preproenkephalin and 4-iodo-2-5-dimethoxyphenylisopropylamine

Serotonin (5-HT) 2A receptor-mediated regulation of striatal preprotachykinin (PPT) and preproenkephalin (PPE) mRNAs was studied in adult rodents that had been subjected to near-total dopamine (DA) depletion as neonates. Two months following bilateral 6-hydroxydopamine (6-OHDA) lesion, PPT mRNA levels decreased 59-73% across dorsal subregions of the rostral and caudal striatum while PPE transcripts increased 61-94%. Four hours after a single injection of the serotonin 2A/2C receptor agonist, (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1 mg/kg), PPT mRNA expression was significantly increased in DA-depleted rats across all dorsal subregions of the rostral and caudal striatum as compared to 6-OHDA-treated animals alone. In the intact rat, DOI did not influence PPT mRNA levels in the rostral striatum, but did raise expression in the caudal striatum where 5-HT2A receptors are prominent. DOI did not regulate PPE mRNA levels in any striatal sub-region of the intact or DA-depleted rat. Prior administration of the 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg) or the 5-HT2A receptor antagonist, ketanserin (1 mg/kg) completely blocked the DOI-induced increases in striatal PPT mRNA in both lesioned and intact animals. The ability of ketanserin to produce identical results as ritanserin suggests that 5-HT2A receptor-mediated regulation is selectively strengthened within tachykinin neurons of the rostral striatum which are suppressed by DA depletion. The selectivity suggests that 5-HT2A receptor upregulation following DA depletion is capable of regulating tachykinin biosynthesis without influencing enkephalin expression in striatal output neurons.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amphetamines; Animals; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Enkephalins; Gene Expression Regulation; Hydroxyindoleacetic Acid; In Situ Hybridization; Ketanserin; Male; Neurons; Oxidopamine; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sympatholytics; Tachykinins; Transcription, Genetic

The effects of dopamine receptor agonists on the levels of the striatal serotonin 5-HT2A receptor and its mRNA were investigated in rats lesioned with 6-OHDA as neonates. The mRNA encoding for the 5-HT2A receptor was detected by in situ hybridization histochemistry and the binding of 5-HT2A receptors was revealed with [125I](2,5-dimethoxy-4-iodophenyl)2-aminopropane ([125I]DOI). In adult control unlesioned rats, labeling with the 5-HT2A cRNA probe and with [125I]DOI was concentrated in medial sectors of the striatum. In 6-OHDA-lesioned rats, labeling with the 5-HT2A cRNA probe or with [125I]DOI was increased in the striatum, particularly in its lateral subdivisions. These increases were abolished after chronic systemic administration of the dopamine receptor agonists apomorphine or SKF-38393. The mRNA levels encoding for the 5-HT2A receptor were further measured in individual striatal neurons after double-labeling of sections with a 5-HT2A and a preproenkephalin (PPE) cRNA probe. In control unlesioned rats, 5-HT2A mRNA labeling was distributed in PPE-labeled as well as in PPE-unlabeled striatal neurons. In 6-OHDA-lesioned rats, increased 5-HT2A mRNA labeling was found only in PPE-unlabeled neurons and it was abolished after apomorphine or SKF-38393 administration. These results demonstrate that agonists of dopamine receptors inhibit the expression of 5-HT2A receptors in a subpopulation of presumed striato-nigral neurons. We propose that this regulation plays an important role in the control of motor activity by dopamine and 5-HT in the basal ganglia.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adrenergic Agents; Amphetamines; Animals; Animals, Newborn; Apomorphine; Autoradiography; Binding, Competitive; Dopamine Agonists; Enkephalins; Female; In Situ Hybridization; Iodine Radioisotopes; Microinjections; Motor Activity; Neostriatum; Neurons; Oxidopamine; Pregnancy; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Serotonin; RNA, Messenger; Serotonin Receptor Agonists

The effects of lowered serotonin (5-hydroxytryptamine; 5-HT) neurotransmission on preprotachykinin (PPT) and preproenkephalin (PPE) mRNA levels were examined in subregions of the striatum. Adult male rats were treated systemically with para-chlorophenylalanine (pCPA; 350 mg/kg single i.p. injection) which reduced forebrain 5-HT amounts to approximately 20% of saline-injected controls at 24 and 48 h. As measured by Northern analysis, PPT and PPE mRNA levels were elevated 50% and 160% respectively in the anterior ventromedial striatum (region included nucleus accumbens). PPT mRNA levels were raised 90% in posterior striatum (at the level of the globus pallidus) by 48 h post-pCPA injection. To determine if increased PPT and PPE mRNA levels represented a transient response to brief 5-HT inhibition, additional experiments were performed to provide continual suppression of 5-HT within the striatum. First, rats received daily intraperitoneal injections of saline or the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), for 7 days to reduce 5-HT release from raphestriatal terminals. In a parallel experiment, the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT, 5 micrograms), was stereotaxically injected into the striatum as a means to permanently remove 5-HT terminals. Although levels of each mRNA species were differentially sensitive to 5,7-DHT or 8-OH-DPAT, PPT and PPE mRNAs were lowered between 30-55% within the anterior dorsolateral and ventromedial striatum. Although these results support previous studies suggesting an overall positive regulatory role of serotonin on striatal tachykinin biosynthesis, PPT and PPE gene regulation in certain striatal subregions may by differentially sensitive to lowered 5-HT neurotransmission. This suggestion is supported by observations that acute systemic stimulation of 5-HT2A/C receptors with DOI (7 mg/kg single i.p. injection) raised PPT and PPE mRNA levels within anterior dorsolateral (30-60%) and posterior (100-200%) striata, but not within the anterior ventromedial striatum.

Topics: 5,7-Dihydroxytryptamine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Amygdala; Animals; Corpus Striatum; Enkephalins; Fenclonine; Male; Nerve Endings; Organ Specificity; Prosencephalon; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Serotonin; Serotonin Agents; Tachykinins; Time Factors; Transcription, Genetic