The role of MK-801 in sensitization to stimulants

Behavioral responses to stimulants can be progressively and persistently enhanced by their repeated administration. This phenomenon, called behavioral sensitization, may underlie substance abuse, psychosis, recurrence in bipolar disorder, or other psychiatric problems. A growing body of work has implicated excitatory amino acid systems in behavioral sensitization. Most of the evidence for a role of excitatory amino acids has come from experiments demonstrating prevention of sensitization by excitatory amino acid antagonists, especially the noncompetitive NMDA receptor antagonist MK-801. Results of studies with MK-801 have varied, however, leading to conflicting interpretations of its relationship to behavioral sensitization. This paper critically discusses the design of experiments that have used MK-801, and interprets data from these experiments in terms of the two leading explanations for the role of MK-801: 1) that sensitization is an example of the family of plastic events that require excitatory amino acid transmission or 2) that interoceptive cues associated with MK-801 lead to state-dependent learning that modifies sensitization because, in essence, the animal does not recognize the stimulant as the same drug if it is given in close association with MK-801. Based on conflicting reports on effects of MK-801, we propose 1) strategies for distinguishing components of MK-801's effects on responses to stimulants, 2) a model that is a hybrid of the two interpretations of its effects on sensitization, and 3) experimental strategies for testing this model.