Regulatory effects of reboxetine treatment alone, or following paroxetine treatment, on brain noradrenergic and serotonergic systems.
When patients do not respond to an initial antidepressant, one clinical approach is to switch to an agent in a different pharmacological class. However, few studies have examined the neurochemical consequences of this practice. To study this, we examined changes in binding sites in rat brain for norepinephrine (NET) and serotonin transporters (SERT), alpha1, alpha2, and beta1 adrenergic receptors after chronic administration of paroxetine (PRX), reboxetine (RBX), or PRX followed by RBX. We also examined the effects of these treatments on mRNA expression for tyrosine hydroxylase (TH). RBX treatment for 3 weeks reduced NET binding significantly, by approximately 40% in terminal field areas, and 6 weeks of RBX reduced it even more, by approximately 60%. RBX treatment for 3 and 6 weeks reduced beta1 adrenergic receptor-binding sites equally, by 50-60%. At no time did RBX treatment reduce SERT-binding sites. PRX treatment had no effect on beta1 adrenergic or NET-binding sites, but reduced SERT-binding sites by 75-80%. Neither treatment altered mRNA for TH, alpha1, or alpha2 adrenergic receptor-binding sites. When 3 weeks of RBX treatment followed 3 weeks of PRX treatment, NET-binding sites were reduced to the same extent as measured after 6 weeks of RBX treatment alone, indicating that PRX pretreatment may have 'primed' the subsequent regulatory effect of RBX on the NET. Thus, pretreatment of rats with PRX actually enhanced at least one regulatory effect of RBX treatment on the noradrenergic system, and did not interfere with any other pharmacological effect caused by RBX treatment.
Gould
Georgianna G
GG
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. gouldg@uthscsa.edu
Pardon
Marie-Christine
MC
Morilak
David A
DA
Frazer
Alan
A
D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule / Q000662:veterinary; D004347:Drug Interactions; D019329:Idazoxan / Q000493:pharmacokinetics; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009025:Morpholines / Q000097:blood / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D011941:Receptors, Adrenergic / Q000145:classification / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D002352:Carrier Proteins; D019329:Idazoxan; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine; D000077593:Reboxetine; D011941:Receptors, Adrenergic; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D014446:Tyrosine 3-Monooxygenase; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat