A Neurochemical and Electrophysiological Study on the Combined Effects of Caffeine and Nicotine in the Cortex of Rats

Objective: Caffeine and nicotine are the most consumed psychostimulants worldwide. Although the effects of each drug alone on the central nervous system (CNS) were studied extensively, the literature on the neurochemical and electrophysiological effects of their combined treatments is scarce. The present study investigates the cortical electrophysiological and neurochemical alterations induced by acute administration of caffeine and nicotine in rats. Methods: Rats received caffeine and nicotine with 1h interval between the two treatments. Results: Caffeine and nicotine administration resulted in a significant decrease in the concentrations of cortical amino acid neurotransmitters namely glutamate, aspartate, glycine and taurine while γ-aminobutyric acid (GABA) was significantly increased. An increased cortical lipid peroxidation and decreased reduced glutathione and nitric oxide levels and acetylcholinesterase and Na+, K+-ATPase activities were also observed. The electroencephalogram (EEG) showed an increase in delta frequency power band while theta, beta-1 and beta-2 were decreased after caffeine and nicotine treatment. These findings suggest that caffeine and nicotine adversely exacerbate their stimulant effects. This was manifested by the EEG changes and mediated by increasing cholinergic transmission, disturbing the balance between the excitatory and inhibitory amino acids leading to oxidative stress.

A new approach to understanding structure, functions and classificasion of GABA-benzodiazepine receptor complex, a molecular target for creation of new anticonvulsants on the base of inhibitory amino acids

The GABA molecule was shown to the methods of quantum mechanic characteristics and molecular geometry has three conformational states: linear (GABA-1 conformer), cyclic (GABA-2 comformer) and bucket-like (GABA-3 conformer). The play different functions in the brain neurons: cyclic and bucket-like conformers play role of endogenous transmitters, and linear conformer participates in neuronal metabolism. The theoretical conformational analysis shows there are two types of GABA receptors in the CNS neurons: GABA-2 receptors, agonists of which are cyclic conformer of GABA, glycine and β-alanine and antagonists are bemegride, pentilentetrazol and strychnine; and GABA-3 receptors, agonists of which is bucket-like conformer of GABA and antagonists are picrotoxin and bicuculline. Anticonvulsive and other behavioral effects of derivatives of barbituric acid, benzazepine, benzodiazepine, gidantoine, succinimide and oxasolidindione are realized probably via GABA-2 receptors to switch on them the following functional centers of their structure are nessesary: α, γ and [δ-ε] for barbitirates; β, [δ-ε] and γ for carbamazepine; β and [δ-ε] for benzodiazepine derivatives, gabapentine and vigabatrine; α, β, γ and [δ-ε] for gidantoine and oxasolidindione derivatives; α, β, γ for succinimide derivatives. The power of any behavioral effect of anticonvulsants and inhibitory amino acids depends on power, location and numbers of hydrogen bounds developed between active centers of pharmacophore of anticonvulsant or inhibitory amino acids and active centers of functional skeleton of GABA-2 receptor complex, these properties determine absense of nootropic activity in anticonvulsive drugs and presense of them in inhibitory amino acids. It is concluded there are perspectives of synthesis of conpounds, pharmacophore of which should be like as cyclic conformer of GABA, glycine and β-alanine on their quantum mechanic characteristics and molecular geometry

Changes in intracellular potentials and ionic currents of the mollusk and activity of Cl--channels under exposure to some inhibitory amino acids and new litium-containing compounds of them

The Changes of membrane rest potential (RP), action potential (AP), impulse activity (IA) as well as sodium, calcium and potassium ionic currents in neurons of isolated central nervous system of the Planorbarius corneus mollusk (pedal ganglia) under the extracellular action of inhibitory amino acids GABA, glycine and β-alanine and their litium-containing derivatives (LCD) in 0.1, 1 and 5 mM concentrations have been studied using a microelectrode technique. They induced the same dose-dependent and irreversible depolarization of neurons on 2-10 mV accompanied by increase of AP frequency, prolongation of their duration and decrease of summmerized ionic currents (dV/dt). According to degree of depolarization, the drugs were placed in the following range in decreasing activity: compound 3 > compound 2 > compound 1. In identified pedal ganglion neurons (PPed1), compound 3 in contrast to other compounds induced hyperpolarization by 2-10 mV and blocked impulse activity. The amplitude of sodium and calcium channels was decreased by 7-15 %, in the same degree after application of all compounds exposed in concentration of 5 mM. Efflux potassium ionic currents were increased in dose-dependent manner and irreversibly about by 3-7 % assessed on amplitude indexes without changes in kinetic parameters after application of LCD. Therefore, the decrease of ionic current amplitudes was due to both depolarization of neurons and direct action of LCD on ionic channels. Thus, LCD possess membranotropic activity and can modulate functional state of neurons. In the study of chloride channels in cells culture of rat glioma C6 in vitro by patch-clamp method, GABA, glycine, β-alanine and their LCD 10 µM/l activated chloride channels, shifting equiliblium membrane potential of glioma cells from -90… -70 mV to -55... -60 mV. All compounds (transmitters and LCD) were placed in the following range: glycine > GABA > β-alanine and compound 1 > compound 3 > compound 2 according to descending activity. Therefore, the most active compounds activating Cl--channels were glycine and compound 1 (LCD). Glycine was shown to be coagonist GABA receptors and its litium salt possessed significant membranotropic activity.