Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes

Abstract

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 ␣ 1 -, ␣ 2 -, ␣ 3 -, and ␣ 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 ␣ 2 and ␣ 3 and none at ␣ 1 and ␣ 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 ␣ 1 subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced ␣ 2/3 subtype efficacy.When they were introduced in the early 1960s, the benzodiazepines, typified by diazepam, represented a major advance in the treatment of generalized anxiety disorder relative to older treatments (Lader, 1993). They had a rapid onset of anxiolytic efficacy, were generally well tolerated, and relatively safe in overdose. Nevertheless, beginning in the late 1970s, concerns over the abuse potential and dependence liability of benzodiazepines resulted in more restrictive legislation (i.e., legal scheduling under the Controlled Substances Act in the United States in 1975 and by the World Health Organization in 1982) as well as a general reluctance of physicians to prescribe benzodiazepines (Williams and McBride, 1998). Benzodiazepines are abused by people who have a history of drug abuse, those on long-term benzodiazepines may independently escalate their dosage, patients can be overly reluctant to comply with physician recommendations to reduce benzodiazepine use, and there is considerable evidence of adverse ...

Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

“…Supporting this, the a1-sparing compound, TPA023, was not self-administered by baboons up to doses that completely occupied benzodiazepine binding sites as measured via positron emission tomography (Ator et al, 2010). Moreover, mice with point mutations rendering the a1GABA A receptor insensitive to benzodiazepines did not show a preference for oral midazolam vs sucrose solutions, in contrast to wild-type mice (Tan et al, 2010).…”

“…A possibility is the differences in the pharmacological profiles of the two compounds: TPA023 has notably lower intrinsic efficacy in vitro (measured via Cl-conductance in cloned human receptor subtypes) than L-838,417, with the highest efficacy for TPA023 at a3GABA A receptors whereas L-838 417 is equi-effective at a2GABA A , a3 GABA A , and a5GABA A receptors, raising the possibility that differences in levels of intrinsic efficacy could be key factors mediating selfadministration (for reviews, see Licata and Rowlett, 2008;Atack, 2011). Moreover, TPA023 likely has a relatively long duration of action (Atack et al, 2006Ator et al, 2010) while that of L-838 417 is shorter (Rowlett et al, 2005;Licata et al, 2010;J.R. Atack, unpublished data).…”

“…Although there are several differences between the studies of Ator et al (2010) and Rowlett et al (2005), one potentially important difference is training/maintenance drug (cocaine vs methohexital). 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).…”

“…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).…”

Neural Basis of Benzodiazepine Reward: Requirement for α2 Containing GABAA Receptors in the Nucleus Accumbens

“…First, there is evidence of abuse of the a1-preferring compound zolpidem by polydrug users (eg, Hajak et al, 2003;Evans et al, 1990) and second, some evidence that this drug might also have at least mild positive subjective effects in drug-naïve subjects (Licata et al, 2011). This drug has also been shown to maintain self-administration in primates (eg, Rowlett and Lelas, 2007;Ator, 2002;Griffiths et al, 1992, Rowlett et al, 2005; see also Ator et al, 2010). In mice, the positive modulation of a1GABA A Rs was found to be necessary for midazolam preference in a two-bottle choice drinking paradigm, which has also been called 'oral midazolam self-administration' (Tan et al, 2010).…”