The dopamine D2 receptor is necessary for the neurotoxic effects of methamphetamine and MDMA (ecstasy) in mice. In wild-type mice, both drugs caused hyperthermia, loss of dopamine markers (tyrosine hydroxylase and dopamine transporter) in the striatum, inflammation, and dopaminergic cell death in the substantia nigra pars compacta. In mice lacking the D2 receptor (D2R−/−), all these effects were blocked, including the loss of dopaminergic neurons. The neuroprotective effect of D2R inactivation was not solely due to preventing hyperthermia, as reserpine lowered body temperature in both genotypes but potentiated toxicity only in wild-type mice. These results indicate that D2R is essential for methamphetamine and MDMA neurotoxicity, independent of body temperature.
Mice given repeated doses of ketamine and then tested after six months of abstinence showed lasting disruptions in brain function and cognition. The animals had reduced amplitude of later auditory event-related potential components (N40 and P80) and diminished stimulus-evoked theta oscillations, indicating impaired information processing. They also displayed deficits in reversal learning and spatial memory. Brain analysis revealed increased astrocyte proliferation and decreased expression of the glial glutamate transporter GLT-1, without signs of neuronal degeneration. These findings suggest that subchronic ketamine induces long-term adaptive or plastic brain changes that persist well beyond drug exposure, closely resembling cognitive impairments seen in human ketamine abusers.