A cell's ability to generate different responses to different levels of stimulus is an important component of an adaptive environmental response. Transcriptional responses are frequently controlled by transcription factors regulated by phosphorylation. We demonstrate that differential phosphorylation of the budding yeast transcription factor Pho4 contributes to differential gene expression. When yeast cells are grown in high-phosphate growth medium, Pho4 is phosphorylated on four critical residues by the cyclin–CDK complex Pho80–Pho85 and is inactivated. When yeast cells are starved for phosphate, Pho4 is dephosphorylated and fully active. In intermediate-phosphate conditions, a form of Pho4 preferentially phosphorylated on one of the four sites accumulates and activates transcription of a subset of phosphate-responsive genes. This Pho4 phosphoform binds differentially to phosphate-responsive promoters and helps to trigger differential gene expression. Our results demonstrate that three transcriptional outputs can be generated by a pathway whose regulation is controlled by one kinase, Pho80–Pho85, and one transcription factor, Pho4. Differential phosphorylation of Pho4 by Pho80–Pho85 produces phosphorylated forms of Pho4 that differ in their ability to activate transcription, contributing to multiple outputs.

Acute pharmacological blockade of ␣1 adrenoreceptors (ARs) attenuates the locomotor response to amphetamine (LRA). We took a genetic approach to study how norepinephrine (NE) signaling modulates psychostimulant responses by testing LRA in dopamine ␤-hydroxylase knockout (Dbh؊͞؊) mice that lack NE. Surprisingly, Dbh؊͞؊ animals were hypersensitive to the behavioral effects of amphetamine. Amphetamine (2 mg͞kg) elicited greater locomotor activity in Dbh؊͞؊ mice compared to controls, whereas 5 mg͞kg caused stereotypy in Dbh؊͞؊ mice, which is only observed in control mice at higher doses. Prazosin, an ␣1AR antagonist, attenuated LRA in Dbh؉͞؊ mice but had no effect in Dbh؊͞؊ mice. Changes in the sensitivity of dopamine (DA)-signaling pathways may contribute to the altered amphetamine responses of Dbh؊͞؊ mice because they were relatively insensitive to a D1 agonist and hypersensitive to a D2 agonist. Daily amphetamine administration resulted in behavioral sensitization in both Dbh؉͞؊ and Dbh؊͞؊ mice, demonstrating that NE is not required for the development or expression of behavioral sensitization. Daily prazosin administration blunted but did not completely block locomotor sensitization in Dbh؉͞؊ mice, suggesting that ␣1AR signaling contributes to, but is not required for sensitization in Dbh؉͞؊ control animals. We conclude that in contrast to acute ␣1AR blockade, chronic NE deficiency induces changes similar to sensitization, perhaps by altering DA-signaling pathways.A mphetamine is a psychostimulant that is used both recreationally and therapeutically for diseases such as attentiondeficit͞hyperactivity disorder. The primary sites of amphetamine action are monoamine transporters, where it blocks reuptake and facilitates release of dopamine (DA), norepinephrine (NE), and serotonin. Although DA signaling is the focus of most amphetamine research, it is also clear that NE plays an important role in modulating cellular and behavioral responses to psychostimulants. Lesions of the locus coeruleus (the major central noradrenergic nucleus) or administration of prazosin, an ␣1-adrenoreceptor (␣1AR) antagonist, attenuate amphetamine-induced locomotion (1-3). Prazosin decreases burst firing of dopaminergic ventral tegmental area neurons and blocks the excitatory effect of amphetamine on these cells (4-6). Finally, inactivation of the ␣1bAR gene in mice attenuates amphetamine responses (7). These results suggest that NE signaling through ␣1ARs is important for the locomotor and cellular responses to amphetamine.Amphetamine produces behavioral sensitization, an enhancement of the locomotor response after repeated administration, which may model drug craving and psychosis. Sensitization is thought to involve long-term changes in both DA and other signaling pathways (8, 9). Because amphetamine sensitization is blunted in mice lacking ␣1bARs and rats treated with prazosin, ␣1AR signaling may inf luence the neural and behavioral changes that result from chronic psychostimulant use (7, 10).Drug addiction develops over time and is a ...

Although norepinephrine (NE) has been implicated in animal models of ethanol consumption for many years, the exact nature of its influence is not clear. Lesioning and pharmacological studies examining the role of NE in ethanol consumption have yielded conflicting results. We took a genetic approach to determine the effect of NE depletion on ethanol-mediated behaviors by using dopamine beta-hydroxylase knockout (Dbh -/-) mice that specifically lack the ability to synthesize NE. Dbh -/- males have reduced ethanol preference in a two-bottle choice paradigm and show a delay in extinguishing an ethanol-conditioned taste aversion, suggesting that they drink less ethanol in part because they find its effects more aversive. Both male and female Dbh -/- mice are hypersensitive to the sedative and hypothermic effects of systemic ethanol administration, and the sedation phenotype can be rescued pharmacologically by acute replacement of central NE. Neither the decreased body temperature nor changes in ethanol metabolism can explain the differences in consumption and sedation. These results demonstrate a significant role for NE in modulating ethanol-related behaviors and physiological responses.