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      Homeostatic regulation of serotonergic function by the serotonin transporter as revealed by nonviral gene transfer.

      The Journal of neuroscience : the official journal of the Society for Neuroscience
      Animals, Autoradiography, Carrier Proteins, genetics, physiology, Cell Line, Cerebral Cortex, Citalopram, pharmacokinetics, DNA, Antisense, Dopamine, metabolism, Gene Transfer Techniques, Guanosine 5'-O-(3-Thiotriphosphate), Homeostasis, Male, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Neurons, drug effects, Plasmids, Pyrimidines, pharmacology, Raphe Nuclei, Rats, Rats, Sprague-Dawley, Receptors, Serotonin, Receptors, Serotonin, 5-HT1, Recombinant Proteins, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Receptor Agonists, Swine, Synaptic Transmission, Transfection

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          Abstract

          With the aim of exploring the relationship between the serotonin transporter (5-HTT or SERT) and the activity level of serotonin (5-HT) neurotransmission, in vivo expression of this protein was specifically altered using a nonviral DNA transfer method. Plasmids containing the entire coding sequence or a partial antisense sequence of the 5-HTT gene were complexed with the cationic polymer polyethylenimine and injected into the dorsal raphe nucleus of adult male rats. Significant increase or decrease in both [(3)H]citalopram binding and [(3)H]5-HT synaptosomal uptake were observed in various brain areas up to 2 weeks after a single administration of the sense plasmid or 7 d after injection of the short antisense plasmid, respectively. Such changes in 5-HTT expression were associated with functional alterations in 5-HT neurotransmission, as shown by the increased capacity of 5-HT(1A) receptor stimulation to enhance [(35)S]GTP-gamma-S binding onto the dorsal raphe nucleus in sections from rats injected with the sense plasmid. Conversely, both a decrease in 5-HT(1A)-mediated [(35)S]GTP-gamma-S binding and a reduced potency of the 5-HT(1A) receptor agonist ipsapirone to inhibit neuronal firing were observed in the dorsal raphe nucleus of antisense plasmid-injected rats. Furthermore, changes in brain 5-HT and/or 5-HIAA levels, and sleep wakefulness circadian rhythm in the latter animals demonstrated that altered expression of 5-HTT by recombinant plasmids has important functional consequences on central 5-HT neurotransmission in adult rats.

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