Tonic modulation of anxiety-like behavior by corticotropin-releasing factor (CRF) type 1 receptor (CRF1) within the medial prefrontal cortex (mPFC) in male mice: role of protein kinase A (PKA).
The medial prefrontal cortex (mPFC) and the neuropeptide corticotropin-releasing factor (CRF) have recently been receiving more attention from those interested in the neurobiology of anxiety. Here, we investigated the CRF pathway in the modulation of anxiety-like behaviors in male mice exposed to the elevated plus-maze (EPM), through intra-mPFC injections of CRF, CP376395 [N-(1-ethylpropyl)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-4-pyridinamine hydrochloride, a CRF type 1 receptor antagonist (CR F1)] or H-89 [N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride, a protein kinase (PKA) inhibitor]. We also investigated the effects of intra-mPFC injections of H-89 on the behavioral effects induced by CRF. Mice received bilateral intra-mPFC injections of CRF (0, 37.5, 75 or 150pmol), CP376395 (0, 0.75, 1.5 or 3nmol) or H-89 (0, 1.25, 2.5 or 5nmol) and were exposed to the EPM, to record conventional and complementary measures of anxiety for 5min. Results showed that while CRF (75 and 150pmol) produced an anxiogenic-like effect, CP376395 (all doses) and H-89 (5nmol) attenuated anxiety-like behavior. When injected before CRF (150pmol), intra-mPFC H-89 (2.5nmol, a dose devoid of intrinsic effects on anxiety) completely blocked the anxiogenic-like effects of CRF. These results suggest that (i) CRF plays a tonic anxiogenic-like role at CRF1 receptors within the mPFC, since their blockade per se attenuated anxiety indices and (ii) the anxiogenic-like effects following CRF1 receptor activation depend on cAMP/PKA cascade activation in this limbic forebrain area.
Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas - UNESP, Araraquara, SP 14801-902, Brazil.
Tarciso Tadeu
TT
Miguel
Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas - UNESP, Araraquara, SP 14801-902, Brazil.
Karina Santos
KS
Gomes
Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas - UNESP, Araraquara, SP 14801-902, Brazil. Electronic address: souzarn@fcfar.unesp.br.
Ricardo Luiz
RL
Nunes-de-Souza
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008845:Microinjections; D017397:Prefrontal Cortex / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
C529296:(3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine; D000631:Aminopyridines; D014151:Anti-Anxiety Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D018019:Receptors, Corticotropin-Releasing Hormone; D013449:Sulfonamides; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
Anxiety; CRF1 receptor; Corticotrophin-releasing factor (CRF); Elevated plus maze; Medial prefrontal cortex (mPFC); Mice; PKA