The role of the SLC6A3 3' UTR VNTR in nicotine effects on cognitive, affective, and motor function.

RATIONALE: Nicotine has been widely studied for its pro-dopaminergic effects. However, at the behavioural level, past investigations have yielded heterogeneous results concerning effects on cognitive, affective, and motor outcomes, possibly linked to individual differences at the level of genetics. A candidate polymorphism is the 40-base-pair variable number of tandem repeats polymorphism (rs28363170) in the SLC6A3 gene coding for the dopamine transporter (DAT). The polymorphism has been associated with striatal DAT availability (9R-carriers > 10R-homozygotes), and 9R-carriers have been shown to react more strongly to dopamine agonistic pharmacological challenges than 10R-homozygotes. OBJECTIVES: In this preregistered study, we hypothesized that 9R-carriers would be more responsive to nicotine due to genotype-related differences in DAT availability and resulting dopamine activity. METHODS: N=194 non-smokers were grouped according to their genotype (9R-carriers, 10R-homozygotes) and received either 2-mg nicotine or placebo gum in a between-subject design. Spontaneous blink rate (SBR) was obtained as an indirect measure of striatal dopamine activity and smooth pursuit, stop signal, simple choice and affective processing tasks were carried out in randomized order. RESULTS: Reaction times were decreased under nicotine compared to placebo in the simple choice and stop signal tasks, but nicotine and genotype had no effects on any of the other task outcomes. Conditional process analyses testing the mediating effect of SBR on performance and how this is affected by genotype yielded no significant results. CONCLUSIONS: Overall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype.

Raman Imaging as a powerful tool to elucidate chemical processes in a matrix: Medicated chewing gums with nicotine.

Extruded medicated chewing gum is a convenient but complex drug delivery system. Description of gum ingredient distribution and interactions in literature is sparse, but fundamental in product characterization and stability prediction. Although Raman spectroscopy has been used for such characterization of numerous dosage forms, its applicability to medicated chewing gum has not been studied until now. The objective was to investigate the applicability of confocal Raman imaging on chewing gum for identification and distribution of excipients and the model drug nicotine, including changes occurring during shelf life. A sample preparation protocol was composed to present an even surface of a gum cross section without altering the gum matrix texture. High-resolution Raman maps were obtained by Non Negative Least Squares (NNLS) analysis for a reference gum and gums stored for 6 months at mild (25 °C/60% RH) and accelerated (40 °C/75% RH) conditions. Additional Empty Modelling™ analysis confirmed the results of NNLS. The NNLS analysis located nicotine and the following excipients: gum base, calcium carbonate, sorbitol, xylitol, sodium carbonate, sodium bicarbonate and talc in distinct domains of the reference sample. Changes of the sample stored at accelerated conditions was discovered as sodium carbonate was not observed in this sample. Additionally, stereo light microscopy showed changes in product appearance and high-performance liquid chromatography confirmed formation of the oxidation product nicotine-1'-N-oxide in this sample. The gum formulation and its ingredients displayed characteristic Raman spectra, proving Raman imaging as a useful method for characterizing medicated chewing gums, including changes occurring during stability testing.

A novel microdialysis-dissolution/permeation system for testing oral dosage forms: A proof-of-concept study.

A novel microdialysis-dissolution/permeation (M-D/P) system was developed for the biopharmaceutical assessment of oral drug formulations. This system consists of a side-by-side diffusion chamber, a microdialysis unit fixed within the dissolution chamber for continuous sampling, and a biomimetic Permeapad® as the intestinal barrier. In the M-D/P system, the concentration of the molecularly dissolved drug (with MWCO <20kDa) was measured over time in the dissolution compartment (representing the gastrointestinal tract) while the concentration of the permeated drug was measured in the acceptor compartment (representing the blood). The kinetics of both the dissolution process and the permeation process were simultaneously quantified under circumstances that mimic physiological conditions. For the current proof-of-concept study, hydrocortisone (HCS) in the form of slowly dissolving solvate crystals and buffer and the biorelevant fasted state simulated intestinal fluids (FaSSIF), were employed as the model drug and dissolution media, respectively. The applicability of the M-D/P system to dissolution and permeation profiling of HCS in buffer and in FaSSIF has been successfully demonstrated. Compared to the conventional direct sampling method (using filter of 0.1-0.45µm), sampling by the M-D/P system exhibited distinct advantages, including (1) showing minimal disturbance of the permeation process, (2) differentiating "molecularly" dissolved drugs from "apparently" dissolved drugs during dissolution of HCS in FaSSIF, and (3) being less laborious and having better sampling temporal resolution. M-D/P system appeared to be a promising, simple and routine tool that allows for the researchers' intensive comprehension of the interplay of dissolution and permeation thus helping for better oral formulation screening and as an ultimate goal, for better dosage forms assessment.