Ester Alves1,2, Nikolay Lukoyanov3, Paula Serrão2,4, Daniel Moura2,4, Mónica Moreira-Rodrigues5,6,7. 1. Laboratory of General Physiology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS/UP), Porto, Portugal. 2. Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal. 3. Department of Anatomy, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal. 4. Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal. 5. Laboratory of General Physiology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS/UP), Porto, Portugal. mirodrigues@icbas.up.pt. 6. Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal. mirodrigues@icbas.up.pt. 7. Laboratory of General Physiology, ICBAS, University of Porto, R. Jorge Viterbo Ferreira, 228, Building 2, Floor 4, Cabinet 22, 4050-313, Porto, Portugal. mirodrigues@icbas.up.pt.
Abstract
RATIONALE: Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. OBJECTIVES: Our aim was to study the mechanism of epinephrine-dependent contextual learning. METHODS: Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective β-adrenoceptor agonist), fenoterol (selective β2-adrenoceptor agonist), epinephrine plus sotalol (non-selective β-adrenoceptor antagonist), and dobutamine (selective β1-adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. RESULTS: Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. CONCLUSIONS: Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral β2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood-brain barrier, it may enhance hippocampal-dependent contextual learning.
RATIONALE: Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. OBJECTIVES: Our aim was to study the mechanism of epinephrine-dependent contextual learning. METHODS: Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective β-adrenoceptor agonist), fenoterol (selective β2-adrenoceptor agonist), epinephrine plus sotalol (non-selective β-adrenoceptor antagonist), and dobutamine (selective β1-adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. RESULTS: Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. CONCLUSIONS: Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral β2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood-brain barrier, it may enhance hippocampal-dependent contextual learning.
Authors: Mónica Moreira-Rodrigues; Ana L Graça; Marlene Ferreira; Joana Afonso; Paula Serrão; Manuela Morato; Fátima Ferreirinha; Paulo Correia-de-Sá; Steven N Ebert; Daniel Moura Journal: J Pharmacol Exp Ther Date: 2014-08-26 Impact factor: 4.030