partial agonist (MRK-696, see Table 1; Figure 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Benzodiazepines are prescribed widely but their utility is limited by unwanted side effects, including abuse potential. The mechanisms underlying the abuse-related effects of benzodiazepines are not well understood, although α1 subunit-containing GABA A receptors have been proposed to have a critical role. Here, we examine the reinforcing effects of several compounds that vary with respect to intrinsic efficacy at α2, α3, and α5 subunit-containing GABA A receptors but lack efficacy at α1 subunit-containing GABA A receptors ('α1-sparing compounds'): MRK-623 (functional selectivity for α2/α3 subunit-containing receptors), TPA023B (functional selectivity for α2/α3/α5 subunit-containing receptors), and TP003 (functional selectivity for α3 subunit-containing receptors). The reinforcing effects of the α1-sparing compounds were compared with those of the non-selective benzodiazepine receptor partial agonist MRK-696, and non-selective benzodiazepine receptor full agonists, midazolam and lorazepam, in rhesus monkeys trained to self-administer midazolam or cocaine, under a progressive-ratio schedule of intravenous (i.v.) drug injection. The α1-sparing compounds were self-administered significantly above vehicle levels in monkeys maintained under a midazolam baseline, but not under a cocaine baseline over the dose ranges tested. Importantly, TP003 had significant reinforcing effects, albeit at lower levels of self-administration than non-selective benzodiazepine receptor agonists. Together, these results suggest that α1 subunit-containing GABA A receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of stimulant self-administration, whereas α3 subunit-containing GABA A receptors may be important mediators of the reinforcing effects of benzodiazepine-type compounds in animals with a history of sedative-anxiolytic/benzodiazepine self-administration.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; 38(6). DOI:10.1038/npp.2012.265 · 7.05 Impact Factor
  • Source
    • "It is important for future research to investigate whether anxiolytic cross-tolerance to the effect of TPA023 (or other subtype selective compound) is demonstrable in rodents chronically exposed to diazepam. If GABAA-α2/α3 subtype selective drugs do not induce tolerance in man, such subtype selective compounds might not engender clinical dependence [12], [61] or potentially drug abuse [62], [63]. This would constitute a significant clinical improvement over classical benzodiazepines in addition to GABAA-α2/α3 selective compounds' reduced propensity to engender sedation and postural instability [64]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Within the GABA(A)-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABA(A)-receptor subtypes. We investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABA(A)-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (α(1) selective) and TPA023 (α(2/3) selective). In-vivo binding studies with [(3)H]flumazenil confirmed compounds occupied CNS GABA(A) receptors. Chronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects. OUR DATA INDICATE THAT: (i) GABA(A)-α(2)/α(3) subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions); (iii) tolerance to diazepam's sedative actions needs concomitant activation of GABA(A)-α(1)/GABA(A)-α(5) receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABA(A) α(1), α(2) or α(5) subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABA(A) α(2), or α(3) receptors does not engender tolerance development, subtype-selective GABA(A) drugs might constitute a promising class of novel drugs.
    PLoS ONE 08/2012; 7(8):e43054. DOI:10.1371/journal.pone.0043054 · 3.23 Impact Factor
Show more

Similar Publications


19 Reads
Available from