Preclinical abuse liability assessment of ABT-126, an agonist at the α7 nicotinic acetylcholine receptor (nAChR).

ABT-126 is a nicotinic acetylcholine receptor (nAChR) agonist that is selective for the α7 subtype of the receptor. nAChRs are thought to play a role in a variety of neurocognitive processes and have been a pharmacologic target for disorders with cognitive impairment, including schizophrenia and Alzheimer's disease. As part of the preclinical safety package for ABT-126, its potential for abuse was assessed. While the involvement of the α4ß2 subtype of the nicotinic receptor in the addictive properties of nicotine has been demonstrated, the role of the α7 receptor has been studied much less extensively. A number of preclinical assays of abuse potential including open-field, drug discrimination and self-administration were employed in male rats. ABT-126 had modest effects on locomotor activity in the open-field assay. In nicotine and d-amphetamine drug discrimination assays, ABT-126 administration failed to produce appreciable d-amphetamine-like or nicotine-like responding, suggesting that its interoceptive effects are distinct from those of these drugs of abuse. In rats trained to self-administer cocaine, substitution with ABT-126 was similar to substitution with saline, indicating that it lacks reinforcing effects. No evidence of physical dependence was noted following subchronic administration. Overall, these data suggest that ABT-126 has a low potential for abuse. Together with other literature on this drug class, it appears that drugs that selectively activate α7 nAChRs are not likely to result in abuse or dependence.

N-vinylpyrrolidone dimer, a novel formulation excipient, causes hepatic and thyroid hypertrophy through the induction of hepatic microsomal enzymes in rats.

N-vinylpyrrolidone dimer (VPD) is a novel experimental formulation excipient intended for preclinical toxicology studies. In a previous 4-week toxicity study, VPD induced dose-dependent hepatocellular and thyroid gland hypertrophy in Sprague-Dawley (SD) rats. The objectives of the current investigation were to define the underlying molecular mechanisms of these changes. Two separate studies were conducted using male SD rats, daily doses of 300, 1000 or 3,000 mg/kg of VPD, and a positive control (phenobarbital at 75 mg/kg/day): (1) a 28-day study to monitor thyroid hormone levels after 7 and 28 days of dosing; (2) a 5-day study to evaluate hepatic and thyroid gland transcriptomic changes, as well as hepatic UGT activity levels. At VPD dosages of 300 mg/kg/day and higher, 2-fold increases of serum thyroid stimulating hormone (TSH) levels were observed in male SD rats after 28 days of dosing, while serum thyroxine (T4) and triiodothyronine (T3) levels were unchanged. Liver UGT enzyme activity levels were increased in VPD-treated rats after 5 days. In addition, in the 5-day study, VPD caused increased hepatic mRNA levels of a panel of drug metabolizing enzymes (DMEs) and transporters, including Cyp3a1, Cyp2b1, Ugt 2b1, and Abcc3. Similar patterns of induction were observed in primary rat hepatocytes exposed to VPD. Transcriptomic changes in the thyroid gland were identified for genes involved in thyroid hormone biosynthesis and in the FAK, PTEN, and Wnt/ß-catenin signaling pathways. Collectively, these data indicate that VPD acts as an inducer of hepatic DMEs in SD rats and that this likely leads to enhanced peripheral metabolism of T3/T4, resulting in a feedback response characterized by increased serum TSH levels, and thyroid gland hypertrophy and hyperplasia.