Conclusions

Synaptic plasticity at excitatory synapses has been proposed as the cellular substrate of information processing and memory formation in the brain under both physiological1,43 and pathological conditions, including addiction22. Experiments characterizing the nature of synaptic plasticity in sensitized animals have demonstrated both LTP44,45 and LTD24 in the NAc. Furthermore, increased excitatory drive in the NAc is observed during drug-seeking behavior1. Within a given nucleus such as the NAc, it is suggested that the relative balance between LTP and LTD at different afferent inputs determines the expression of specific patterns of behavior46. In sensitized animals the abnormal induction of LTD at PFC inputs to the NAc may disrupt the influence of this pathway on neural activity involved in goal-directed behavior46.

To date, conclusive evidence for a causal relationship between synaptic plasticity and memory has been lacking due, in part, to the absence of specific drugs that block the expression of LTP or LTD without affecting any upstream signaling. Recent data demonstrate the utility of peptides that disrupt the expression of synaptic plasticity as tools to examine the critical role of LTP and/or LTD in specific aspects of learning and memory in conscious animals. Given the links between behavioral sensitization and enduring drug-induced neuroplasticity, it is possible that drugs that can disrupt LTD may form the basis for a rational drug development strategy for repairing abnormal synaptic functions that are related to exposure to addictive substances.

The evidence that LTD and/or behavioral sensitization may be linked to a number of pathological conditions raises the possibility that interference peptides such as the GluR23Y peptide may have broad therapeutic potential in the treatment of mental illness. For example, behavioral sensitization has been proposed as a model of psychostimulant-induced psychosis47 with possible links to schizophrenia. There is also evidence to suggest that LTD triggered by the activation of mGluR1/5 is affected in a number of pathological conditions that involve alterations in the refinement of neuronal circuitry. Evidence for its involvement in drug addiction-related behavioral sensitization is particularly strong48. In addition, mGluR1-mediated LTD is enhanced in mice lacking the fragile X mental retardation protein 1 (5; Chapter 30). Taken together, these observations suggest that there are several targets for developing interference peptides aimed at repairing some of the synaptic abnormalities associated not only with drug addiction, but also with other neurological disorders including schizophrenia and certain forms of mental retardation.

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