Long-Lasting Induction of Astrocytic Basic Fibroblast Growth Factor by Repeated Injections of Amphetamine: Blockade by Concurrent Treatment with a Glutamate Antagonist

Abstract

Repeated administration of stimulant drugs leads to lasting changes in their behavioral and neurochemical effects. These changes are initiated by drug actions in the somatodendritic regions of midbrain dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) and continue to develop for a period of time after termination of drug treatment. Here we show that repeated administration of amphetamine (3.0 mg/kg, i.p.; three injections, once every other day) results in sustained increases in basic fibroblast growth factor immunoreactivity (bFGF-IR) in both VTA and SNc, 200-500% over that seen in saline-treated animals. Increases were observed 24 hr, 72 hr, 1 week and 1 month after the last drug injection. Because glutamate participates in the development of sensitization to stimulant drugs, we assessed the effect of the glutamate antagonist, kynurenic acid (KYN), on amphetamine-induced bFGF-IR. Coadministration of KYN prevented the increases in bFGF-IR in both VTA and SNc assessed 1 week after the amphetamine treatment. No changes in bFGF-IR were observed in the nucleus accumbens or dorsal striatum. bFGF-IR was found to be associated with astrocytes and not with dopaminergic neurons. These findings suggest that sustained enhancement of astrocytic bFGF expression in DA somatodendritic regions is a mechanism whereby stimulant drugs exert enduring effects on midbrain DA function. We hypothesize that increased glutamatergic activity elicited by amphetamine and other stimulant drugs places excessive demands on the functioning of DA neurons recruiting regulatory and neuroprotective processes that lead to enduring changes in DA neuron functioning and connectivity.