dynorphins and vanoxerine

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

The acute and long-term effects of a single injection of psychomotor stimulants (amphetamine (1.5 mg/kg i.p.), cocaine (30 mg/kg i.p.) and GBR 12909 (10 mg/kg i.p.)) were studied with in situ hybridization histochemistry to assess alterations in the mRNA expression of enkephalin, dynorphin and substance P in the striatum. The greatest alterations on mRNA levels of enkephalin, dynorphin and substance P were observed 2 h following the first administration of each drug compared to that observed following a second challenge injection 14 days later. Of the drugs tested, the dopamine uptake inhibitory agents cocaine and GBR 12909 acutely elevated mRNA levels of all three neuropeptides, while amphetamine elevated mRNA levels of substance P only. A second challenge administration of the stimulants 14 days subsequent to the initial single injection re-elevated the mRNA level of substance P. An overall tolerance is speculated to account for diminution of the enkephalin and dynorphin responses to a challenge injection while a relative sensitization is suggested for the enkephalin response due to a reduction in the baseline level of expression produced by the first injection. The data also show that there are regional variation within the striatum following systemic administration of psychomotor stimulants, with greater elevations in the sensorimotor dorsolateral striatum than in the ventromedial 'limbic' nucleus accumbens region.

Topics: Amphetamine; Animals; Central Nervous System Stimulants; Cocaine; Corpus Striatum; Dynorphins; Enkephalins; In Situ Hybridization; Male; Neuropeptides; Neurotransmitter Uptake Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substance P

Topics: Animals; Cocaine; Corpus Striatum; Dizocilpine Maleate; Dynorphins; Male; Neurotensin; Neurotransmitter Uptake Inhibitors; Piperazines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Substantia Nigra

The principal central nervous system effects of cocaine are a consequence of its ability to inhibit monoaminergic uptake systems. This agent influences dopamine-related behavior in a manner similar to other sympathomimetics, such as methamphetamine; however, the effect of these two agents on neurochemical dopaminergic parameters are distinct. Several peptidergic neurotransmitter systems, such as the dynorphin pathways, have been shown to be distal to and regulated by the postsynaptic activity of dopaminergic pathways; therefore, we evaluated the response of extrapyramidal and limbic dynorphin A1-17 (Dyn) systems to cocaine by measuring Dyn content in associated structures. Extrapyramidal and limbic dynorphin-like immunoreactivity (DLI) content markedly increased after cocaine treatment. This change appeared to be due primarily to the ability of cocaine to block dopamine re-uptake; consequently, the increase in DLI levels was either totally or partially blocked by coadministration of selective D1 (SCH 23390) and D2 (sulpiride) receptor blockers and multiple doses of the selective dopamine uptake blockers, amfonelic acid and GBR 12909, caused cocaine-like enhancement of extrapyramidal DLI content. Serotonin did not appear to play a major role in mediating the cocaine effects on Dyn systems as multiple doses of the selective serotonin uptake blocker, fluoxetine, did not alter extrapyramidal DLI levels, and depletion of serotonin by pretreatment with parachloroamphetamine did not significantly alter the increases in extrapyramidal Dyn content caused by cocaine administration. Because the behavioral effects of cocaine and methamphetamine are similar, the neurochemical response of Dyn systems to both of these agents is compared and discussed.

Topics: Animals; Benzazepines; Cocaine; Dopamine Antagonists; Dynorphins; Extrapyramidal Tracts; Limbic System; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Rats; Rats, Inbred Strains; Receptors, Dopamine