Decreased activity of brain phospholipid metabolic enzymes in human users of cocaine and methamphetamine.
Phospholipids are essential components of cell membranes which may also function to mediate some of the behavioural effects of dopamine receptor stimulation caused by psychostimulant drugs. Neuroimaging and pharmacological data suggest that abnormal brain metabolism of phospholipids might explain some of the consequences of chronic exposure to drugs of abuse including drug craving. We previously reported decreased activity of calcium-stimulated phospholipase A(2) (Ca-PLA(2)) in autopsied putamen of human cocaine users. To establish the specificity of this change in phospholipid metabolism and whether decreased Ca-PLA(2) might be a general feature of all abused drugs which enhance dopaminergic neurotransmission, we measured activity of 11 major phospholipid metabolic enzymes in dopamine-rich (putamen) and poor brain areas of chronic users of cocaine and of methamphetamine. Enzyme changes were restricted to the putamen which showed decreased (-21%, as compared with the control subjects) Ca-PLA(2) activity in users of methamphetamine and reduced (-31%) activity of phosphocholine cytidylyltransferase (PCCT), the rate-limiting enzyme of phosphatidylcholine synthesis, in the cocaine users. We suggest that chronic exposure to psychostimulant drugs might cause a compensatory downregulation of Ca-PLA(2) in dopamine-rich brain areas due to excessive dopamine-related stimulation of the enzyme. Decreased striatal Ca-PLA(2) and/or PCCT activity in cocaine users might also help to explain why CDP choline, which enhances phospholipid synthesis, reduces craving in some users of the drug cocaine.