Repeated administration of methamphetamine (m-AMPH) can induce long-lasting changes in brain function, including (I) regulatory events related to the phenomena of tolerance, sensitization, and craving, and (II) injurious effects associated with prolonged exposure to this stimulant drug. The ability of repeated m-AMPH administration to injure the dopamine terminals of the neostriatum is well characterized; this injury is a consequence of the drug-induced overflow of both glutamate and dopamine within the caudate-putamen.

The involvement of striatal glutamate in these effects of repeated m-AMPH treatments suggests a progressive recruitment of the corticostriatal projections during repeated drug exposure. Evidence that cerebral cortical neurons are activated, and that some of them degenerate, during the course of repeated m-AMPH administration is provided by studies of immediate early gene expression, quantification of glutamate receptors, and cellular markers for cortical neuron degeneration. Degenerating cortical neurons include pyramidal and stellate cells in layers III and IV of parietal cortex. As the neuronal degeneration occurs in concert with the intense stimulant-induced stereotypical behaviors, it is possible that the behavior itself may drive the circuits that trigger the injured neurons, promoting further damage. The implications of this progressive alteration in cortical and striatal circuits for the progress of amphetamine self-administration are discussed.Extracts from Wired for Addiction’ Frontiers in Neuroscience – June 1998 John Marshall, Ph.D., University of California at Irvine