The short- and long-term effects of chronic late postnatal blockade of the dopamine transporter on cerebral glucose utilization and dopamine D(1)/D(2) receptors in the rat brain

In the adult nervous system, neurotransmitters act as chemical signals between neurons by binding to ligand-gated and second-messenger-coupled receptors. This role appears to have evolved from a more primitive function in lower organisms where these same molecules often subserve roles other than intercellular communication. Dopamine (DA) is one of the neurotransmitters that has been shown to act as a growth-regulatory signal or morphogenic factor during prenatal development in the rat. Although DA is no longer believed to be acting as a morphogenic factor during postnatal development, this neurotransmitter has been shown to continue to play an important role guiding development during the postnatal period. Therefore, one can hypothesize that an alteration of the levels of synaptic DA during critical periods of development could potentially lead to changes in the normal functioning of the dopaminergic system which may persist into adulthood and thus be permanent in nature.; The present study examined the short- and long-term effects on cerebral glucose utilization (GU) and DA D₁ and D₂ receptor binding of DA reuptake transporter blockade during the late postnatal period (postnatal days 11–21) of development in the rat. Blockade of the DA transporter elevates extracellular DA by preventing the normal removal of DA from the synapse following release from synaptic vesicles. DA D₁ and D₂ receptor binding was examined following chronic late postnatal blockade of the dopamine transporter at 21- and 60-days-of-age.; At 21-days-of-age, chronic selective blockade by GBR12909 (GBR) (25mg/kg) and nonselective blockade by cocaine (25mg/kg) produced widespread increases in cerebral glucose utilization and marked decreases in Dopamine D₁and D₂ receptor binding. The majority of these changes occurred in female rats. The changes in D₁ and D₂ receptor binding appear to reflect a downregulation of these receptors in response to increased levels of synaptic DA which is suggested by the increases in cerebral GU rates, in many brain regions in these same animals.; At 60-days-of-age, no significant changes in DA D₁ or D ₂ receptors by analysis of variance (ANOVA) were observed in any individual brain regions compared to control following late postnatal blockade of the DA transporter in female rats. On the other hand, significant changes in the patterns of receptor binding were seen (significant Chi-square result). Both low-dose GBR (25mg/kg) and cocaine (50mg/kg) produced a significant pattern of decreased D₁ and increased D₂ receptor binding while high-dose GBR (50mg/kg) produced a significant pattern of increased D ₁ binding and had no effect on D₂ binding. These patterns likely represent the effects of chronic late postnatal alteration of synaptic DA concentration. Furthermore, both cocaine and low-dose GBR produced changes in the patterns of DA D₁/D₂ receptor binding that were similar and likely the result of a common mechanism. However, the significant patterns of increased cerebral GU in the low-dose GBR group and decreased cerebral GU in the cocaine group suggest that additional mechanisms may also be responsible for the significant changes in the patterns of DA D₁/D ₂ receptor binding in each of the treatment groups.; The results of this body of work suggest that blockade of the DA transporter is an important mechanism of cocaine's actions in the developing brain. These studies lend support to the hypothesis that DA continues to act as a development-regulating factor in the brain during the late postnatal period in the rat, and that alteration of the levels of this neurotransmitter during this critical period of development has both short- and long-term effects on brain development.