Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs: studies in the rat

Rationale: Repeated exposure to stimulant drugs, such as the indirect dopaminergic agonists amphetamine or cocaine, results in increased sensitivity to their effects on behavior and dopaminergic function. Neuroadaptations initiated in the ventral tegmental area (VTA), a cell body region of midbrain dopaminergic neurons, and dependent on glutamatergic transmission, underlie the development of this persistent drug-induced sensitization. How precisely drug actions in the VTA initiate long-lasting changes in dopaminergic function, and how glutamate participates in these events is not clear. Objective: To discuss the idea that neurotrophic, neuroprotective factors are involved. Results: We review the few studies that have been concerned with a role for neurotrophic factors in the changing response to stimulant drugs and present a summary of those conducted in our laboratory on basic fibroblast growth factor (bFGF), a neurotrophic factor produced by astrocytes. Conclusion: We argue that repeated exposure to stimulant drugs increases the demands on dopaminergic cell functioning, and, by stimulating glutamate release, recruits neurotrophic and neuroprotective substances such as bFGF. We propose that the actions of these factors, in turn, give rise to long-lasting neuronal adaptations that underlie sensitized responding to further drug exposure. Possible mechanisms whereby bFGF participates in the development of sensitization, including interactions with other neurotrophic factors, are discussed. In addition, we show how the evidence reviewed in this paper provides further support for the idea that repeated treatment with stimulant drugs induces synaptic plasticity.