Cocaine attenuates acid sphingomyelinase activity during establishment of addiction-related behavior-A translational study in rats and monkeys.

Cocaine addiction is a severe psychiatric condition for which currently no effective pharmacotherapy is available. Brain mechanisms for the establishment of addiction-related behaviors are still not fully understood, and specific biomarkers for cocaine use are not available. Sphingolipids are major membrane lipids, which shape neuronal membrane composition and dynamics in the brain. Here, we investigated how chronic cocaine exposure during establishment of addiction-related behaviors affects the activity of the sphingolipid rheostat controlling enzymes in the brain of rats. As we detected specific effects on several enzymes in the brain, we tested whether the activity of selected enzymes in the blood may serve as potential biomarker for cocaine exposure in non-human primates (Callithrix penicillata). We found that intravenous cocaine self-administration led to a reduced mRNA expression of Cers1, Degs1 and Degs2, and Smpd1 in the prefrontal cortex of rats, as well as a reduction of Cers4 expression in the striatum. These effects reversed after 10 days of abstinence. Monkeys showed a robust cocaine-induced place preference (CPP). This coincided with a reduction in blood acid sphingomyelinase (ASM) activity after CPP establishment. This effect normalized after 15 days of abstinence. Altogether, these findings suggest that the establishment of cocaine addiction-related behaviors coincides with changes in the activity of sphingolipid controlling enzymes. In particular, blood ASM levels may serve as a translational biomarker for recent cocaine exposure.

Scopolamine and MK-801 impair recognition memory in a new spontaneous object exploration task in monkeys.

The spontaneous object recognition (SOR) task is one of the most widely used behavioral protocols to assess visual memory in animals. However, only recently was it shown that nonhuman primates also perform well on this task. Here we further characterized this new monkey recognition memory test by assessing the performance of adult marmosets after an acute systemic administration of two putative amnesic agents: the competitive muscarinic acetylcholine receptor antagonist scopolamine (SCP; 0.05 mg/kg) and the noncompetitive N-methyl-d-aspartate glutamate receptor antagonist MK-801 (0.015 mg/kg). We also determined whether the acetylcholinesterase inhibitor donepezil (DNP; 0.50 mg/kg), a clinically-used cognitive enhancer, reverses memory deficits caused by either drug. The subjects had an initial 10 min sample trial where two identical neutral objects could be explored. After a 6 h retention interval, recognition was based on an exploratory preference for a new rather than familiar object during a 10 min test trial. Both SCP and MK-801 impaired the marmosets' performance on the SOR task, as both objects were explored equivalently. Co-administration of 0.50 mg/kg of DNP reversed the SCP- but not the MK-801-induced memory deficit. These results indicate that cholinergic and glutamatergic pathways mediate object recognition memory in the monkey SOR task.