Differences in serotonergic neurotransmission between rats displaying high or low anxiety/depression-like behaviour: effects of chronic paroxetine treatment.
Disturbances in serotonergic neurotransmission have been suggested to be closely interlinked with hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, and are likely to be involved in the pathophysiology of anxiety disorders and major depression. We therefore investigated markers of serotonergic transmission and their modulation by chronic paroxetine in rats selectively bred for high (HAB) or low (LAB) anxiety-related behaviour, both under basal conditions and in response to emotional stress. Hippocampal serotonin 1 A (5-HT1A) receptor mRNA expression was reduced in HAB rats, whereas 5-HT concentrations in hippocampal microdialysates did not differ between HAB and LAB rats under basal conditions. In the hippocampus, overall expression of serotonin transporter binding sites was increased in HAB compared with LAB rats. Exposure to emotional stress failed to increase intrahippocampal 5-HT release in HAB rats whereas LAB rats displayed a physiological, albeit small rise. Chronic paroxetine treatment markedly increased the stress-induced rise in hippocampal 5-HT in HAB, but not LAB rats. This effect may be (at least in part) related to a greater down-regulation of hippocampal serotonin transporter binding sites by paroxetine in HABs compared with LABs, while 5-HT1A receptor expression remained unaffected in this brain area. The findings indicate reduced hippocampal serotonergic transmission in HAB rats as compared with LAB rats, which is evident both at the presynaptic (5-HT release) and the postsynaptic (5-HT1A receptor) level. Chronic paroxetine enhanced the presynaptic responsivity in HAB rats, but not LAB rats, pointing to a preferential efficacy of paroxetine in rats with enhanced anxiety/depression-related behaviour.
Keck
Martin E
ME
Max Planck Institute of Psychiatry, Munich, Germany. keck@mpipsykl.mpg.de
Sartori
Simone B
SB
Welt
Tobias
T
Müller
Marianne B
MB
Ohl
Frauke
F
Holsboer
Florian
F
Landgraf
Rainer
R
Singewald
Nicolas
N
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001665:Binding Sites / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003907:Dexamethasone / Q000097:blood; D004195:Disease Models, Animal; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D017551:Microdialysis / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017374:Paroxetine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D000928:Antidepressive Agents; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D017374:Paroxetine; D003907:Dexamethasone