Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping

1 Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slice s of whole brain, grey (cerebral cortex) and white (corpus callosum, intern al capsule) matter of the brain and by neuronal and astroglial cell culture s. 2 Moreover, we assessed the contribution of lysosomal trapping to total dru g uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue s lices or cells conducting experiments in the presence and absence of `lysos omal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 m m) or the Na+/H+-ionophore monensin (10 muM), which elevated the internal p H of lysosomes. The initial concentration of psychotropic drug in the incub ation medium was 5 mum. 3 Both total uptake and lysosomal trapping of the antidepressants investiga ted (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (p romazine, perazine, thioridazine) were higher in the grey matter and neuron es than in the white matter and astrocytes, respectively. Lysosomal trappin g of the psychotropics occurred mainly in neurones where thioridazine sertr aline and perazine showed the highest degree of lysosomotropism. 4 Distribution interactions between antidepressants and neuroleptics took p lace in neurones via mutual inhibition of lysosomal trapping of drugs. 5 A differential number of neuronal and glial cells in the brain may mask t he lysosomal trapping and the distribution interactions of less potent lyso somotropic drugs in vertically cut brain slices. 6 A reduction (via a distribution interaction) in the concentration of psyc hotropics in lysosomes (depot), which leads to an increase in their level i n membranes and tissue fluids, may intensify the pharmacological action of the combined drugs.