Effects of 5-HT(6) receptor blockade on the neurochemical outcome of antidepressant treatment in the frontal cortex of the rat.
Using in vivo microdialysis in the freely moving rat we have examined the effects of 5-HT(6) receptor antagonism on the neurochemical outcome of antidepressant treatment. Acute administration of both desipramine (10 mg/kg s.c.) and venlafaxine (10 mg/kg s.c.) produced a 2 fold increase in extracellular noradrenaline (NA) but no change in frontal cortex dopamine (DaA), 5-HT or glutamate. Fluoxetine (20 mg/kg s.c.) produced no change in extracellular levels of any of the neurotransmitters examined. SB-271046 produced a 3 fold increase in extracellular glutamate. Combination treatment of SB-271046 with each antidepressant produced no change in the antidepressant-induced changes in NA, DA or 5-HT. In contrast, both fluoxetine and venlafaxine attenuated the SB-271046-induced increase in extracellular glutamate, suggesting that 5-HT and possibly NA may be having an inhibitory action on the excitatory pathways enhanced by 5-HT(6) receptor blockade. Furthermore, these data indicate that the neurochemical effects induced by NA and/or 5-HT reuptake inhibitors are not enhanced by 5-HT(6) receptor blockade indicating that 5-HT(6) receptor antagonists are unlikely to augment the therapeutic efficacy of these types of antidepressants.
Dawson
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LA
Neuroscience Research, Wyeth-Ayerst, Princeton, NJ, USA. Lee_A-Dawson@gsk.com
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D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003891:Desipramine / Q000494:pharmacology; D004357:Drug Synergism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D003511:Cyclohexanols; D003891:Desipramine; D005473:Fluoxetine; D018698:Glutamic Acid; D009638:Norepinephrine; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D000069470:Venlafaxine Hydrochloride; C097216:serotonin 6 receptor; C117443:SB 271046