Effect of 5-HT1A 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 6-HT1A r eceptor agonists on brain noradrenergic transmission using Fos-like immunor eactivity (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 n umber of cells positive for Fos-LI in the locus coeruleus (LC), the main so urce of noradrenergic projections to the forebrain. This effect was also in duced by the non-selective, partial 5-HT1A receptor agonist buspirone (10 m g/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-HT1A rec eptor antagonist WAY 100635 (1 mg/kg). The active S(-)-enantiomer of the pa rtial 5-HT1A 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 ar eas including the medial prefrontal cortex (infralimbic and cingulate corti cal areas). More detailed analysis of the Fos response to 8-OH-DPAT in the medial prefrontal cortex revealed that the effect was attenuated by pretrea tment with a combination of the beta(1)- and beta(2)-adrenoceptor antagonis ts ICI 118551 (4 mg/kg) and metoprolol (4 mg/kg), but not the al-adrenocept or antagonist prazosin (5 mg/kg). Taken together, the present findings prov ide immunocytochemical evidence that 6-HT1A receptor agonists activate nora drenergic neurones in the LC and that this leads to increased noradrenergic transmission at postsynaptic sites in the forebrain (specifically medial p refrontal cortex). (C) 1999 Wiley-Liss, Inc.