preproenkephalin and vanoxerine

Cocaine binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters blocking the reuptake of these monoamines into presynaptic terminals. As previously reported, continuous infusion of cocaine for seven days or GBR 12909, a selective dopamine uptake inhibitor, produced significant decreases in prodynorphin (PDYN) gene expression in the hypothalamus. Cocaine also produced a significant increase in PDYN mRNA in the caudate putamen, whereas GBR12909 has no effect and the selective serotonin uptake inhibitor fluoxetine decreases PDYN mRNA in the same brain region. The effect of the selective norepinephrine uptake inhibitor nisoxetine was examined on PDYN gene expression. Nisoxetine or vehicle was infused continuously for 7 days via osmotic minipump into male rats. This treatment produced significant increases in PDYN gene expression in the hypothalamus (183% of control), nucleus accumbens (142% of control) and hippocampus (124% of control) and a significant decrease in the caudate putamen (69% of control). These data suggest that nisoxetine affects PDYN gene expression and support a role for NE in the mechanisms underlying the effects of chronic exposure to psychoactive drugs. Moreover, nisoxetine, as well as fluoxetine, decreases PDYN mRNA in the caudate putamen, in contrast to the up-regulation produced by cocaine. Thus, the inhibition of NE uptake alone cannot account for the cocaine-induced increase of PDYN gene expression. These findings suggest that PDYN gene expression regulation by cocaine in the caudate putamen might be due to a combination of effects on two or three monoamine transporters, or to a mechanism unrelated to transporters inhibition.

Topics: Adrenergic Uptake Inhibitors; Animals; Blotting, Northern; Central Nervous System; Cocaine; Dopamine Uptake Inhibitors; Enkephalins; Fluoxetine; Gene Expression; Male; Piperazines; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Selective Serotonin Reuptake Inhibitors

The effect of the selective dopamine uptake inhibitor 1-[2-[bis(4-flourophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909) was examined on prodynorphin gene expression. GBR 12909 or vehicle was continuously infused for 7 days via osmotic minipump, or injected daily into male rats. Both continuous infusions and daily injections of GBR 12909 produced significant decreases in prodynorphin expression in the hypothalamus (37% and 31% decreases, respectively). There were no significant changes in the caudate putamen, hippocampus or nucleus accumbens. One injection of GBR 12909 had no effects on prodynorphin expression in any of the brain regions studied, suggesting that the effect in the hypothalamus is not an acute effect. As previously reported for other treatment regimens, continuous infusion of cocaine produced a 35% significant decrease in the hypothalamus, consistent with the effects of GBR 12909. In contrast to GBR 12909, however, cocaine also produced a significant increase in prodynorphin expression in the caudate putamen. Thus, chronic inhibition of dopamine uptake can regulate prodynorphin expression in the hypothalamus. In contrast, the increase in the caudate putamen following cocaine administration may not be related to the inhibition of dopamine uptake, since it was not produced by a selective dopamine uptake inhibitor. These findings suggest that regulation of prodynorphin gene expression by cocaine in the caudate putamen may be mediated by the inhibition of norepinephrine or serotonin uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition.

Topics: Animals; Brain; Cocaine; Dopamine Uptake Inhibitors; Enkephalins; Gene Expression; Male; Piperazines; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

The present study examined the modulatory role of dopamine (DA) on striatonigral preprotachykinin (PPT) and prodynorphin (PD) gene expression, employing the DA uptake inhibitor, GBR-12909 (GBR), as a tool. The striatal and nigral levels of tachykinin (substance P (SP), neurokinin A (NKA)) and dynorphin (dynorphin A(1-8) (DYN)) peptides were determined by radioimmunoassays. The abundance of mRNAs in the striatum was quantified by Northern blot analysis. The rate of transcription of PPT and PD genes in the striatum was measured by transcription run-on assays. A regimen of repeated administration of GBR (20 mg/kg/day, i.p., for 1-4 days) to female Sprague-Dawley rats increased striatal and nigral SP, NKA, and DYN peptide levels. The increased peptide levels were associated with increases in the abundance of PD mRNA and PPT mRNA and increases in the rate of transcription of PD and PPT genes in the striatum, suggesting a GBR-induced activation of the striatonigral tachykinin and dynorphin neurons. Dopaminergic denervation with 6-hydroxydopamine (6OHDA) blocked the GBR-induced increases in SP and DYN and PPT and PD mRNAs. The concurrent administration of the D1 DA antagonist, SCH-23390, blocked the GBR-induced increases in SP, NKA and PPT mRNA but failed to affect DYN or PD mRNA levels; the concurrent administration of the D2 DA antagonist, spiperone, blocked the GBR-induced increases in SP, NKA and PPT mRNA and also DYN and PD mRNA. The study reveals that repeated administration of GBR enhances the levels of tachykinin and dynorphin peptides in striatonigral neurons by a stimulus-transcription-biosynthesis coupling mechanism. The GBR-induced effects are dependent on the integrity of nigrostriatal dopaminergic neurons and the presence of D1 and/or D2 DA receptors.

Topics: Animals; Cell Nucleus; Corpus Striatum; Denervation; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Dynorphins; Enkephalins; Female; Gene Expression Regulation; Kinetics; Organ Specificity; Piperazines; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substantia Nigra; Tachykinins; Transcription, Genetic