Showing papers by "Ann M. Graybiel published in 1996"

Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor

Abstract: Stimulation of dopamine D1 receptors has profound effects on addictive behavior, movement control, and working memory. Many of these functions depend on dopaminergic systems in the striatum and D1–D2 dopamine receptor synergies have been implicated as well. We show here that deletion of the D1 dopamine receptor produces a neural phenotype in which amphetamine and cocaine, two addictive psychomotor stimulants, can no longer stimulate neurons in the striatum to express cFos or JunB or to regulate dynorphin. By contrast, haloperidol, a typical neuroleptic that acts preferentially at D2-class receptors, remains effective in inducing catalepsy and striatal Fos/Jun expression in the D1 mutants, and these behavioral and neural effects can be blocked by D2 dopamine receptor agonists. These findings demonstrate that D2 dopamine receptors can function without the enabling role of D1 receptors but that D1 dopamine receptors are essential for the control of gene expression and motor behavior by psychomotor stimulants.

D1-class dopamine receptors influence cocaine-induced persistent expression of Fos-related proteins in striatum.

Abstract: Chronic intermittent exposure to psychomotor stimulants induces in the striatum the expression of Fos-related proteins (Fras) that persist after the end of drug treatment. We carried out experiments to determine whether such Fras ("chronic Fras') require dopamine D1-class receptor function for their persistent expression in the striatum. We chronically administered cocaine to rats in a behavioral sensitization protocol and blocked D1-class receptors with SCH23390 before a final cocaine challenge. Western blotting and immunohistochemical analyses indicate that Fras persistently expressed in response to chronic treatment include proteins of two types: those that have become independent of D1-class dopamine receptor activation and those that remain dependent on D1-class receptors for their expression following drug challenge.

Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum.

Abstract: Atypical and typical neuroleptics, when administered chronically, can bring about profound but contrasting changes in schizophrenic symptoms and motor activation and dramatically modulate brain neurochemistry. To explore the transcriptional events that might be involved in this neurochemical regulation, we used immunohistochemistry and immunoblotting to examine the expression patterns of two bZip transcription factors, c-Fos and FosB, in the striatum of rats treated acutely and chronically with neuroleptic drugs of different classes. Typical and atypical neuroleptic drugs produced contrasting regulatory effects on a FosB-like protein of ca. 36–39 kDa, the molecular weight of truncated FosB (ΔFosB). Chronic treatments with two typical neuroleptics, haloperidol and metoclopramide, but not with the atypical neuroleptic clozapine, led to markedly enhanced FosB-like immunoreactivity in the caudoputamen. Further, c-Fos-like protein in the striatum, considered a marker for the induction of antipsychotic actions by neuroleptic treatments, was downregulated by chronic treatment with the two potent antipsychotic drugs tested, but not by chronic treatment with metoclopramide, which has low antipsychotic efficacy but induces extrapyramidal side effects. These results suggest that chronic treatments with neuroleptics having different effects on cognitive and motor behavior induce different long-term changes in transcription factor expression in the striatum. Nevertheless, we found that neuroleptics of both classes regulated transcription factor expression in overlapping populations of striatal neurons expressing enkephalin or DARPP-32. Contrasting patterns of transcriptional regulation in these neurons may thus contribute to the distinct neurochemical and behavioral effects that characterize neuroleptics of different classes. © 1996 Wiley-Liss, Inc.

Protein Phosphatases Regulate Creb Phosphorylation and Fos Expression in the Developing Striatum

Abstract: Dopamine is a classical neurotransmitter of multiple functions. Dopamine not only can modulate short-term synaptic activity, but also can regulate long-term changes in gene expression. In the dopamine-containing mesostriatal system, dopamine can modulate plasticity of gene expression, including induction of immediate-early genes and regulation of neuropeptide gene expression (Graybiel et al, 1994; Gerfen, 1992; Graybiel, 1990; Hong et al., 1978). The alterations of gene expression mediated by dopamine may underlie dopamine-mediated neuronal and behavioral plasticity.