Abstract

Repeated exposure to the stimulant drug, amphetamine, results in long-lasting increases in its effects on locomotor activity, reward and dopaminergic function. The precise mechanisms responsible for this persistent drug-induced sensitization are unknown, but evidence suggests that neuroadaptations initiated in the cell body region of midbrain dopaminergic neurons and dependent on glutamatergic transmission underlie its development. In this thesis, the hypothesis that basic fibroblast growth factor (bFGF), a neurotrophic factor produced by astrocytes, plays a crucial role in the development of sensitization was tested. A series of experiments was conducted to assess whether bFGF expression in cell body regions of dopaminergic neurons is altered by repeated administration of amphetamine, whether this effect is dependent on glutamatergic activation, and whether blockade of bFGF actions in midbrain dopaminergic cell body regions prevents the development of sensitization. It was found that repeated administration of amphetamine induces prolonged increases in the expression of astrocytic bFGF in midbrain dopaminergic cell body regions and that this effect depends on glutamatergic activation. Furthermore, it was shown that, in animals that exhibit behavioral sensitization, bFGF expression in midbrain dopaminergic cell body regions is strongly and positively correlated with the magnitude of sensitization that develops. In a final experiment it was found that when amphetamine injections are preceded by infusions of a neutralizing antibody to bFGF into the cell body region of dopaminergic cells, the development of behavioral sensitization is prevented indicating that bFGF plays a critical role in the development of sensitization to amphetamine. It is argued that repeated exposure to stimulant drugs increases the demands on dopaminergic cell functioning and, thus, stimulates the recruitment of neurotrophic and neuroprotective substances, such as bFGF. The actions of bFGF, in turn, give rise either directly or indirectly to enduring neuronal changes that underlie sensitized responding to further drug exposure. Although, the mechanisms whereby bFGF exerts its effects to induce the kinds of long-lasting neuroadaptations underlying sensitization to the effects of amphetamine remain to be unraveled, the findings from this thesis provide the first evidence that the neurotrophic factor bFGF is critically involved.