Effect of 5-HT(1A) receptor ligands on Fos-like immunoreactivity in rat brain: evidence for activation of noradrenergic transmission.
This study investigated the effects of 8-OH-DPAT and various other 5-HT(1A) receptor agonists on brain noradrenergic transmission using Fos-like immunoreactivity (Fos-LI) as a marker of neural activation. Administration of 8-OH-DPAT (0.1 and 1 mg/kg) induced a marked and dose-related increase in the number of cells positive for Fos-LI in the locus coeruleus (LC), the main source of noradrenergic projections to the forebrain. This effect was also induced by the non-selective, partial 5-HT(1A) receptor agonist buspirone (10 mg/kg). The effect of both 8-OH-DPAT (0.1 mg/kg) and buspirone (10 mg/kg) on Fos-LI in the LC was blocked by pretreatment with the selective 5-HT(1A) receptor antagonist WAY 100635 (1 mg/kg). The active S(-)-enantiomer of the partial 5-HT(1A) receptor agonist (+/-)-MDL 75005EF (1 mg/kg) also induced the expression of Fos-LI in the LC, whereas the inactive R(+)-enantiomer of (+/-)-MDL 73005EF at the same dose did not. In addition to the LC, 8-OH-DPAT (0.1 mg/kg) also induced a marked increase in Fos-LI in various forebrain areas including the medial prefrontal cortex (infralimbic and cingulate cortical areas). More detailed analysis of the Fos response to 8-OH-DPAT in the medial prefrontal cortex revealed that the effect was attenuated by pretreatment with a combination of the beta(1)- and beta(2)-adrenoceptor antagonists ICI 118551 (4 mg/kg) and metoprolol (4 mg/kg), but not the alpha(1)-adrenoceptor antagonist prazosin (5 mg/kg). Taken together, the present findings provide immunocytochemical evidence that 5-HT(1A) receptor agonists activate noradrenergic neurones in the LC and that this leads to increased noradrenergic transmission at postsynaptic sites in the forebrain (specifically medial prefrontal cortex).
Hajós-Korcsok
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University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, UK.
Sharp
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000320:Adrenergic Fibers / Q000187:drug effects*; D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002065:Buspirone