UC San Diego

Psychostimulants such as methamphetamine, MDMA, MDA have been used as treatment options for attention deficit disorders and narcolepsy; however, the vast majority of users take such amphetamines recreationly which can eventually develop into addiction to these drugs. Pharmacodynamic studies show that chronic exposure to these drugs produces neurotoxicity which is evident as adverse affects on serotonergic and dopaminergic neurons in the limbic system of the brain, and these effects are hypothesized to promote and perpetuate addiction to the drugs. Though monoamine neurotoxicity as a function of cell death is valid for psychostimulant addiction, neurotoxicity by these drugs as a function of decreased neurogenesis in the dentate gyrus of hippocampus can be valid for relapse to psychostimulant addiction, as the hippocampus is important for relapse to drug seeking behaviors. In this context, only a small body of research has been devoted to understanding the effect of these drugs on neurogenesis in the hippocampus. Recent studies from others and our lab have found that both MDMA and methamphetamine significantly reduce levels of neurogenesis in the hippocampus of adult rodents. Furthermore, excessive psychostimulant intake was shown to reduce levels of neurogenesis in the dentate gyrus of the hippocampus in adult rodents and have been positively correlated with enhanced relapse to drug seeking behaviors. However, whether the detrimental effects of psychostimulants on developmental stages of neurogenesis are limited to rodent brain or occur in non human primates is unknown and was the focus of the current investigation. Our study investigated the levels of developmental stages of neurogenesis, cell death and the cell density of granule cell neurons after MDMA or MDMA in combination with MDA and methamphetamine exposure in young adult macaque monkeys in hopes to model the effects of these drugs on the young adult human hippocampus. Results from quantitative immunohistochemical analysis show that the two treatment conditions over 9.6 months causes > 80% decrease in the number of Ki-67 (neural progenitor) cells, and > 50% decrease in the number of Neuro D (immature neuron) cells, indicating a neurotoxic environment in the neurogenic niche in the hippocampus by MDMA alone or in combination with other amphetamines. Notably, the reduction in the number of newly born progenitors and neurons were not associated with changes in cell death (via apoptosis) or granule cell neuron numbers, indicating that psychostimulants selectively affected the generation and maturation of newly born granule cell neurons. In sum, our findings suggest that alterations in the cellular composition in the hippocampus during exposure to illicit drugs can promote maladaptive plasticity of hippocampal neurons during withdrawal, which may enhance relapse to drug seeking behaviors