Short-term pharmacokinetics and brain distribution of mecamylamine as a preliminary to carbon-11 labeling for nicotinic receptor investigation.

As a preliminary to development and evaluation of labeled mecamylamine as a potential in vivo imaging ligand for human central nicotinic receptors (nAchRs), this work was intended to determine whether the pharmacokinetic properties of mecamylamine are suitable for experimental studies using (11)C-radiolabeled mecamylamine preliminary to positron emission tomography (PET) in humans. An original gas chromatographic method for rapid and simple determination of mecamylamine in biological samples was developed and validated (within run precision, 3.8-5.2%; between assay variation, 5.3-6.9%; assay accuracy, 5.6-11.8%). The results of the pharmacokinetic investigation in the rat demonstrated a very fast clearance of mecamylamine from blood [half-life, 1.2 h; clearance (CL), 1.2 L/kg/h) concomitant with an uptake that was higher in kidney, intermediate in lung, and lower in heart, liver, and brain. Brain tissue kinetics of mecamylamine showed a similar pattern for all the regions, with a rapid increase followed by a plateau after 15 min. This plateau differed according to the region of the brain; it was higher in colliculi, hippocampus, and cortex (area of high density of nAchRs) than in cerebellum or white matter (area with a limited population of nAchRs). No other lipophilic metabolites that were able to disturb the specific binding to nAchRs were identified during the investigation. Thus, mecamylamine shows peculiar qualities making it a good candidate for carbon-11 labeling for experimental studies in view of final PET imaging.

[Effect of an irreversible inhibitor (RMI71645) of gamma-aminobutyric acid (GABA) transaminase on spontaneous and conditioned activities of mice]. / Effet d'un inhibiteur irréversible (RMI 71645) de'l acide gamma-aminobutyrique (GABA) transaminase sur les activités spontanée et conditionée de la Souris

The RMI, an irreversible inhibitor of GABA transaminase, inhibited, at the dose of 100 mg/kg, the activity of Mice placed in an open-field. At lower doses, RMI improved the activity in open-field and the number of conditioned avoidance reactions. Results are correlated with increase of the level of brain GABA, following administration of RMI.

Effects of 2-propyl 2-pentenoic acid on the acquisition of conditioned behavior with negative reinforcement in mice.

2-Propyl 2-pentenoic acid (PP delta), at a dose of 6 mg/kg (0.04 mM/kg), has a facilitating action on the acquisition of conditioned avoidance reactions. This effect of PP delta is correlated with increase of the level of brain gamma-aminobutyric acid, following administration of PP delta.